Gene expression regulation by retinoic acid

      Over the last quarter century, more than 532 genes have been put forward as regulatory targets of retinoic acid. In some cases this control is direct, driven by a liganded heterodimer of retinoid receptors bound to a DNA response element; in others, it is indirect, reflecting the actions of intermediate transcription factors, non-classical associations of receptors with other proteins, or even more distant mechanisms. Given the broad range of scientific questions continually under investigation, researchers do not always have occasion to classify target genes along these lines. However, our understanding of the genetic role of retinoids will be enhanced if such a distinction can be made for each regulated gene. We have therefore evaluated published data from 1,191 papers covering 532 genes and have classified these genes into four categories according to the degree to which an hypothesis of direct versus indirect control is supported overall.
      We found 27 genes that are unquestionably direct targets of the classical pathway in permissive cellular contexts (Category 3 genes), plus 105 genes that appear to be candidates, pending the results of specific additional experiments (Category 2). Data on another 267 targets are not evocative of direct or indirect regulation either way, although control by retinoic acid through some mechanism is clear (Category 1). Most of the remaining 133 targets seem to be regulated indirectly, usually through a transcriptional intermediary, in the contexts studied so far (Category 0).

      Background

      Beginning in at least the late 1960s, there was tremendous interest in whether the differentiating and tumor suppressing activities of retinoids reflected a genetic mechanism, on analogy to the steroid hormones, or an epigenetic one. It had been known for some time that retinoids could influence mRNA levels in certain cells, but also that they could increase activity on membrane-bound ribosomes. Any number of different mechanisms were possible, and quite a few were proposed. In a particularly prescient statement of 1976, Sani and Hill (
      • Sani B.P.
      • Hill D.L.
      A retinoic acid-binding protein from chick embryo skin.
      ) wrote, “The action of retinoic acid in reversing preneoplastic and neoplastic lesions may be due to a hormone-like effect involving induction and/or suppression of gene activity.” However, no conclusive experimental evidence had yet been adduced. As far as we know, it was Blalock and Gifford (
      • Blalock J.E.
      • Gifford G.E.
      Retinoic acid (vitamin A acid) induced transcriptional control of interferon production.
      ) who first provided such evidence when they showed, in 1977, that interferon synthesis can be suppressed at a transcriptional level by a protein induced by all-trans retinoic acid (RA). To make their case they used transcription blockers, protein synthesis inhibitors, and a kinetic argument.
      It is now known that RA can influence gene expression and protein production in many ways, but in terms of molecular mechanisms, a single, predominant, classical pathway has emerged: all-trans retinoic acid plus a dimer composed of a retinoic acid receptor and a retinoid X receptor (an RAR.RXR dimer) and a more or less regular DNA response element. In this paper, genes that respond through this pathway are called “direct” targets of the classical RA pathway; those that respond to RA through other molecular mechanisms, but do respond, are called “indirect” targets. Since Blalock and Gifford's paper nearly a quarter century ago, more than 532 genes have been put forward as regulatory targets of RA; and while the distinction between direct and indirect regulation is now well entrenched, it is not necessarily germane to every study. Nevertheless, a great deal of suggestive data has been generated and it can be used to construct a tentative classification of RA's targets along these lines.

      Constructing a classification table

      There is a simple but powerful motivation for constructing such a classification: progress in understanding RA's role at a genomic or proteomic level will require determining which regulatory events are handled through which cellular circuits. This paper is an attempt to begin that process in a systematic way. In what follows, we have evaluated the experimental evidence presented in more than 1,191 published articles and have prepared a preliminary categorization of RA's targets according to the degree to which current research supports an hypothesis of direct versus indirect control. More specifically, we have constructed a table (see Gene Table at the end of this article) that briefly summarizes the experimental evidence available for each target gene and “rates” the degree to which the combined evidence supports or opposes the notion of direct regulation in at least one cellular context. Where the evidence is very strong, constituting proof or something close to it, we call the gene a Category 3 gene. Where the combined evidence suggests or demonstrates indirect regulation (in the contexts studied, and no other investigations show or suggest direct regulation elsewhere), we have called the gene a Category 0 gene. Categories 1 and 2 are positioned between these two, with the evidence for direct regulation somewhat stronger for Category 2 genes. All four categories are more rigorously characterized below.
      It should be stressed that the numeric designations used for the categories are nothing more than tags. With a very few exceptions (which always clearly marked), the Category 0 genes are regulatory targets of RA every bit as much as Category 3 genes. They are simply regulated in different ways. Category 1 and Category 2 genes are also targets, although current research does not allow us to conclude quite so much about the mechanisms employed in these cases. Emphatically, the classification does not mean to impugn the work reported in the any of papers considered. The distinction between direct and indirect regulation is not necessarily relevant to many valid research goals, and a great deal of valuable work has been done in clinical, developmental, and basic science without addressing these questions even obliquely.
      Of necessity, the Gene Table is long and complex. However, the genome projects, various proteomic studies, and the preliminary gene ontologies produced over the last few years have made it clear that work on some very interesting biological questions will require dealing with vast amounts of data. Gene expression regulation by RA encompasses a number of such questions and a compilation like the Gene Table would seem to be an economical way to approach some of them.

      The classical RA pathway

      Four basic concepts are central to any description of the classical RA pathway: ligand involvement, receptor dimerization, DNA binding, and the resulting transcriptional modulation of the gene (occasionally, one of the genes) whose regulatory element has been bound. It sometimes happens that the gene under investigation is not the gene whose regulatory unit has been bound, but that RA has regulated an intermediary which in turn regulates the gene of interest. In these cases, the intermediary factor (usually another transcription factor) may be a direct target, while the gene under study is an indirect target. Other types of indirect regulation include RA's ability to influence mRNA stability, to activate nuclear receptor dimers other than an RAR.RXR, and so forth.
      It might seem arbitrary, uninformative, or unnecessarily stringent to restrict “direct” regulation to the classical RA pathway and to consign all other regulatory modalities to the catch-all category, “indirect” regulation. However, each alternative regulatory pathway represents a distinct type of genetic event. Perhaps each deserves its own Gene Table. We chose the classical RA pathway as a branch point in the present work, i) because of its preeminent historical position, ii) because the distinction between direct and indirect regulation through this pathway is well established and frequently studied, and iii) because many suggestive and highly relevant studies are available, even though questions of molecular mechanism are not necessarily raised in them.
      The Gene Table is intended to cover every gene now known to be regulated by retinoic acid. The last attempt at delineating a complete set of such genes was published by Chytil and Raiz-ul-Haq in 1990 (
      • Chytil F.
      • Riaz-ul-Haq
      Vitamin A mediated gene expression.
      ). They listed more than 125 proteins that we now take to be monogenic, plus a number of other proteins of less clear provenance. Gudas et al. took a slightly different starting point 4 years later, and wrote detailed descriptions of most RA targets known at the time. They categorized them primarily along functional or homology lines (
      • Gudas L.J.
      • Roberts A.B.
      • Sporn M.B.
      Cellular biology and biochemistry of the retinoids.
      ).

      Literature reviews

      Retinoid science is an immense field. Two recent reviews, both of which are comprehensive within their scopes but neither of which attempts a complete list of RA-regulated genes, are by Nagpal and Chandraratna (
      • Nagpal S.
      • Chandraratna R.A.
      Vitamin A and regulation of gene expression.
      ) and a cross-lab group led by De Luca (
      • Ross S.A.
      • McCaffery P.J.
      • Drager U.C.
      • De Luca L.M.
      Retinoids in embryonal development.
      ). Two more specialized reviews, on receptor-specific ligands (
      • Nagpal S.
      • Chandraratna R.A.
      Recent developments in receptor-selective retinoids.
      ) and on discoveries made through receptor knockouts (
      • Mark M.
      • Ghyselinck N.B.
      • Wendling O.
      • Dupe V.
      • Mascrez B.
      • Kastner P.
      • Chambon P.
      A genetic dissection of the retinoid signalling pathway in the mouse.
      ), expand on topics that turn up frequently in the Gene Table, but are treated only generically. Beyond these, virtually every area of regulatory, clinical, and developmental application has its own reviews. To mention just a few, see (
      • Petkovich P.M.
      Retinoic acid metabolism.
      ) for retinoid metabolism, (
      • Kurie J.M.
      The biologic basis for the use of retinoids in cancer prevention and treatment.
      ) for retinoids and cancer, (
      • Gavalas A.
      • Krumlauf R.
      Retinoid signalling and hindbrain patterning.
      ) or (
      • Schier A.F.
      Axis formation and patterning in zebrafish.
      ) for two topics in developmental work, and (
      • Zouboulis C.C.
      Retinoids–which dermatological indications will benefit in the near future?.
      ) for dermatological issues. An updated collection of methods papers has recently been published. It contains valuable information on traditional as well as innovative experimental techniques involving the retinoids, their receptors, and associated molecules. See (
      • Barua A.B.
      • Furr H.C.
      Properties of retinoids. Structure, handling, and preparation.
      ) and the papers following it. A detailed characterization of what is currently known about the molecular and even atomic mechanisms that permit direct RA-activated transcriptional regulation is presented in (
      • Gronemeyer H.
      • Miturski R.
      Molecular mechanisms of retinoid action.
      ). Although these events are beyond the scope of the present paper, they underpin many of the routes of gene regulation covered here.
      The retinoid receptors are members of a much larger group of transcription factors, the so-called nuclear receptors. An encyclopedic overview of this large and important class of proteins is Gronemeyer and Laudet's 1995 monograph (
      • Gronemeyer H.
      • Laudet V.
      Transcription factors 3: nuclear receptors.
      ). It remains invaluable even though its publication preceded some of the more recent work on co-regulators, intermediary factors, and the chromatin connection. For an update in those areas, see Rosenfeld and Glass (
      • Rosenfeld M.G.
      • Glass C.K.
      Coregulator codes of transcriptional regulation by nuclear receptors.
      ). Chawla et al. (
      • Chawla A.
      • Repa J.J.
      • Evans R.M.
      • Mangelsdorf D.J.
      Nuclear receptors and lipid physiology: opening the X-files.
      ) recently reviewed the connection between the nuclear receptors and lipid physiology, and both RARs and RXRs play roles in this. Finally, two collections of particularly noteworthy reviews appeared in the mid-1990s: one covering various aspects of the nuclear receptors and the other, various aspects of the retinoids. See (
      • Mangelsdorf D.J.
      • Thummel C.
      • Beato M.
      • Herrlich P.
      • Schutz G.
      • Umesono K.
      • Blumberg B.
      • Kastner P.
      • Mark M.
      • Chambon P.
      The nuclear receptor superfamily: the second decade.
      ) and (
      • Bollag W.
      The retinoid revolution. Overview.
      ), respectively, and the articles that accompany them.

      METHODS

       Selecting genes for inclusion in this analysis

      The Gene Table does not cover every gene ever investigated in conjunction with retinoic acid, although we hope it includes every known target. Because RA has the power to initiate fundamental phenotypic changes in many cells, it is sometimes used only as an agent to set up an experiment: differentiated versus non-differentiated cells, for example. Genes investigated only in such settings were excluded. Overall, our basic filter for including or excluding genes was whether or not an explicit claim of regulation by retinoic acid had been advanced. We did not require that the regulation be attributed to the classical RA pathway. In some cases, direct regulation was investigated or implied; in others it was indirect regulation; and in some, the mode of regulation was not addressed, either explicitly or implicitly.
      Although we made every effort to identify and follow up on “novel” genes identified in differential display-type experiments, we have not included any genes so totally uncharacterized that they have not yet even been named. See (
      • Chen Y.
      • Talmage D.A.
      Subtractive cDNA cloning and characterization of genes induced by all-trans retinoic acid.
      ) for some examples. Nor have we included fragments so far identified only as ESTs. See (
      • Wang K.C.
      • Cheng A.L.
      • Chuang S.E.
      • Hsu H.C.
      • Su I.J.
      Retinoic acid-induced apoptotic pathway in T-cell lymphoma: Identification of four groups of genes with differential biological functions.
      ) and (
      • Qiu H.
      • Zhang W.
      • El Naggar A.K.
      • Lippman S.M.
      • Lin P.
      • Lotan R.
      • Xu X.C.
      Loss of retinoic acid receptor-beta expression is an early event during esophageal carcinogenesis.
      ) for examples of these.
      An analysis of this sort would ideally be limited to work done in “normal” cells or individuals; the activities of RA and its receptors in aberrant cell types would then be handled separately as exceptions. We have tried to do this up to a point. Work on cells that have suffered catastrophic DNA events that are likely to have affected RA's activity, certain viral integrations, extraordinary recombinations, engineering experiments, and the like, have been excluded except to make occasional special points. In particular, work on acute promyelocytic leukemia (APL) cells, which generally express oncogenic RARα fusions, have been largely excluded on this ground. Nevertheless, a great deal of research has been done on RA's activities in APL cells and we refer the reader to (
      • Pandolfi P.P.
      Oncogenes and tumor suppressors in the molecular pathogenesis of acute promyelocytic leukemia.
      ) for a review. Of course, many common cell lines contain genomic anomalies that are not likely to have affected RA's activity overall: HepG2 and Caco-2 lines, for example. For the purposes of this work, such cell lines are considered normal.
      As a rule, we did not consider experiments in which RA was used in conjunction with another treatment, although we tried to take note of any controls using RA alone. The exception to this is where some form of external “activation” seems to be required for any expression of the target gene, for example, the interleukins. It should be stressed that by excluding combo-treatments we automatically ruled out many studies using RA plus cAMP (or RA plus cAMP and theophylline) rather than RA alone. We did, however, consider these experiments if they confirmed points suggested elsewhere by RA alone. This is an admitted limitation of the present work, but the complexity of regulatory interactions in these cases is still overwhelming.

       Constructing a database of papers and genes

      Using various free text and MeSH (Medical Subject Headings) strategies at the United States National Library of Medicine's PubMed gateway, we created a database of more than 4,000 papers relevant to the regulation of gene expression by retinoic acid. We identified the gene or genes considered in each paper, and, based on abstracts, selected what appeared to be the most relevant studies for each gene. Using this set of abstracts and the associated MEDLINE coding, we determined which species had been investigated, located the gene's official name at LocusLink (
      • Pruitt K.D.
      • Maglott D.R.
      RefSeq and LocusLink: NCBI gene-centered resources.
      ), and performed supplementary searches based on official nomenclature, curated aliases, and any novel names or aliases applied to orthologs. This process was iterated as necessary, and eventually led to a list of relevant papers for each gene. These entries were then re-evaluated at the abstract level and the most promising papers (for our purposes) were gathered and consulted for data, discussions, and further citations. New candidate genes went through the same process as they turned up. By the end of the project, nearly 8,000 papers (not including reviews) had been considered to one degree or another.
      For each gene, we then studied the scientific evidence presented in the selected papers and evaluated the degree to which a direct regulatory pathway had been demonstrated, suggested, or brought into question. This information was distilled into several short standardized phrases and incorporated into the Gene Table, along with species information, any alternative names and symbols used in the selected studies, and references to the most essential papers.

       Concordance of working and official gene names

      Most genes have several names. By “official nomenclature” we mean names and symbols approved by (or pending before) the Human Genome Organization Nomenclature Committee, the Mouse Genome Informatics Nomenclature Committee, the International Rat Genetic Nomenclature Committee, or the Zebrafish Nomenclature Committee. We have followed official nomenclature whenever possible. This can be confusing when the official name of a gene is either uninformative, uncommon, or simply designed for a purpose that is not one's own. For example, most readers probably would not recognize Nr2f1 as the name of the gene that encodes COUP-1. However, while understandable from a historical perspective, the proliferation of trivial names (for both genes and proteins) has been scientifically unhelpful and using official names solves the problem. The lists of alternatives and aliases kept by the nomenclature committees and at LocusLink should quickly resolve any questions.
      It is not always easy to determine which gene has been studied in a given paper, or which papers deal with the same gene; and this is not limited to older papers. It can be particularly problematic when several species, or several apparently unrelated scientific questions, have been studied in different papers. In a number of cases, we had to align published primer sequences with groups of homologs, follow LinkOuts to cited sequences at the National Center for Biotechnology Information's Entrez system, or even BLAST nucleotides strings taken from journal figures.
      As a rule, the Gene Table uses the gene symbol from the species discussed in the earliest paper cited; when no approved, pending, or interim name was available for the gene in that species, we generally chose the mouse version. The nomenclature committees try to keep symbols and leading phrases invariant over vertebrate species (except for orthographic differences) so this is little more than a matter of choice. In order to save space, only symbols, not full names, are used in the first column of the table.

       Trivial names from cited papers

      The second column of the Gene Table, “Name in refs,” lists only the gene or protein designations used in the papers cited. It does not include other aliases, no matter how common they may be in the literature. Table 1 provides a concordance between these working names (or abbreviations) and the symbols used in the Gene Table, but only for cases where the two are very different. Throughout, we have suppressed the distinction between genes and the proteins they encode.
      TABLE 1Concordance of trivial names and symbols
      Common NameGene Table
      14.5-D lectinLgals1
      25-hydroxyvitamin D3-24-hydroxylaseCYP24
      34 kDa lectinLgals3
      92 kDa gelatinaseMMP9
      A4Clta
      ACSFACL2
      Activin AINHBA
      Acyl-coA synthaseFACL2
      ADD1Srebf1
      ADH3ADH1C
      AggrecanaseADAMTS4
      α 1-microglobulinAmbp
      α-SMActa2
      Aminopeptidase-BRNPEP
      AML2RUNX3
      ANFNppa
      ANPNppa
      Antithrombin IIISERPINC1
      AP-2TFAP2A
      AP-2.2Tcfap2c
      Ap-BRNPEP
      Apolipoprotein(a)LPA
      ARP-1Nr2f 2
      ArrestinSAG
      ATXENPP2
      β 1-ARAdrb1
      β-amyloid precursor proteinApp
      Bone sialoprotein (BSP)IBSP
      Bone sialoprotein ISpp1
      Brn-3.2Pou4f 2
      c-ablAbl1
      Calcineurin APPP3CA
      Calcineurin BPPP3CB
      CBFA3RUNX3
      CD10MME
      CD11aITGAL
      CD11bITGAM
      CD15Fut4
      CD157BST1
      CD18ITGB2
      CD23FCER2
      CD31PECAM1
      CD43SPN
      CD50ICAM3
      CD51Itgav
      CD71TFRC
      CD82KAI1
      CD95PTPN13
      CD95TNFRSF6
      CD95 ligandTnfsf6
      c-fmsCSF1R
      Cg BChgb
      CGRPCal1
      Cholesterol sulfotransferaseSULT2B1
      CIP1Cdkn1a
      CL-20EMP1
      clusterinTrpm2
      c-mybMYB
      c-mycMYC
      CollagenaseMMP1
      Connexin31Gjb3
      Connexin43Gja1
      ContactGdf 5
      CornifinSPRR1B
      COUP-TF IINr2f 2
      COUP-TF1Nr2f1
      COX-1Ptgs1
      COX-2PTGS2
      CRBPIRbp1
      CRBPIIRbp2
      CTCal1
      Common NameGene Table
      Cu/Zn superoxide dismutaseSod1
      Cx43Gja1
      Cyclin D3CCND3
      Cyclin ECcne1
      Cyclooxygenase-1Ptgs1
      D3Dio3
      D9Stra13
      DEAD box proteinDDX1
      DEAD box protein p72DDX17
      D-IIIDio3
      Dopamine D2 receptorDrd2
      DOROPRD1
      Drg1NDRG1
      Dystroglycan α, βDAG1
      E3Laptm5
      EATMCL1
      E-cadherinCDH1
      E-MAP-115Mtap7
      EndoAKRT8
      EndoBKRT18
      EndolynCd164
      eNOSNOS3
      EpithelinGrn
      ERA-1Hoxa1
      Erk2Mapk1
      ET-1EDN1
      F1Ngp
      F3Cntn1
      FAKPTK2
      FasTNFRSF6
      FasLTnfsf6
      FATPSLC27A1
      FBPase isozymeFbp2
      FGF-BPHBP17
      Focal adhesian kinasePTK2
      Fra-1Fosl1
      Fru-1, 6-P2aseFbp1
      Galectin-7LGALS7
      GCNFNr6a1
      Gelatinase AMMP2
      Gene 33MIG-6
      GLUT 2Slc2a2
      GLUT 3Slc2a3
      gp91-phoxCYBB
      gp96TRA1
      GRNR3C1
      GST 5.7Gsta4
      H218Gpcr13
      HAKR eAKR1C3
      HB-EGFDTR
      HER4ERBB4
      HERGKCNH2
      HGFLMST1
      HIOMTASMT
      hlx-1dbx1a
      HNF-1 αTcf1
      HNF-1 βTcf2
      HNF-3 βFoxa2
      HNF-3 αFoxa1
      Hox-1.6Hoxa1
      HOX3DHOXC5
      Hox-2.bHoxb4
      Hox-4.2Hoxd4
      hRDH-TBERDHL
      HSP86Hsp86-1
      HSP90Hsp86-1
      HSPCAHsp86-1
      HSPGSDC2
      Htf 9-a/RanBP1Ranbp1
      IAPALPI
      ICECASP1
      OsteopontinSpp1
      OTOXT
      p15CDKN2B
      p190 GAP-associated proteinArhgap5
      p21Cdkn1a
      p34(CDC2)CDC2
      P450RAICyp26
      p47-phoxNCF1
      p53Trp53
      p67-phoxNCF2
      p68 kinasePRKR
      p75NTRNgfr
      PACAPADCYAP1
      PACAP1 (Type I) receptorADCYAP1R1
      PACAP2 (Type II) receptorVIPR1
      PAFRPTAFR
      PAI-1SERPINE1
      PAI-2SERPINB2
      P-cadherinCDH3
      PCD5Pcp2
      PCDHXPCDH11
      PCDHYPCDH22
      PEPCKPck1
      PGHS1Ptgs1
      PGHS2PTGS2
      pgp1ABCB1
      PKPk3
      PKCPkca
      PKC β 1PRKCB1
      Placental lactogenCSH1
      Plasminogen activator inhibitor 1SERPINE1
      Plasminogen activator inhibitor 2SERPINB2
      pRbAp46Rbbp7
      proinsulinINS
      promyelocytic defensin-1DEFA1
      ProT αPTMA
      PsoriasinS100A7
      PTHrPPthlh
      RA28FXYD3
      Rae-28Edr1
      Rae-30Fbp2
      RbRB1
      RBPRBP4
      RC3NRGN
      RDHRsdr1
      Retinal fascinFSCN2
      Rex-1Zfp42
      Rh1Rho
      RIG1RARRES3
      RIHBMdk
      RIP140NRIP1
      RIS-1S100A7
      RMUC176Muc3
      Rod-specific opsinRho
      RTPNDRG1
      RTRNr6a1
      S14Thrsp
      Sar1aSara
      SCCEKLK7
      SCFKitl
      Sgp-2Trpm2
      SLAPSLA
      SPASftpa1
      SP-BSFTPB
      SP-CSFTPC
      Spr1SPRR1B
      SSATSat
      SSEA-1Fut4
      SSeCSAkap12
      ST3MMP11
      Stem cell factorKitl
      IkarosZnfn1a1
      IL-1b stimulating geneBIRC3
      Importin αKpna2
      INK4BCDKN2B
      iNOSNos2
      J6 serpinSerpinh1
      K2eKRT2A
      K6KRT6A
      k-caseinCsnk
      K-FGFFGF4
      KOROprk1
      Krox-24Egr1
      L-14Lgals1
      L-34Lgals3
      Lamins A/CLmna
      LeftyEbaf
      Lewis xFut4
      LFA-3CD58
      Liver/bone/kidney APAkp2
      l-mycMYCL1
      LNGFRNgfr
      LOX-1Olr1
      LPLLpl
      l-selectinSELL
      MAC-1ITGAM
      Major histocompatibility class I (H2K, -D, -L, -Q, etc.)H2
      MASH1Ascl1
      Mash-2Ascl2
      MCADACADM
      MCP-1SCYA2
      M-CSFCSF1
      mda-6Cdkn1a
      MDR1ABCB1
      mdr3ABCB1
      Meis2Mrg1
      MKMdk
      MLN/CAB1MLN64
      MnSODSOD2
      MOROPRM1
      Mox1Meox1
      mph1Edr1
      mrp2ABCC2
      MRP-8S100A8
      Msx-1Msx2
      mWnt-8Wnt8d
      MZF-1ZNF42
      Na, K-ATPaseAtp1a3
      Na+/H+ antiporterSLC9A1
      N-cadherinCDH2
      Ndr1NDRG1
      NEPMME
      NGFI-BNR4A1
      NHE-2Slc9a2
      NISSLC5A5
      NKX3.2Bapx1
      nm23-H1NME1
      NMDAR1GRIN1
      NN8-4AGRrg1
      nNOSNOS1
      NOR-1NR4A3
      NSP-ARTN1
      NSP-CRTN3
      ntcpSLC10A1
      Nur77NR4A1
      Nurr1NR4A2
      obLep
      Oct3Pou5f1
      Oct3/4Pou5f1
      OPSpp1
      OsteocalcinBGLAP
      OsteonectinSparc
      Stra1Efnb1
      Stra10Mrg1
      Stra11Wnt8d
      Stra3Ebaf
      Stra7Gbx2
      StromelysinMMP3
      Stromelysin-3MMP11
      SurvivinBIRC5
      TBRIITgfbr1
      TFF3
      TF CA150TAF2S
      TfRTFRC
      TGase KTgm1
      TIG1RARRES1
      TIG2RARRES2
      TIG3RARRES3
      TIS10PTGS2
      Tissue factorF3
      TMTHBD
      TNAPAkp2
      TopoIITOP2A
      t-PAPLAT
      TR2-11Nr2c1
      TR4NR2C2
      TrkANtrk1
      TrkbNtrk2
      TrkCNTRK3
      TRP-2DCT
      UlipDPYSL3
      u-PAPLAU
      VAChTSlc18a3
      Vesicular acetylcholine transporterSlc18a3
      Vitronectin receptorItgav
      WAF1Cdkn1a
      Xlim-1Lhx1
      Y1RNPY1R
      zif 268Egr1
      Concordance of common names and the official symbols used in the Gene Table for cases where there are significant differences between them.
      Tabled 1
      SymbolName in RefsSppDirSummaryRef PMIDsCat
      ADH1CADH3HsUpInduction; functional binding site; negative TRE nearby.0001996113; 0001321136; 00083881583
      CD38CD38Hs, MmUpInduction; differentiation controls; specific ligands; functional binding sites; evidence from transgenics.7690555; 0008394323; 0007511050; 0009160665; 0009624127; 109698053
      Cdx1Cdx1Mm, HsaUpInduction; conserved functional binding site.7649373; 109381323
      CEBPEC/EBP epsilonHsUpRapid induction during differentiation; functional binding site; specific ligands.9376579; 9177240; 00103304223
      CRABP2CRABP-IIHs, MmUpInduction; conserved functional binding sites.0001654334; 1309505; 0001313808; 0001327537; 0001334086; 0008071361; 00098568253
      CryabαB-crystallin/small HSPMmUpInduction; functional binding site.00096514023
      Drd2dopamine D2 receptorHs, Mm, RnUpInduction; functional binding site; evidence from transgenics.7990648; 0009405615; 0009721718; 94523863
      Egr1Egr-1, zif268, Krox-24Mm, RnUpInduction; functional binding site (characterized as a single half-site).1936556; 1793734; 1708092; 0007877619; 81762543
      ETS1Ets1, ets-1Hs, MmUpRapid induction during differentiation; functional binding motifs (single hexamer and DR5).3060792; 7689222; 0010773887; 113273093
      Foxa1HNF-3αMmUpRapid induction during differentiation; no protein synthesis required; functional binding site.8029022; 7649373; 9260895; 00103885163
      H1F0H1° histone, H1 degreeMm, HsUpEarly induction during differentiation; functional binding site (DR8); other NRs.2846273; 1988682; 0008078070; 0007576177; 00085596623
      Hoxa1ERA-1, Hox-1.6, Hoxa-1Mm, DrUpInduction; conserved functional binding site; whole animal evidence (including transgenics).0003422432; 0002906112; 0001360810; 0007743939; 0008631251; 0008999919; 00090533163
      HOXA4hoxa-4Hs, MmUpInduction; upstream functional binding site and downstream RA-responsive enhancer; whole animal evidence including transgenics; site conservation.0008759021; 0009570764; 9272954; 00106799303
      Hoxb1Hoxb-1Mm, Gg, Tr, HsvrsbInduction; functional binding sites (5′ and several 3′); whole animal evidence including transgenics; site conservation.0007914354; 0007916164; 0007831296; 0007831297; 0008999919; 0009463349; 0009671595; 00098692973
      Hoxb4Hox-2.6, Hoxb-4Mm, Tr, GgUpInduction; conserved functional binding site; evidence from transgenics.0007878040; 9272954; 00096978503
      Hoxd4Hox-4.2, Hoxd-4Mm, HsUpInduction; functional binding sites (5′ and several 3′); whole animal evidence including transgenics; site conservation; some discussion that at least some effects may be indirect.2898782; 0008093325; 0007908827; 0008674428; 0009360992; 0009347914; 109406263
      HSD17B117HSD type 1cHsUpInduction; specific ligands; functional binding site.0008013376; 0008614400; 90485883
      IL2RAIL-2R αHsUpInduction; an upstream region at least partly responsible has been identified; additional paracrine effect from RA induction of IL2 has been discussed.7678784; 0008157276; 91305123
      Pck1PEPCKRn, Hs, MmUpInduction; functional binding sites; whole animal evidence; other NRs.2176887; 0001848696; 0001656224; 0007831301; 0008626419; 0009078282; 92020793
      Pit1dPit-1Mm, Rn, Ma, HsUpInduction; conserved functional binding site (also acts as VDRE); Pit1 binding required for activity; clinical evidence.0008504933; 0007588287; 0009027335; 00100770043
      RARARAR-α2Hs, Mm, TrUpIsoform 2 induction; conserved functional binding site.2825025; 2825036; 0001658797; 00104529513
      RARBRARβHs, Mm, Rn, GgUpInduction (isoforms 2, 4); conserved functional binding site; isoforms 1, 3 appear not be RA regulated.2833708; 2836738; 0002542014; 0002153268; 0002177841; 0002164682; 0001663808; 0008384988; 0008011555; 7649373; 110739743
      RARGRAR γHs, Mm, RnUpIsoform 2 induction; conserved functional binding site.0001320193; 0008394693; 00091424993
      Rbp1CRBPIMm, RnUpInduction; conserved functional binding site.2546063; 0001648481; 00013392753
      SFTPBSP-BHs, Rn, MmUpInduction; region responsible for RA effect binds receptors; indirect effect likely as well; functional motifs; evidence from dominant negative.0008404646; 0008944731; 0009575874; 0009700083; 0010070102; 00106175853
      Tgm2TGase 2Mm, Hs, RnUpInduction; controls for differentiation; specific ligands; unusual functional binding site of three hexamers: hex(n7)hex(n5)hex; requirement for both RA and 9-cis, at least in some systems.6149218; 2859286; 2900242; 2565341; 1705423; 9516142; 0008626785; 95161423
      Ucp1ucp, upc-1Rn, MmUpInduction; conservede functional binding sites; specific ligands; whole animal studies; other NRs/factors.0007929091; 0007890689; 0008754778; 0008940169; 9659286; 10921912; 00106006433
      ABCC2mrp2Hs, RnfUpNatural induction not shown (Rn promoter plus exogenous RARa.RXRa in Hs cells); dose not clear; binding site functional in hybrid system.00107227292
      ACADMMCADHsUpReporter induction; functional binding site; other NRs; considerable discussion of physiological relevance.0001328196; 0008314750; 8754802; 00092714172
      Adrb1β 1-ARRn, MmUpInduction during differentiation (although rapid in some systems); functional binding site (also DR5 TRE); appears indirect at least in some systems.9025717; 0009441829; 00094487452
      Akp2TNAP, liver/bone/kidney APMm, Rn, HsUpInduction; motif; an additional (and perhaps more important) indirect enhancement of steady state mRNA levels may occur during precursor mRNA processing.1849403; 1939166; 0008071372; 0008817450; 0010530919; 00106919702
      APOA1apo A-IHs, Mf, RnUpgNo good d/t data; several functional binding sites; possibly RXR.RXR; other NRs; specific ligands; at least one study found opposite in vivo and in vitro effects.0001646397; 8399088; 0007918317; 0007658149; 0008626539; 0008604295; 0009392425; 00101945132
      APOA2apo A-IIHs, RnUpNo good d/t data; specific ligands; functional binding site; possibly RXR.RXR; RXR transfection may activate without addition of ligand; other NRs; no RA effect in some systems.0007918317; 00086681502
      APOC3apolipoprotein C-IIIHsUpNo good d/t data; several functional binding sites; other NRs; specific ligands; possibly RXR.RXR.0009691099; 00098939922
      APODapoDHsUpInduction; independent of protein synthesis; specific ligands.7929425; 89432632
      ASMTHIOMTHsUpInduction.87521092
      AT-RA 6hAT-RA 6HsUpInduction.00094158242
      BIRC3IL-1b stimulating geneHsUpInduction.111461662
      CDKN2Bp15, INK4BHsUpInduction with borderline d/t conditions; no significant change reported (but data not shown) in one short-term mRNA study.10479451; 108122412
      CETPCETPHsUpNo good d/t data; reporter induction (measured at 48 h); region responsible for RA effect identified and binding verified.00103294012
      Cfhcomplement factor HMmUpInduction possible but not clearly showni; functional binding site.0001700780; 18282292
      CHATChATHs, MmUpInduction, but d/t borderline; many studies have been in differentiating systems; potential motifs; specific ligands; other NRs; may be at least partly post-translational.2924123; 2924124; 8057782; 7919195; 0007673184; 0007790895; 77456082
      Crabp1CRABP IMm, RnvrsNo good d/t data; appears to be part of a complex autoregulatory system; binding motif; may require protein synthesis; several indirect mechanisms have been proposed, as well as direct regulation.2546063; 8382159; 0007528580; 7588278; 0008617785; 0008663043; 0009392513; 9142496; 9390004; 00107147632
      Crygfγ F-crystallinMmUpNo good d/t data; a functional binding site is also functional for the TR and ROR systems.0008436299; 0007877618; 00076500342
      CSH1placental lactogenHs, RnUpNo good d/t data; functional binding sites;
 other NRs.8174790; 0007867602; 0007589779; 00078676022
      Csnkk-caseinMmUpInduction.76493732
      CTSKjcathepsin K/OC-2OcUpInduction.00076396842
      CYP2424(OH)ase, 25-hydroxyvitamin D3-24-hydroxylaseRn, Hs, MmUpNo good d/t data; functional binding sites (which are also VDREs); specific ligands; that RAR.VDR or RXR.VDR may explain RA induction has not been conclusively ruled out.0007592579; 00092280862
      Cyp26kP450RAI, CYP26AIDr, Mm, HsUpInduction (but long-term exposure may lead to repression); specific ligands.0008939936; 0009228041; 0009250660; 0009740237; 0009442090; 0009716180; 0010583049; 110239962
      DTRHB-EGFHs, MmUpInduction; evidence from transgenics.9858142; 00100759252
      EbafLefty, Stra3Mm, GgUpInduction; binding motif (Pal8); appears indirect, at least in some systems.7649373; 0009496783; 0010331971; 00105001842
      Edr1Rae-28, mph1MmUpEarly induction during differentiation.0008070621; 00106533592
      Efnb1Stra1MmUpInduction.76493732
      EGFREGF receptorMm, Rn, HsvrsInduction shown in some systems; d/t data for reduction (where it occurs) is not good; exogenous RAR plus nuclear proteins bind an identified upstream region; other NRs; there have been several proposals for indirect mechanisms.6245371; 2540431; 2783693; 0002169350; 1748717; 0001515368; 00078599222
      EpoEpoRn, Mm, HsUpNo good d/t data; functional binding site; other NRs; evidence from receptor knockouts.8050571; 11050012; 112975122
      Fbp2Rae-30, FBPase isozymeMmUpEarly induction during differentiation.0008070621; 80340422
      FOLR1folate receptor αHs, MmUpInduction; no motif found.7707421; 102162602
      Gbx2lGbx-2, Stra7Mm, XlUpInduction, but at least partly indirect (Hoxa-1).7649373; 8601031; 8652408; 109425992
      Gdf5ContactDrUpInduction (using dechorionated embryos soaked in RA-solution then extensively washed).00092563532
      Gh1GHRn, HsUpInduction; functional binding site; specific ligands; other NRs; indirect in some systems but possibly not all; other factors, such as Pit1, may be required for effective induction.0002707148; 0008384845; 0007956917; 0008524311; 0008768885; 00097377232
      Glut4GLUT4RnUpSome data hard to interpret; induction likely;
 other NRs.8119934; 77588302
      Gnrh1GnRHRnUpInduction; other NRs; (weak) functional binding site.0009526050; 11245923; 112459242
      GPX2Gpx2HsUpInduction likely (but early data hard to read); motifs.00104987572
      GSTP1mGSTP1-1, GSTP1*CHsvrsNo good d/t data; repression appears indirect (AP-1 or tTG), however, induction may be direct; functional binding site.8546677; 0009407047; 0009679546; 00105363612
      H2major histocompatibility class I (H2K, -D, -L, and
 -Q, etc.)Mm, Hs, vrsnUpNo good d/t data; functional binding sites, one of them highly conserved.0003467324; 0001736309; 0008413217; 0008604312; 0008618036; 0009758167; 00097903912
      HSD17B217 β-HSD type 2HsUpInduction; specific ligands.113978772
      Igf1IGF-IRnvrsRapid induction in some differentiating systems (followed by late decrease); down-regulation in probably indirect.1572288; 00092583462
      Igf bp6IGFBP-6Rn, HsvrsAssociated with growth or differentiation regulation; induction; motif and somewhat conserved functional binding site (DR15); at least partly indirect in some systems (protein synthesis and mRNA stability for induction, Hoxa-1 for reduction).0007682065; 0008603611; 10942599; 112676702
      Il1aIL-1 αMm, HsUpInduction of pre-mRNA; may require additional special factors for processing.0008083217; 00077632622
      IL1BIL-1 βHsUpInduction of pre-mRNA likely; RA may also have an effect secondary to induction by other transcription activators.0001646841; 0008489769; 0008360592; 0008083217; 0008702428; 00097838092
      IL2RBIL-2R βHsUpInduction; upstream control region not found.7678784; 92684952
      IRF1IRF-1HsUpInduction (independent of GAS motif).8704165; 9393879; 103199962
      Itgb3β 3 integrinGgUpNo good d/t data; functional binding site overlaps a VDRE; other NRs.0008891892; 00087028132
      KRT5K5HsDnSuppression; an upstream cluster of hexamers that can bind RAR and suppress a CAT reporter has been found; AP-1 regulation; other NRs.1711202; 0007505782; 7505756; 7519609; 00093263922
      Lamb1-1laminin B1Mm, HsUpDelayed induction in RA-differentiable cells; unusual putative RAR binding site that is somewhat conserved; induction requires protein synthesis; evidence from knockouts and lacZ transgenics; may be directly regulated but in an unusual way, perhaps.6310600; 0002981185; 0002842348; 0002556699; 0001975589; 0001850696; 113351082
      Lhx1oXlim-1XlUpInduction, but the persistence of an unintended RA effect after the 30 minute exposure and subsequent washes is discussed.0007914163; 111123282
      LYNlynHsUpInduction; some differentiation controls.1987282; 75120792
      MCL1Mcl-1, EATHs, MmUpInduced early in differentiation but with some controls.8790944; 8600156; 9655929; 10816607; 113398302
      MdkpRIHB, MKGg, Mm, HsUpInduction data not good; functional binding site conserved in Hs and Mm; some discussion that it may be indirect in chick.0001993066; 0002018506; 8507561; 0007925417; 0007982887; 0007592548; 00092660252
      Meis1Meis1GgUpInduction (ectopic beads loaded with RA at an apparently physiological dose).109528942
      MGPmatrix Gla proteinHs, RnvrsNo good d/t data; potential positive motifs; putative negative binding region.2394711; 0001727694; 8214087; 0008319825; 00091221762
      MIG-6qgene 33RnUpInduction.00081569272
      MMP11stromelysin-3, ST3Hs, MmUpNo good time data for induction; conserved functional binding site; evidence from receptor knockouts; repression seen under extreme d/t conditions.0007657606; 0009111003; 0009824353; 109939032
      Mrg1Meis2, Stra10Mm, GgUpInduction.7649373; 9337137; 109528942
      Mtap7E-MAP-115MmUpInduction.00108370262
      MYCc-mycHsvrsRapid induction in some systems; rapid inhibition on others, but that appears to be indirect; some differentiation controls have been done.2414665; 3691668; 0002459072; 2163931; 0008490200; 0008239509; 00080185612
      MYCNN-mycHs, MmDnEarly and rapid suppression; differentiation associated; upstream region responsible has been identified.3977910; 3855502; 2405249; 0001565467; 95703572
      NCF1p47-phoxHsUpInduction; other NRs.2398896; 7578267; 91453352
      NCXNcxHs, Mm, RnrUpEarly induction during differentiation but with some controls; conserved motif necessary for RA effect.00104462202
      NESnestinMm, Hs, RnUpDifferentiation associated; no good d/t data; conserved binding motif which other NRs also bind.8522959; 0009104587; 9057134; 0010222142; 108760352
      NgfrLNGFR, p75NTRRn, HsUpInduction; a promoter region conferring the RA response has been identified; other NRs.1964179; 0001446821; 1325442; 10816607; 106618352
      Nr2c1TR2-11MmUpNo good d/t data; late reporter induction with exogenous RAR and RXR, or during differentiation with endogenous receptors; functional binding site (DR0).0010393558; 108079542
      NR2C2TR4Hs, MmUpInduction.0009593676; 00102015242
      NR4A3NOR-1HsUpInduction.90702912
      NRD1NRD convertaseHsDnInduction; specific ligands; no motif found.0009049835; 110421312
      NRIP1RIP140HsUpInduction; upstream region identified.114678472
      OXTOTHs, Rn, BtUpsInduction, but d/t data borderline; conserved functional motifs; other NRs.0001657967; 0001311087; 0008383287; 0008195142; 00086748532
      Pcp2Pcp-2, PCD5MmUpReporter induction; no good d/t data; functional binding site; other NRs.00092246602
      PIK3CGPI3KγHsUpInduction.00103929062
      PkcaPKCMmUpInduction is relatively rapid (or during differentiation), but appears to be at least partly indirect; functional binding site.0002743337; 0001550338; 0010486248; 00106088972
      PLATt-PAHsUpNo good d/t data; functional DR5 binding site, but induction may depend on protein synthesis; requirement for Sp1.0002542775; 0007706255; 00104525482
      PTAFRPAFRHs, RnUpNo good d/t data; functional binding site.0008570633; 00091311302
      RAI3RAIG3HsUpInduction.00098570332
      RARRES3TIG3, RIG1HsUpInduction, but d/t borderline; specific ligands; motifs noted in contig.0009843971; 0010687848; 109558112
      RBP4RBPHs, MmUpNo good d/t data; two upstream regions of about 30 bp each, separated by another 30 bp region that apparently functions as an SP1 site, weakly bind various combinations of RARs and RXRs and drive a reporter, however, they contain no obvious classical binding sites.0008077297; 0008810324; 110555512
      RDHLhRDH-TBEHsUpInduction.113045342
      RUNX3AML2, CBFA3HsUpEarly inductiont during differentiation but with some controls; specific ligands.00104194742
      S100A7RIS-1, psoriasinHsUpInduction.0007715611; 00089318682
      SERPINB2PAI-2, plasminogen activator inhibitor 2HsUpInduction; single hexamer motif noted but not tested.2513217; 0008578452; 00105832142
      Sftpa1SPARnUpInduction; motif.00089447312
      shhShhGg, Dr, Cj, Mm, HsvrsRegulation rapid in some systems, but little good d/t data; evidence from dietary studies; specific ligands; functional binding site appears not to be conserved; the relationship between Shh and RA and several possible intermediate genes is not at all clear.8269518; 7601313; 0008575626; 8625827; 8805369; 0009233805; 0009878825; 9753672; 0010331971; 00105001842
      SLC10A1ntcpHs, RnuUpNo good d/t data; functional binding site.8662994; 00107227292
      SLC5A5NISHsUpInduction, but d/t borderline; specific ligands.9398654; 108908952
      Spp1osteopontin, bone sialoprotein I, OPMm, Gg, Oc, RnUpInduction; additional RA effect at mRNA processing step; other NRs.2175918; 8344389; 7746099; 0008702678; 96181392
      Srebf1ADD1MmUpInduction.00091214912
      StarStARMm, RnUpInduction; an upstream region responsible for a 9-cis inductive effect was isolated but not tested with RA.102217652
      STAT1STAT1Hs, MmUpNo good d/t data; binding site (DR0) apparently functional, but with somewhat unusual characteristics; possibly indirect or reliant on RARb synthesis.0008631848; 0009092506; 00105972802
      Stra12Stra12MmUpInduction.76493732
      Stra13Stra13, D9MmUpInduction.0008839844; 92840452
      Stra2Stra2MmUpInduction.76493732
      Stra4Stra4MmUpInduction.76493732
      Stra6Stra6MmUpInduction; evidence from receptor knockouts.7649373; 00076445032
      Stra8Stra8MmUpInduction; evidence from receptor knockouts.7649373; 91547992
      Stra9Stra9MmUpInduction.76493732
      STSSTSHsUpInduction probable but data hard to read; specific ligands; no motif found in published promoter sequence.112847232
      Tcfap2cAP-2.2MmUpEarly induction during differentiation.00086609222
      Tgfb3TGF-β 3Mm, Gg, RnvrsUsually studied in association with differentiation or growth arrest; induction can be rapid; no motif found; other NRs.1964159; 2146270; 1734039; 8385738; 0008557772; 97317432
      Tgfbr1TBRIIHs, BtUpInduction.7757990; 96995092
      Tgfbr2TGFb type II receptorBtUpInduction.96995092
      THBDTMHs, MmUpA so-called 'late response’ gene; direct induction is possible, although other factors, particularly Sp1, seem to be involved; the response is enhanced by cAMP and blocked by cyclohexamide; specific ligands; RAR and RXR appear to be involved with a conserved DR4, but the involvement of ligand in this complex has been questioned.1370608; 1312715; 0008389207; 0008207015; 7878635; 0008918245; 0010565546; 110360682
      Ucp3UCP3Rn, HsvrsNo good d/t data; binding site functional in the presence of MyoD.10694373; 110240012
      Wnt8dmWnt-8, Stra11MmUpRapid induction.7649373; 88873232
      AanatAANATCjDnNo good d/t data.00104510221
      ABCB1MDR1, mdr3, pgp1Hs, Mm, MaUpInduction during differentiation; some differentiation controls; no good t/d data; conserved AP-1 site seems required.2573830; 0001661134; 8101511; 00096676381
      Abl1c-ablMmUpNo good d/t data; induced during differentiation.2458954; 13713351
      Acta1α-skeletal actinMmDnNo good d/t data; other NRs.86016211
      Acta2α-SMMm, Rn, HsvrsDuring differentiation, growth control, wound healing, or other phenotype change; no good d/t data; specific ligands; probably indirect.7728990; 10364073; 11230985; 113197551
      ADAMTS5Aggreganase-2Bt, Hs, RnUpSee ADAMTS4.7531436; 0007852317; 8603731; 10395742; 0010403768; 109364501
      ADCYAP1PACAPHsDnNo good d/t data.00092859321
      ADCYAP1R1PACAP1 (Type I) ReceptorHsDnNo good d/t data.00092859321
      Akap12vSSeCSRnUpNo good d/t data.111810721
      AKR1C3HAKR eHsUpNo good d/t data.00098624461
      Aldh1a1ALDH1MmvrsNo good d/t data; possible induction with low dose but suppression at higher dose; conserved (Hs, Mm, Rn) binding region but no clear motif; probably indirect (C/EBP β).109957521
      ALPIwIAPHsDnNo good d/t data.00106919701
      Ambpα 1-microglobulinRnUpNo good d/t data.00013719721
      Appβ-amyloid precursor
 proteinRn, Hs, MmUpNo good d/t data; delayed induction; motifs in Intron 7 (including one in an Alu) but induction data usually relies on upstream regions only.0007500834; 0008714200; 0009121703; 0009748493; 00107270791
      ARARHs, RnvrsNo good d/t data; other NRs.1428232; 8022710; 9182860; 100678451
      Ascl1MASH1Mm, HsvrsNo good d/t data; differentiation associated.1576967; 10080936; 114146961
      Ascl2Mash-2MmDnNo good d/t data; decreased during differentiation.15769671
      B3GNT5β3Gn-T5HsUpNo good d/t data; induction during differentiation but with some controls.86217261
      Bapx1NKX3.2, BapX1Mm, GgUpNo good d/t data.00104696001
      BCL2Bcl-2HsvrsNo good d/t data; most studies use differentiating systems, but some controls have been done; at least partly indirect; specific ligands.8402688; 8572591; 8642855; 9192771; 10557066; 111818291
      BIRC5survivinHsDnNo good d/t data.10698506; 113132721
      Bmp2Bmp2Mm, Gg, Hs, DrvrsInduction in some systems, but d/t borderline; no good d/t for suppression; generally studied during differentiation, development, or growth inhibition; specific ligands; yeast system; one upstream region conferring small RA effect has been isolated, but no functional binding motif has been found anywhere in the gene; several indirect mechanisms have been discussed, both in up-regulated and down-regulated cases.1550961; 8385738; 8119128; 8788040; 0008739045; 9753672; 0009880512; 11054542; 109425991
      Bmp4Bmp-4Mm, HsDnNo good d/t data; at least partly indirect (Hoxa-1).8788040; 10862743; 109425991
      BST1CD157HsUpNo good d/t data; mRNA studies lacking.110899181
      CA2CA IIHs, GgUpInduction during differentiation or with exogenous RARs; motif; other NRs (THRa, c-ErbA, VDR); down-regulated by long-term exposure to high RA concentration.1700414; 0007916146; 7615086; 00107993231
      Calb1xCalbindin-D 28kRn, Hs, GgUpLate induction; increased mRNA stability; other NRs.0008076693; 0008584029; 97735021
      CAMK2ACaM kinase II, α-CaMKIIHs, RnUpNo good d/t data; promoter region responsible identified.0007913411; 87956261
      Camk2ddelta CaM kinase IIMmUpNo good d/t data.11146121; 110801891
      Camkk1CaMKKαMmUpRapid induction during differentiation, but no good dose data; cell lines used have dominant negative RARa.105609161
      CASP1ICEHsUpNo good d/t data; late induction.92764751
      Casp3caspase 3Rn, HsUpNo good d/t data.10733907; 114648631
      CbgCBGRnvrsNo good d/t data.0007514032; 86456091
      Ccne1cyclin EMmUpNo good d/t data; no significant change reported (but data not shown) in one short-term mRNA study; evidence from transgenics.10479451; 110718771
      Cd164yendolyn, sialomucinRnUpNo good d/t data.111810721
      CD44CD44HsvrsNo good d/t data; differentiation associated but some controls.7576948; 95254821
      CD58LFA-3, CD58HsvrsRegulated during differentiation but some controls have been done; mRNA data lacking.1706327; 1354203; 109595551
      CD59CD59HsvrsNo good d/t data; differentiation associated.7507222; 00091095131
      CDC2p34(CDC2)HsDnNo good d/t data; during differentiation but some controls; at least partly post-translational.1751405; 9259311; 9233783; 00104470031
      CDH1E-cadherinHsvrsNo good d/t data.7984043; 8519658; 95901301
      CDH2N-cadherinMm, GgvrsNo good d/t data.0008314004; 10590479; 114146961
      CDH3P-cadherinHsDnNo good d/t data.79840431
      Cdh6cadherin-6MmUpNo good d/t data; increased during differentiation; probably indirect (Hoxa-1) at least in some systems.0009109513; 109425991
      Cdkn1amda-6, p21, WAF1, CIP1Mm, Hs, RnvrsNo good d/t data; no significant change reported (but data not shown) in one short-term mRNA study; regulated during differentiation or growth arrest; differentiation controls; functional binding motif; knockout evidence; other NRs; probably at least partly indirect.7936668; 0008702678; 0008940196; 8895764; 0009490650; 10479451; 0010645889; 110328201
      CHGACHGAHsUpNo good d/t data; promoter region conferring RA effect isolated.00075769431
      ChgbCg BMmUpNo good d/t data; no motif found; probably indirect.110142211
      CltaA4MmUpRapid induction with high RA dose during differentiation in receptor-modified cells.00088398441
      CNTFRCNTF receptorHs, GgUpNo good d/t data.0008989665; 00094881621
      Cntn1F3MmUpNo good d/t data; dispersed half-site motifs; probably indirect (possibly with Hox involvement).00093327251
      Col3a1zα1(III) collagenGgUpNo good d/t data.36535211
      Col4a2collagen IV (α 2)MmvrsSlight early decrease followed by larger increase much later; this was an early work and the hybridizing clone was not sequenced; nor was a sequence for either Col4 chain available at the time; the clone was designated α 2 on the basis of estimated weight following in vitro translation; α 1 is discussed as well.63106001
      CR1CR1HsUpNo good d/t data.100238531
      Cryd1aadelta 1-crystallinGgUpInduction of a cross-species transgene in the presence of exogenous RARb; no good time data.92160651
      CSF1M-CSF, CSF-1HsvrsNo good d/t data; may be at least partly post-transcriptional (when it is suppressed).8217219; 96161791
      CTSBcathepsin BHsUpInduction during differentiation; no good d/t data.00105341171
      CYBBgp91-phoxHsUpNo good d/t data; may require γ interferon.7578267; 94478311
      CYP1A1cytochrome P4501A1Hs, RnvrsNo good d/t data; DR4 binding site drives T3 and RA reporters.0008024563; 0007697808; 00104625151
      Cyp3a3CYP3ARnUpNo good d/t data.00091544431
      CYP4F2CYP4F2HsUpNo good d/t data; specific ligands; functional binding sites; other NRs; possibly RXR.RXR.10860554; 111624411
      Dab2mDab2MmDnNo good d/t data.103404731
      DAG1dystroglycan α, βHsDnNo good d/t data; decreased during differentiation.00091095131
      Dbx1Dbx1MmvrsNo good d/t data; specific ligands.103999181
      dbx1ahlx-1DrDnNo good d/t data.90192481
      Dbx2Dbx2MmUpNo good d/t data; specific ligands.103999181
      DCTdopachrome conversion factor, TRP-2Mm, HsvrsNo good d/t data.2107263; 111809711
      DDX1bbDEAD box proteinHsDnNo good d/t data; decreased during differentiation.00091095131
      DDX17DEAD box protein p72Rn, GgDnDown-regulated during differentiation; no good d/t data.00107182941
      DIO1type 1 iodothyronine deiodinaseHsUpNo good d/t data; TRE motif can mediate RA regulation.8077363; 0009249039; 00094920501
      Dio3ccD-III, D3RnUpSlow induction; other NRs involved (including THRb).7525478; 8770927; 103428851
      DPYSL3UlipHsUpNo good d/t datadd; increased during differentiation; the possibility of indirect action has been discussed.00091152931
      DSC2desmocollin 2HsDnNo good d/t data; down-regulated during “apparent” inhibition of differentiation.104210611
      DSC3desmocollin 3HsDnNo good d/t data; down-regulated during “apparent” inhibition of differentiation.104210611
      DSG3desmoglein 3HsDnNo good d/t data; down-regulated during “apparent” inhibition of differentiation.104210611
      EMP1CL-20HsDnNo good d/t data; inhibition during inhibition of squamous differentiation; specific ligands.00074994201
      ERBB2c-erbB-2HsDneeNo good d/t data; during growth inhibition or other phenotypic change.9662255; 0009791009; 00106748831
      ERBB3c-erbB-3HsDnffNo good d/t data.0009791009; 00106748831
      ERBB4c-erbB-4, HER4HsDnNo good d/t data; studied during growth inhibition.103833751
      eve1eve1DrvrsNo good d/t data.00098797091
      Evx1Evx-1MmDnDecreased during differentiation; no good d/t data.19717861
      F3TF, tissue factor, F3HsDnMany studies involve differentiating systemsgg; suppression rapid in some lines; other NRs; specific ligands; at least partly indirect (several mechanisms have been proposed).7949172; 8632672; 9269772; 9585253; 104004221
      FCER2CD23HsUpNo good d/t data; some differentiation controls.7682243; 00088771041
      FGF5FGF-5MmUpIncreased during differentiation; no good d/t data.2318343; 105573541
      Fgf 9FGF9MmUpInduced during differentiation; no good d/t data.76569831
      FGFR2FGFR-2HsDnSuppressed during differentiation; no good d/t data.76805531
      FGFR3FGFR-3HsDnSuppressed during differentiation; no good d/t data.76805531
      FGFR4FGFR-4Hs, MmDnSuppressed during differentiation; no good d/t data.7680553; 80772931
      FGRfgrHsUpInduced during differentiation; no good d/t data.19872821
      FKBP1AFKBP12HsUpNo good d/t data; increased during differentiation; mRNA data lacking.00094721031
      FOLR2FR-βHsvrsNo good d/t data; late induction in some leukemic, non-APL lines; some differentiation controls; no motif found.110716511
      Fosc-fosRn, Mm, GgvrsVery little good d/t data for mRNA; no significant change reported (but data not shown) in one short-term mRNA study; several indirect mechanisms proposed (including SRE and mRNA stability);
 other NRs.3691668; 2108933; 2163931; 1909429; 0001400313; 1568207; 8336949; 8226882; 0007999013; 7851664; 0010395942; 104794511
      Foxa2HNF-3 βMmUpDelayed induction during differentiation.7925656; 92608951
      FshrFSH-RSs, RnvrsNo good mRNA d/t data using RA alone.3118982; 00106994591
      Fut4CD15, Lewis x, SSEA-1RnvrsNo good d/t data; generally observed only as a marker; other NRs.0001362196; 7905817; 8621726; 96787201
      FXYD3RA28HsUpNo good d/t data.00106672261
      FynfynMm, HsUpNo good d/t data.8643689; 19872821
      GAP43hhGAP-43HsUpInduction (sometimes very rapid) during differentiation; some differentiation controls; requires protein synthesis, at least in some systems.1645738; 7649373; 8679712; 111203881
      GATA2GATA-2HsvrsNo good d/t data.1370462; 77381981
      Gata4GATA-4Mm, Rn, CjUpNo good d/t data; other NRs; evidence from receptor knockouts; evidence from dietary studies.8455608; 0008007990; 7823950; 99867331
      Gata6GATA-6MmUpNo good d/t data; induced in Gata4 −/− animals.92563441
      GckglucokinaseRnUpNo good d/t data.1537314; 9220022; 103854011
      Gfra1GFRα-1RnUpNo good d/t data.00107514441
      Gfra1GFRα-1RnUpNo good d/t data.00107514441
      Gjb3connexin31RnDnNo good d/t data.88064471
      Gpcr13H218MmDnSuppressed during differentiation; no good d/t data.95218491
      GraspGRASPMmUpInduction (partially inhibited by cyclohexamide).108280671
      GRPGRPHsUpNo good d/t data.00094685881
      HCKHckHsUpNo good d/t data.8018933; 7512079; 89952341
      HNF4AHNF4αHsvrsNo good d/t data; DR1 binding site, may be RXRE.0009792724; 110275561
      HOXC5HOX3DHsUpDelayed induction; motif.00013467611
      Hoxd10Hoxd-10MmDnShared regulatory silencing region that binds RARs and COUPs; no good d/t data; brings inappropriate expression when mutated in transgenics.00088245911
      Hoxd11Hoxd-11MmvrsShared regulatory silencing region that binds RARs and COUPs; no good d/t data; brings inappropriate expression when mutated in transgenics.0008824591; 87926111
      Hoxd13Hox D13Gg, Mm, RnDnNo good d/t data.7958440; 8792611; 106338661
      HSD11B211β-HSD2HsUpInduction data at 6 hours “detectable” but not statistically significant.100260961
      Hsp86-1HSP86, HSP90, HSPCAMm, HsvrsUp or down during differentiation or apoptosis; regulation within hours in some cases; some differentiation controls; induction, at least, is thought to be independent of RA.2806771; 1655528; 8612676; 11146166; 107183711
      ICAM1ICAM-1Hs, RnUpNo good d/t data; late induction; functional binding site (and functional GAS sites); may be secondary to calmodulin, CaM kinase II, or other activity.0001983003; 0001680399; 0007914515; 0007913411; 0007737364; 0007647034; 0007913411; 00104111241
      ICAM3CD50, ICAM-3HsUpNo good d/t data for mRNA.9497494; 112617821
      Igf1rIGF-IRRnUpNo good d/t data; other NRs.90486271
      IGFBP2IGFBP-2HsvrsNo good d/t data.0001382963; 00086403001
      IGFBP3IGFBP-3 (42–46kD)Hs, BtvrsIncrease in most cases, but late decrease in Bt cells and at extreme dose/time points in Hs cells; associated with growth inhibition; specific ligands; early, rapid increase appears to require protein synthesis.0001382963; 0008620495; 0008655603; 0009153223; 0010580834; 00103642501
      IGFBP5IGFBP-5Hs, RnvrsNo good d/t data; generally decreased, but there may be an opposing increase in mRNA stability.0007536661; 0008603611; 00093686781
      IL6IL-6HsDnNo good d/t data.0010704257; 107852301
      IL6RIL-6RHsDnRepressed during inhibition of proliferation; no good d/t data.0002033252; 00079491751
      INHBAActivin AHsvrsNo good d/t data.1690989; 87743521
      INSiiproinsulin, insulinRn, HsUpNo good d/t data; there is a binding site in the uniquely Hs insulin-linked polymorphism.1537314; 0007639703; 00092601961
      ITGALCD11aHsUpNo good d/t data; some differentiation controls.7512079; 87743611
      ITGAMCD11b, MAC-1HsvrsMotifs; no good d/t data; some differentiation controls; specific ligands; other NRs.0001347945; 7512079; 8025272; 0010704061; 11426618; 113398311
      ItgavIntegrin α v, vitronectin receptor, CD51Mm, Hs, Gg, OcUpNo good d/t data.1939209; 7529599; 0008891892; 105202211
      ITGB2CD18HsUpNo good d/t data; motifs.2901419; 0001346252; 9337080; 106417471
      Itgb4β 4 integrinMmvrsNo good d/t data.0008287622; 00088750791
      Junc-junMm, RnUpRapid induction probably indirect; no good d/t data for suppression.1963081; 0001851295; 0001310930; 8670250; 0009436983; 0010395942; 104794511
      JUNBjun-BHs, MmUpNo good d/t data; some differentiation controls; report (data not shown) of no RA effect under low-dose, short-term conditions.0001667479; 2113273; 104794511
      KAI1CD82HsUpNo good d/t data; induced during differentiation.106303091
      KCNH2HERGHsUpNo good d/t data; induced during differentiation.9535729; 104134511
      Kitlc-kit ligand, stem cell factor, SCFMm, HsUpNo good d/t data.7537079; 8874749; 9827903; 112052721
      KLK7SCCEHsDnNo good d/t data; mRNA data lacking.81056131
      KRT10K10Hs, OcDnNo good d/t data; region that responds to RA identified; RAR (only) binding demonstrated; hexamer motifs.1712634; 1375251; 1284070; 105421381
      KRT13K13Hs, Oc, Rn, MmUpNo good d/t data; induced during differentiation, but some differentiation controls have been done; potential response element found not to be active; AP-1 regulation; specific ligands.6205395; 2470609; 7687243; 0007525098; 8634095; 00088538951
      KRT14K14Hs, OcvrsNo good d/t data; associated with differentiation (or inhibition of differentiation); upstream region responsible for RA effect (suppression) identified; in vitro RAR binding; AP-1 regulation; other NRs.1700022; 1711202; 1375251; 0001281867; 107131771
      KRT16K16Hs, OcvrsDuring differentiation (or inhibition of differentiation); no good d/t data; upstream region responsible for RA effect identified.2470609; 1711202; 1375251; 89776661
      KRT17K17HsUpNo good d/t data; an upstream cluster of hexamers that can bind RAR (weakly) and suppress a CAT reporter has been found; other NRs.1708801; 8977666; 00093263921
      KRT2AK2eHsDnNo good d/t data.106921071
      KRT3K3Hs, OcDnNo good d/t data; upstream region responsible for RA effect identified.13752511
      KRT6AjjK6Mm, HsvrsRecent duplications make it difficult to be sure which K6 gene is being studied in many papers; there appear to be significant difference between RA effects in vitro and in vivo, with up-regulation perhaps the most likely in vivo effect; both positive and negative motifs have been proposed; AP-1 regulation; no good d/t data in vivo.2439609; 1711202; 0007682522; 0007545670; 0009326392; 9790766; 108871741
      KRT7K7HsUpNo good d/t data.2459129; 75057561
      Laptm5E3MmUpRapid induction with high RA dose during differentiation in receptor-modified cells; no good d/t data for other cells; binding motif in region responsible.00088398441
      Lepleptin, obRn, HsDnNo good d/t data; other NRs.9659286; 9514867; 10381155; 10902807; 11479138; 113694441
      Lgals114.5-D lectin, L-14Mm, Hs, RnvrsDifferentiation associated; no good d/t data; no likely binding site found.2555043; 8135794; 7954433; 9865605; 107605651
      Lgals334-kD lectin, L-34Hs, MmvrsDifferentiation associated; no good d/t data.2555043; 2537146; 98656051
      LGALS7Galectin-7HsDnNo good d/t data.77295681
      LORLorcrinHsDnNo good d/t data.0001710017; 0002007780; 0001378029; 00075163971
      LPAapolipoprotein(a), apo(a)Hs, MfDnNo good d/t data; motif.0009299449; 0009535807; 00104231671
      LtflactoferrinMmUpNo good d/t data for RA; induction at 6 h with 9-cis; functional binding site; other NRs.8113151; 0007623814; 0009828118; 00105056671
      Mapk1Erk2Hs, MmUpkkNo good d/t data for mRNA; region at least partially responsible for RA effect identified; no apparent response element.0009261178; 9679985; 105484341
      MAXmaxHsvrsDelayed induction in some studies; no change in
 others.0008239509; 8134128; 8570225; 00098048321
      Mc1rmelanocyte-stimulating hormone receptorMm, HsvrsNo good d/t data for mRNA; specific ligands.0002265702; 0008168086; 96108631
      Meox1Mox1MmUpLate induction during differentiation.76493731
      MLN64llMLN/CAB1HsDnData not shown.111461661
      MMECD10, NEPHsvrsNo good d/t data; differentiation associated change; mRNA data lacking.75287531
      MMP13MMP-13Bt, Ss, HsvrsNo good t/d data.10548534; 104299421
      MMP2gelatinase AHs, GgvrsEarly studies of enzyme activity (not mRNA) showed a decrease with high dose/long exposure conditions; later studies have shown late increases; upstream region conferring RA effect identified; probably indirect.6279711; 8314305; 0008858101; 9664142; 9407317; 00103294421
      MSX1Msx-1Mm, Hs, GgvrsNo good d/t data; motif in Mm not Hs; required binding region for induction in Hs; possibility of indirect action discussed.0007916326; 0007866431; 0007650517; 0009045990; 98705331
      Msx2mmMsx-1Gg, CjDnNo good d/t data; whole animal evidence for RA effect.0001685987; 0007650517; 00090459901
      Mt3MT-3MmUpNo good d/t data.00107126061
      MUC2MUC2Hs, MfvrsInduced or inhibited, but no good d/t data; down-regulated following maintenance in retinoid-
 depleted culture; specific ligands.0008179918; 0008997274; 0009870916; 0010024510; 112005891
      Muc3RMUC176RnUpNo good d/t data.00082973361
      MUC5ACMUC5ACHs, RnUpNo good d/t data; down-regulated after maintenance in retinoid-deprived culture; down-regulated in vitamin A deficient animals; specific ligands.0008997274; 0009870916; 0010024510; 11200589; 00106346051
      MUC5BMUC5BHsUpNo good d/t data; specific ligands; down-regulated in retinoid-depleted culture.0009870916; 0010024510; 112005891
      MYBL2B-mybHsDnInhibition during differentiation; no good d/t data.85982281
      MYCL1L-mycHsvrsNo good d/t data for repression; induction may be rapid, but data unclear; induction blocked by cyclohexamide.8123593; 8934535; 00100749291
      NCF2p67-phoxHsUpNo good d/t data; other NRs.7578267; 9145335; 94478311
      NDRG1RTP, Drg1, Ndr1HsUpInduced during differentiation; no good d/t data.00103959471
      NgpF1MmUpRapid induction with high RA dose during differentiation in receptor-modified cells.00088398441
      NME1nm23-H1HsUpNo good d/t data.00106642471
      NOS1n-NOS, nNOSHs, MmUpNo good d/t data; induced during differentiation.8929985; 108202021
      Nos2iNOS, NOS2Hs, RnvrsNo good d/t data.9635256; 00107729141
      NOS3eNOSHsDnDown-regulated late in differentiation; no good d/t data.96352561
      Notch1Notch-1MmvrsNo good d/t data.7615640; 114146961
      NPYNPYHsDnNo good d/t data; no motif found.108549071
      NR3C1GRHs, MmvrsNo good d/t data (or d/t conditions not described).6611455; 8339256; 7994082; 7854351; 111461661
      NR4A2Nurr1HsUpData hard to interpret at early time points.90702911
      Nr6a1GCNF, RTRHs, MmvrsTransient induction followed by repression during differentiation; no good d/t data.9134503; 0009563832; 105241921
      Ntrk2TrkbRn, HsUpInduced during differentiation; no good d/t data.7988722; 00088175331
      NTRK3TrkCHsUpInduced during differentiation; no good d/t data.00088175331
      Olr1nnLOX-1RnUpNo good d/t data; rapid induction with high dose.111810721
      PCDH11PCDHXHsDnNo good d/t data (but only a qualified claim is made in the paper).110037071
      PCDH22PCDHYHsDnNo good d/t data.110037071
      PdgfrbPDGF receptor βMmUpNo good d/t data.2155144; 81801341
      PECAM1PECAM-1, CD31Hs, MmvrsMotifs; regulated during differentiation, but some controls have been done; no good d/t data.0008955189; 9678720; 10830620; 113970021
      PLAUu-PAHs, Bt, MmUpInduction by RA alone is slow or during differentiation; in other assays, RA appears ineffective by itself; no motif found; probably indirect.0008491555; 0008385052; 0008404615; 0009560322; 00103611241
      Pou4f 2Brn-3.2MmDnNo good d/t data for RA alone; inhibition rapid if cAMP is present.00079048221
      Pou5f1Oct-3, Oct-4, Oct3/4Mm, HsvrsNo good d/t data; indirect repression through the upstream 1.2 kb region (no RARE motif); reporter induction through proximal RARE motif; indirect repression through proximal RARE motif; indirect repression through the upstream 2 kb region;
 other NRs.0001915274; 0008289783; 0008289793; 0008152920; 0007823919; 0008832901; 0008631309; 0010512201; 00106924691
      PPP3CAcalcineurin AHsUpNo good d/t data; increased during differentiation; mRNA data lacking.00094721031
      PPP3CBcalcineurin BHsUpNo good d/t data; increased during differentiation; mRNA data lacking.00094721031
      PRAM-1ooPRAM-1HsUpNo good d/t data in non-APL cells.113013221
      PRKCB1PKC β 1Hs, Rn, MmvrsNo good d/t data for mRNA; some differentiation controls; other NRs.3422643; 1868031; 0001550338; 7961696; 9145335; 8732669; 94868511
      PRKRp68 kinaseHsUpNo good d/t data.93938791
      PRLRPRL-RHsDnNo good d/t data for RA, but protein synthesis not required; specific ligands; rapid reduction with 9-cis.00098884581
      PRNPPrPHsvrsNo good d/t data.7984043; 94732201
      PTENPTENHsUpNo good d/t data; increased during differentiation but some controls have been done.112906071
      PtgdsPGDSRnUpNo good d/t data; contains a functional TRE that can act as an RARE in vitro.0009582446; 9579690; 106509531
      Ptgs1Cyclooxygenase-1,
 COX-1, PGHS1Mm, Rn, HsvrsNo good d/t data; induction (when it occurs) may be blocked by cyclohexamide.7851378; 8967521; 8948503; 112993041
      PTGS2TIS10, COX-2, PGHS2Hs, Mm, RnvrsModest induction using RA or platelet-activating factor alone; stronger induction with RA + PAF; binding region for RA + PAF activation contains no obvious motif, but no site for independent RA activity sought elsewhere in the gene; most studies use long incubation periods or high doses.0008202477; 7851378; 8967521; 8948503; 95692361
      PthPthBtDnNo good d/t data; other NRs.8377475; 00081134071
      PthrPthrRn, MmvrsDelayed suppression; no good time data for induction; a DR1 is involved in induction but it is not sufficient; other NRs.0001660713; 0009792954; 00104064681
      PTK2focal adhesian kinase, FAKHsvrsNo good d/t data for mRNA; various non-transcriptional effects have been demonstrated.9566310; 9590130; 9989778; 113691411
      PTMAProT αHsvrsNo good d/t data or data not shown.8416800; 111461661
      PTPN13CD95HsDnNo good d/t data.00097924411
      Rai2RAI2Mm, HsUpNo good d/t data in Mm; Hs ortholog proposed only by analogy.0008314004; 00100495811
      RARRES1TIG1HsUpNo good d/t data; tested only with synthetic retinoids and specific ligands.00086017271
      RARRES2TIG2HsUpppNo good d/t data; tested only with synthetic retinoids and specific ligands.00092049611
      Rbp2CRBPIIRn, Mm, HsUpInduction controversial; motifs; no good d/t data; other NRs; possibly an RXR.RXR system; physiological relevance of RA questioned.0001651173; 0008288643; 00090405371
      RETretHs, RnUpInduced during differentiation; no good d/t data; motif not found.1766678; 7867726; 0009426223; 0009843911; 00107514441
      RhoRod-specific opsin, rhodopsin, Rh1Mm, Dr, DmUpNo good d/t data; evidence from transgenics; evidence from dietary studies.8681798; 8917585; 8994352; 107117161
      RNPEPaminopeptidase-BHsDnLate increase; specific ligands.00090498351
      Rrg1NN8-4AGMmUpInduction seems to occur rapidly but RA activity is blocked by protein synthesis inhibitors (9-cis activity is not); motif binds RAR.RXR and RXR.RXR; RA induction is probably at least partly indirect.00087548341
      RTN1NSP-AHs, RnUpNo good d/t data.95604661
      RTN3NSP-CHs, RnUpNo good d/t data.95604661
      RxraRXR αMmUpqqNo good d/t data; other NRs; AP-1 regulation; message may be superinduced by cyclohexamide.8269997; 8806431; 0008940178; 10403834; 00097177111
      S100A8MRP-8HsDnNo good d/t data; tested only with synthetic retinoids.00103199951
      SAGarrestinHs, MmUpNo good t/d data; partially conserved motif; the Mm site binds RAR.RXR, but the Hs site is “inefficient”; the Mm site drives a heterologous reporter construct, but the Hs site (which is identical to the Bt site) does so only poorly; may be primarily COUP regulation.0007708064; 90686161
      SALFrrSALFRnUpNo good d/t data; rapid induction with high dose.111810721
      SCDSCDHsUpNo good d/t data; specific ligands.113978031
      SCYA2MCP-1Hs, RnvrsNo good d/t for RA but rapid induction with 9-cis; other NRs; suppression, when it occurs, is probably through AP-1.7919389; 10479651; 112742291
      SDC2HSPGHsUpNo good d/t data; increased during differentiation.00091095131
      SELLL-selectinHsDnNo good d/t data.00107040611
      SERPINC1antithrombin IIIHsUpNo good d/t data; motifs are responsive to RXRs and THR; both T3 and RA induce in some systems.8192147; 7531260; 00087614811
      SERPINE1PAI-1, plasminogen activator inhibitor 1HsvrsInduced during differentiation; short term studies report no effect.0001905574; 1908141; 0001935958; 00084915551
      SFTPCSP-CHs, Rn, MmvrsNo good d/t data; possible mRNA stability effect.0008404646; 0008944731; 94587941
      Slc18a3VAChT, vesicular acetylcholine transporterMm, Rn, HsUpNo good d/t data.0007673184; 7616258; 0009237624; 10960602; 113061871
      Slc2a2GLUT 2RnUpNo good d/t data; other NRs.114943051
      SlughSlugGgDnNo good d/t data; possibly indirect (TGFb2 signaling is involved in some cases).9303343; 108644631
      SOD2MnSODHs, RnUpLate increase in protein; mRNA studies (using RA alone) are lacking.107028101
      Sox9SOX9MmUpNo good d/t data.00107538641
      SP100Sp100HsUpNo good d/t data in non-APL cells.93938791
      SparcSPARC, osteonectinMm, GgUpSlow (or differentiation associated) induction; evidence from receptor knockouts.1310471; 1584226; 8344389; 00081054791
      SPNCD43HsUpNo good d/t data; motifs.00091746041
      SPRR1BssSpr1, cornifinHs, Mf, OcDnNo good d/t data; during differentiation or growth arrest; specific ligands; other NRs.1627333; 7769256; 8631988; 8950452; 106150701
      SULT2B1ttcholesterol sulfotransferaseOcDnmRNA studies lacking.34775421
      SUPT4H1SUPT4HHsUpNo good d/t data; increased during differentiation.00091095131
      TAF2STF CA150HsUpData not shown.111461661
      TATTATRnvrsDown-regulation, when it occurs, may be due to decreased mRNA stability; no good d/t data in either direction; other NRs.1350056; 0008100575; 7734399; 00094492051
      Tcf1HNF-1 αMm, HsUpInduced late in differentiation; RXR.RXR binding site.2065662; 110275561
      Tcf2HNF-1 βMmUpInduced late in differentiation.2065662; 76493731
      TFAP2AAP-2HsUpNo good d/t data; upregulated during differentiation; no motif found up to −1.7 kb.0003063603; 0002482225; 0008190633; 00086874531
      TFRCCD71, TfRHsDnNo good d/t data; mRNA stability may be involved in some systems; reduction during differentiation or growth arrest.6573952; 2702640; 2404770; 94917821
      TGFATGF-αHs, MmvrsRegulated during differentiation (or growth arrest) but some controls have been done; upstream region conferring increased expression in vitro identified; no motif found; no good d/t data for RA but suppression can be rapid for synthetics; specific ligands; other NRs.3215396; 2087681; 0001922084; 7536865; 86197891
      TGFB1TGF-β 1Hs, RnvrsNo good d/t data; suppression (when it occurs) is probably through AP-1; no RARE found; other NRs; some differentiation controls have been done.2909528; 1848114; 1334692; 0008264664; 00085577721
      Tgfb2TGF-β 2Mm, Hs, GgUpInduction but d/t borderline; possible mRNA stability effect; upstream region responsible for RA effect probably identified; no RARE found; evidence of other transcription factor changes following RA treatment; specific ligands; other NRs; some differentiation controls have been done.2519621; 2084113; 1734039; 7654367; 0008557772; 00091532231
      Tgm1TGase K, TGase1Oc, Hs, RnuuDnNo good d/t data; decreased during differentiation; gene can be induced in vitro by RA; AP-1 and AP2 response elements; intronic negative DR5 alluded to.2876994; 1356818; 1355099; 0008097865; 8537408; 103218351
      ThTHRnUpNo good d/t data.00085229941
      ThrspS14Mm, RnUpNo good d/t data; other NRs.0001322331; 0007997231; 00101878321
      TncTn-CMm, Rn, HsvrsNo good d/t for increase; rapidvv reduction possible; other NRs.8528505; 10502285; 10078937; 106512291
      TOP2AwwTopoIIHsvrsNo good d/t data; generally studied in differentiating systems; probably indirect.7954372; 97635711
      TRA1gp96HsUpNo good d/t data.96412191
      Trpm2Sgp-2, clusterinRnDnNo good d/t data; motif.1350056; 00095475041
      TshbTSH βRn, MmDnNo good d/t data; dietary evidence; upstream binding region responsible for RA effect identified and found distinct from T3-responsive region; possibly
 9-cis, RXR system; evidence from transgenics.0007835286; 0009296372; 108800501
      TyrtyrosinaseMmvrsNo good d/t data for mRNA; motifs that drive reporter induction identified; other NRs.6260817; 2983883; 2107263; 00076203421
      Ucp2UCP2RnDnNo good d/t data.106943731
      VDRVDRHsUpNo good d/t data directly implicating an undiluted RA/RAR.RXR response; two regions drive reporters; autoregulation (potentially involving retinoid receptors); possibly indirect.0009212063; 0010446999; 109192691
      VegfcVEGF-CMmDnNo good d/t data.113061731
      VIMvimentinHs, MmvrsNo good d/t dataxx; late suppression (or induction) associated with differentiation or cell-cycle arrest; often observed primarily as a marker; no motif found; AP-1 involvement likely at least in some cases.3467175; 2447102; 1352781; 0007790400; 0010631814; 111461661
      VIPR1VIP1 receptor, VIPR1, PACAP2 (Type II) receptorHsDnNo good t/d data; possibly a motif.yy0007708752; 0009285932; 0009809989; 111506431
      Wnt1Wnt-1MmvrsNo good d/t data; regulated during differentiation or development; region conferring RA effect in vitro isolated but its relevance to at least some in vivo systems has been questioned.8441400; 7925022; 8626038; 9636087; 114146961
      Wnt3aWnt-3aMmDnNo good d/t data, although inhibition may be rapid; evidence from receptor knockouts.0009882496; 104731171
      WT1wt1Hs, MmvrsNo good d/t data; regulated during differentiation, but some controls have been done.8142654; 90409351
      X17CzzX17CXlUpNo good d/t data.00088610941
      ZNF42MZF-1HsUpNo good d/t data; differentiation associated; region containing motifs can drive a reporter.0001860835; 00088453781
      Znfn1a1IkarosMmUpNo good d/t data.110928791
      ADAMTS4aaaAggrecanaseBt, Rn, HsUpNo good d/t data; many papers measure enzymatic activity only, so the gene(s) responsible are not clear; probably indirect.7531436; 0007852317; 8603731; 10395742; 109364500
      Adh1Adh-1MmNo mRNA effect; no site found; possibly based on early confusion about the RA inducibility of the Hs gene previously known as ADH1.00080189870
      Afpα-fetoproteinRn, HsUpDelayed induction during differentiation; functional binding sites; some question about whether regulation is primarily by RXRs; other NRs; probably indirect although the –6327 site may mediate direct regulation.0001379951; 0007528016; 0007525384; 0007512261; 0008945636; 0009792724; 00100256640
      AgcAggrecanBt, Rn, HsvrsProbably indirect.8492742; 9779827; 00107538640
      Agtr1aangiotensin II type 1 receptorRnDnIndirect.00106423140
      AHRAhRHsDnA normal increase during differentiation is inhibited by long-term, continuous RA; short-term exposure during differentiation has no effect; some differentiation controls; probably indirect.89501950
      Arhgap5bbbp190 GAP-associated
 proteinRnUpDose and time unclear, but protein synthesis required; probably indirect.106672250
      ARNTARNTHsDnA normal increase during differentiation is inhibited by long-term, continuous RA (1 μM); short-term RA exposure during differentiation has no effect; probably indirect.89501950
      Atp1a3Na,K-ATPaseRnUpNo good d/t data; probably indirect.00099253750
      BGLAPosteocalcinHs, Rn, MmUpcccConflicting gene modulation data; motif (VDRE/
 AP-1) drives heterologous promoter and binds RAR; induction, when observed, is probably indirect, possibly through the induction of Srebf1 or through VDR.RAR or VDR.RXR dimers.0002159384; 1820970; 0008395017; 0008466530; 83829330
      BLR1Blr1HsUpInduction during differentiation but some controls; probably indirect.10640427; 112119360
      Bmp7BMP-7Gg, HsUpProbably indirect (protein synthesis).0009621899; 110321770
      BTKBTKHsMotifs; no other evidence.79275350
      Cal1dddCT, CGRPRnDnLong treatment required; probably indirect.0001569964; 0008413210; 8061571; 90571020
      CCND3cyclin D3Hs, MmDnReduced during growth arrest or differentiation; no good d/t data; no significant change reported (but data not shown) in one short-term mRNA study; evidence from receptor knockouts; probably indirect.9260897; 0009806360; 104794510
      CdrapCD-RAPBt, Mm, Rn, HsDnIndirect.8621736; 9097023; 0009478951; 103205240
      Col1a1α 1(I) collagenMm, Rn, HsvrsNo good d/t data; other NRs; putative response element (a DR37 or a single hexamer) shown to be spurious; probably indirect.3919954; 2915650; 0010729205; 2019574; 7918630; 7988442; 00090774770
      Col1a2α 2(I) collagenMm, Hs, GgvrsNo good d/t data; regulation does not seem to be through the identified motif (an unusual DR6); probably indirect.3919954; 2987306; 1429872; 0010729205; 36535210
      Col4a1collagen IV (α 1), α 1(IV)Mm, Hs, BtUpNo good d/t data; now thought to be indirect.0002981185; 0002842348; 0002327791; 94518070
      COL7A1type VII collagenHsDnNo good d/t data; probably indirect.91305970
      CpceruloplasminRnUpeeeNo good d/t data; probably indirect (protein synthesis).111810720
      CRHcorticotropin-releasing hormoneHsUpIndirect.00104469000
      CSF1Rc-fmsHsUpInduction; no motif found in the region sufficient to impart RA inducibility; regulation attributed to AP-1.RAR.00105540380
      CTNNB1β-cateninHsvrsProbably indirect.8754749; 9414661; 106075660
      CTSDcathepsin DHsUpProbably indirect.0007547509; 00086394640
      CTSGcathepsin GHsDnProbably indirect.85589450
      CTSLcathepsin-LRnUpDelayed induction; probably indirect (protein synthesis).111810720
      Cyp7a1CYP7ARnfff, MmvrsNo good d/t data; largely transfection, cotransfection, or dietary studies; conserved binding motif, but RA response may not be conserved; many other NRs; probably indirect (possibly through RXR.LXR and FXR.RXR).8656080; 0008753804; 0008831673; 0009799805; 109687830
      DEFA1promyelocytic defensin-1HsUpProbably indirect.00095358500
      EDN1ET-1HsDnProbably indirect.00098099840
      ENPP2ATXHsUpNo good d/t data; requires protein synthesis; probably indirect.113468800
      Etnmg1ETnMG1MmDnRepression probably due to decreased mRNA stability.88637320
      Evx2evx2Dr, MmvrsNo good d/t data; probably indirect (Hoxa-1).0009879709; 109425990
      FACL2acyl-coA synthase, ACSHs, RnUpProbably indirect; specific ligands.00107775520
      FasnFASRnvrsNo good d/t data; other NRs; probably indirect.6164877; 7537465; 0009191201; 9070250; 9510066; 00097704740
      Fbp1Fru-1,6-P2ase, FBPaseMm, HsUpSlow induction during differentiation; no RA regulation seen in whole animal study; binding motif (DR3) is also a VDRE; other NRs; probably indirect.9202079; 9556208; 00107317080
      Fgf1acidic FGFMmUpInduced during differentiation; indirect.25446080
      Fgf 2bFGF, basic FGFMm, Cf, BtvrsNo good d/t data; differentiation associated; specific ligands; probably indirect.2544608; 10607884; 112301160
      Fgf 3FGF-3MmUpInduced during differentiation; indirect.8265348; 103580830
      FGF4K-FGFHs, MmDnSuppressed during differentiation; indirect.2009969; 0001723621; 88446880
      Fosl1Fra-1Mm, HsUpInduction, probably indirect.102174070
      FSCN2Retinal fascinHsMotif; no other evidence.107832620
      Gja1connexin43, Cx43Mm, Hs, RnUpOther NRs; probably indirect.0002177604; 0001327514; 7954877; 0007720192; 8941706; 9428648; 101927740
      GRIN1NMDAR1Rn, HsUpNo good d/t data; probably indirect.8866697; 92199480
      GrngggEpithelinRnUpNo good d/t data; probably indirect (protein synthesis).111810720
      GscgoosecoidXl, Dr, MmDnNo good d/t data; generally studied in teratogenicity experiments; specific ligands; no motif found; probably indirect.1684739; 7605750; 9207233; 105121930
      Gsta4GST 5.7MmDnDecreased during differentiationhhh; no good d/t data; probably indirect.00098063600
      H19H19HsUpNo good d/t data; delayed induction; probably indirect.00097209090
      Ha1riiiHoxa-1 RegulatingMmUpProbably indirect (Hoxa-1).00106728990
      HBP17FGF-BPHs, RnDnNo good d/t data; probably indirect.8702908; 10831072; 110770500
      HGFhepatocyte growth factorHsDnRapid repression; specific ligands (in late-measurement studies); other NRs; probably indirect.0009886825; 112231640
      Hoxa5Hoxa5MmUpProbably indirect.00106799300
      Htf 9cHtf 9-cMmIn some cell types, RAR.RXR (as well as other RXR-containing complexes) bind to a DR1; no other evidence of RA regulation either way.00094171080
      IBSPbone sialoprotein (BSP)HsMotif; other NRs, but no direct evidence of RA involvement.0008061918; 0008702678; 109002680
      IfngIFN-γMm, HsDnNo good d/t data for RA alone; other NRs; probably indirect.1907993; 0008900159; 00098081700
      IGF2IGF-II, IGF-2HsvrsEarly induction, but the significance of the increase is not clear; mRNA decrease in some studies seems to be a late effect, probably indirect (possibly IGFBPs).0001375906; 0008364891; 0007527270; 0009258346; 00096889370
      IGFBP4IGFBP-4Hs, SsvrsGenerally studied during growth regulation; no good d/t data; other NRs; probably indirect (protein synthesis).0007686749; 0008640300; 0008536624; 00106019680
      IhhIhhMm, OcUpRapid induction but probably indirect.9242425; 112816440
      Il12bIL-12 p40MmDnProbably indirect (NFκB); specific ligands.100756550
      IL2IL-2HsvrsNo good d/t data; specific ligands in some inhibition studies; probably indirect.0001652063; 0007931079; 91305120
      IL8IL-8Hs, MfUpProbably indirect.0007763262; 00107450310
      Itga8jjjα-8 integrinRnUpDelayed induction during differentiation; probably indirect (protein synthesis).111810720
      Itgb5kkkβ 5 integrinGgDnIndirect.00098930630
      Itgb7β 7 integrinMmMotifs; no other evidence.00083184580
      IVLinvolucrinHsvrsDifferentiation associated; no good d/t; probably indirect (AP-1 in at least some systems).3858572; 2463259; 0001378029; 0008853895; 00089593440
      Kpna2lllimportin αRnUpNo good d/t data; probably indirect (protein synthesis).111810720
      KRT1K1HsDnNo good d/t data; there may be significant differences between in vitro and in vivo RA effects; AP-1 regulation; differentiation associated; probably indirect.2440897; 7522960; 0007516397; 00075102860
      KRT18K18, EndoBMm, Oc, HsUpInduced during differentiation (or growth inhibition), rapidly in some cell types; some proliferation controls have been done; specific ligands; probably indirect (AP-1, Ets2); RA-sensitive Alu in Hs gene.1691021; 7514938; 0007526151; 0007667273; 86415450
      KRT19K19HsUpProbably indirect (mRNA stability and AP-1 have been discussed); other NRs.6205395; 2414289; 0007505782; 0007506253; 8751982; 110265740
      KRT4K4HsvrsNo good d/t data; probably indirect.0008687453; 8751982; 8950195; 106921070
      KRT8K8, EndoAMm, HsUpInduced during differentiation (or growth inhibition); induction rapid in some cell types; some proliferation controls; AP-1 regulation; specific ligands; probably indirect.1691021; 7505756; 8641545; 110108140
      LdhbLDH-BRnUpNo good d/t data; during arrest or differentiation; probably indirect (protein synthesis).111810720
      lef1lef1DrDnProbably indirect.110023470
      Lmnalamins A/CMm, HsvrsProbably indirect.1282809; 1281113; 0009828104; 00106944990
      LplLPLMmNo change in mRNA (but enzymatic activity decreased).00016103910
      MbpMBPRnUpAppears to be primarily a T3/TR system; may be activated by 9-cis/RXR in some cases.00098893310
      MMP1collagenaseHs, OcDnIndirect; several mechanisms proposed.0002178224; 0001320254; 0007615643; 0008908199; 0009111003; 9537651; 00098884610
      MMP3StromelysinRn, Hs, Bt, SsvrsNo good t/d data; possible differences between species in long term exposure; probably indirect.0002176152; 10548534; 104299420
      MMP992-kD gelatinase, MMP-9HsDnmmmProbably indirect.9565574; 9824620; 10646501; 111726060
      MPOMPOHsvrsDifferentiation associated; no good d/t data; a binding site in the Alu includes an allelic Sp1 site that may be important in APL; probably indirect.6321491; 0008662930; 00093262400
      MST1HGFLHsDnNo good d/t data; region responsible for RA inhibition identified; probably indirect.00098868250
      MUC4MUC4HsUpNo good d/t data; probably indirect (TGFb2 involved in some systems).109382820
      MYBc-mybHs, Gc, Rn, MmvrsRapid induction by RA appears to be indirect; there is evidence of physical an RAR.MYB interaction (and mutual antagonism); inhibition appears to be indirect, but RXR-dependent.3380093; 0001323819; 8670250; 8598228; 0009576918; 0009714701; 00106147880
      NORPEGNORPEGHsUpNo good d/t data; probability of indirect mechanisms discussed.110421810
      NppaANF, ANPRn, HsnnnDnNo good d/t data; during growth or hypertrophy control; other NRs; responsive upstream region isolated; specific ligands; probably indirect.7611385; 0007638203; 86016210
      NPY1RY1RHsDnRapid decrease; at least partly due to decreased message stability; slowed by cyclohexamide; probably indirect.8978705; 91654600
      Nr2f1COUP-TF1MmUpNo good d/t data; delayed induction during differentiation in one study, but with some controls; probably indirect.0008314004; 0007947324; 0008804707; 98311190
      Nr2f 2ARP-1, COUP-TF IIMmUpNo good d/t data; delayed induction during differentiation in one study; some differentiation controls; probably indirect.0007947324; 00088047070
      NR4A1NGFI-B, Nur77HsDnThe data from short-term work is hard to interpret but the level of repression is probably insignificant; longer-term work suggests an AP-1 intermediary.9070291; 107728260
      NRGNRC3RnUpEvidence of induction and receptor binding in early papers; no longer thought to be directly regulated
 by RA.0007898304; 0007730337; 00092829110
      Ntrk1oooTrkARn, Gg, HsvrsUpregulation in most papers; various differentiation controls have been used; mRNA stability may be involved; probably indirect.7988722; 0007496626; 7559588; 0008817533; 107844050
      OAS3ppp100-kD OASHsUpNo good d/t data; reporter induction; motif; probably indirect.0006435868; 2472992; 1677311; 111123510
      ODC1ODCHsDnProbably indirect (protein synthesis), but the mRNA is very short-lived.2478272; 22958350
      OPRD1DORHs, RnUpNo good d/t data; probably indirect.7932156; 8866697; 92199480
      Oprk1KORMmvrsIndirect.11092879; 112226490
      OPRM1MORHsUpNo good d/t data; probably indirect.7932156; 92199480
      Otx2Otx2Mm, Xl, GgDnPromoter region conferring RA response identified, but no motif found; specific ligands (TTNPB repressed but TTNPB plus LG69 had no effect); physiological relevance of RA pathway questioned; expression normal in Aldh1a2 -/- embryos; probably indirect.7607086; 7748789; 7720578; 7669695; 9006080; 101924000
      PDGFAPDGF-AHs, MmDnNo good d/t data; down-regulated during differentiation; probably indirect.3215396; 2155144; 82744560
      PdgfraPDGF receptor αMm, HsUpRegion responsible for RA effect identified; no motif found; probably indirect (GATA-4 and Oct-4 have been discussed).2155144; 2174116; 7731723; 0008552100; 00086627860
      Pitx2Pitx2MmUpProbably indirect.0010331971; 112455680
      Pk3PKMmDnIsoform M2 decreased during differentiationqqq; no good d/t data; probably indirect.00098063600
      PlpPLPRnUpIndirect.1374482; 75039830
      PparaPPAR-αMmUpNo good d/t data; probably indirect.00105098050
      PpargPPAR-γMmUpNo good d/t data; probably indirect.00105098050
      PthlhPTHrPMmUpProbably indirect.92800590
      Ranbp1Htf 9-a/RanBP1MmRAR.RXR binding to a DR1 in some cell types; the site is required for maximal transcription; no other information about RA regulation.00094171080
      RB1RbHsVrsrrrNo good d/t data; probably indirect.0001511698; 8502481; 78899810
      Rbbp7ssspRbAp46RnUpDose and time unclear, but protein synthesis required; probably indirect.106672250
      Rex2Rex-2MmDnSuppressed late in differentiationttt; evidence from receptor knockouts; probably indirect.00098063600
      Rex3Rex-3MmDnSuppressed late in differentiationuuu; evidence from receptor knockouts; probably indirect.00098063600
      Rsdr1vvvRDH, retSDR1RnUpNo good d/t data; probably indirect (protein synthesis).111810720
      RxrgRXR γMm, Rn, Hs, GgUpMany studies find no RA regulation; no good d/t data; other NRs; binding motif (prefers RXR.RXR); induction blocked by cyclohexamide; probably indirect.8269997; 8294402; 0009006910; 90757140
      SarawwwSar1aRnUpDose and time unclear but protein synthesis is required; probably indirect.106672250
      SatSSATSs, Bt, RnUpNo good d/t data; probably indirect (protein synthesis).9780334; 9831819; 111810720
      Serpinh1J6 serpinMmUpPromoter region responsible for RA effect identified; indirect (probably through GATA-4).0002981185; 0002842348; 0001639782; 77179740
      Shmt1xxxshmtMmDnIndirect; post-transcriptional.88637320
      SLASLAPHsUpProbably indirect.0009020066; 111796920
      SLC27A1FATPHs, RnUpProbably indirect; specific ligands.00107775520
      Slc2a3GLUT 3MmDnyyyDecreased during differentiation; no good d/t data; probably indirect.00098063600
      SLC9A1Na+/H+ antiporterHs, MmUpNo good d/t data; induced during differentiation; probably indirect.1315322; 8388633; 7737975; 111684010
      Slc9a2NHE-2RnMotif; no other evidence.00098049790
      Sod1Cu/Zn superoxide dismutaseSs, Hs, MmDnThe decrease during differentiation is probably indirect (Hoxa-1); other studies have reported no change in SOD activity.2151307; 8389401; 109425990
      TERThTERTHsDnNo good d/t data; late suppression during differentiation; some differentiation controls; probably indirect.8709642; 10613358; 107866710
      THYb10zzzThymosin β 10Rn, Hs, MmUpProbably indirect.1846397; 0002059565; 0001315216; 89259150
      TIMP1aaaaTimp-1HsUpNo good d/t data; probably indirect (protein synthesis).0002824558; 1661164; 9664142; 108668180
      TNFRSF6CD95, FasHsUpNo good d/t data; some differentiation controls; specific retinoids; probably indirect.0009792441; 10733098; 111038250
      Tnfsf6FasL, CD95 ligandMm, HsDnNo good d/t data for RA; specific ligands; other NRs; probably indirect (NUR77).0007565709; 0009792441; 114650950
      Trhpreprothyrotropin-
 releasing hormoneMmDnIndirect.00105371250
      Trp53p53Mm, HsvrsRegulated during differentiation (or other phenotypic change); specific ligands; probably indirect, several mechanisms discussed.6287239; 2414665; 8484778; 7930673; 10327056; 11420666; 115264430
      Vcam1VCAM-1Mm, Hs, RnUpNo good d/t data; probably indirect (protein synthesis).7533155; 9022083; 111810720
      VEGFVEGF/VPFRn, Hs, CpDnRapid inhibition; specific ligands; AP-1 sites identified; probably indirect.8200985; 9804359; 0010617662; 109645850
      VIPVIPHsUpSlow increase during differentiation but some controls have been done; increase is prior to morphological change; probably indirect.0001319016; 0007925107; 00092859320
      Zfp42Rex-1MmDnNo good d/t data; differentiation associated; probably indirect.0002511439; 0008474450; 00095287580
      c Called 17-β-HSD-II in PMID 0008013376.
      d The Hs symbol and name is POU1F1: POU domain, class 1, transcription factor 1 (Pit1, growth hormone factor 1).
      e It is not yet clear exactly what the active binding site(s) are. Orthologous control regions are definitely involved and there appears to be some degree of conservation in Mm and Rn.
      f Rn promoter in Hs cells.
      g See PMID 0010194513 for a brief review of RA and ApoA1.
      h The sequence appears to come from chromosome 7 but may contain a large Line1 repeat.
      i Figure 2B in PMID 0001700780 appears to show a data point which would satisfy our dose and time criteria. However, it is not discussed in the text.
      j This is the Hs name. There is a 94% aa identity to rabbit OC2 according to OMIN.
      k There has been some controversy about the metabolic products of the the gene(s) in different spp; also, Cyp26 may not be RA-inducible in some cells that nevertheless metabolize RA.
      l It is not clear whether Stra7 and Gbx2 are different genes. The GB entries are virtually identical where they overlap. The Stra7 clone is effectively included in the Gbx-2 Ref Seq.
      m The allelic variant GGTP1*C used in some studies is thought not to effect the generality of the RA work.
      n Site from 2nd intron and flanking exon more or less conserved in Hs, Rn, Ma, Oc, Cf, Ss, Gg, and cats.
      o Mm symbol and name.
      p This assumes the Ggal gene RIHB (NCBI GI 434357) is orthologous to Mm Mdk.
      q Interim Hs name; no Rn assignment.
      r Rn data mentioned but not shown.
      s The ability of RA to counteract estrogen through the OTX ERE is discussed in PMID 0001655807, and the ERE was used as a “negative RARE” in combination with transfected RARa, JUN, and ER.
      t The figure demonstrating this is not easy to interpret.
      u Rn promoter and exogenous RAR/RXR in Hs cells.
      v Interim symbol and name.
      w Earlier papers that do not distinguish enzyme forms are not considered here.
      x Interim symbol and name.
      y Interim symbol and name.
      z Mm symbol and name.
      aa Name by analogy to mammalian crystallins.
      bb We assume DDX1 is the gene in question; there are other DEAD box proteins, of course, but the paper does not clearly distinguish them.
      cc Interim symbol and name.
      dd To us, the figure showing rapid induction is unconvincing; no dose is given, either.
      ee It is not clear what has happened between times 0 and 24 hours in Figure 2b of PMID 0010674883.
      ff It is not clear what has happened between times 0 and 24 hours in Figure 2b of PMID 0010674883.
      gg F3 is frequently studied in APL cells because it is thought to be involved in the pathology of the disease. Some of the work cited here is in APL lines.
      hh Interim symbol and name.
      ii Probably Ins2 in Rn.
      jj KRT6A seems to be the predominantly expressed K6 gene in Hs; the paper cited for Bt (in whom there are 3 K6 genes) is concerned with K6b; the motifs in PMID 0009326392 BLAST identically (and with the same single mismatch) to the provisional refseqs for both Hs K6 genes, KRT6A and KRT6b; the Hs AP-1 work is on K6b.
      kk Most investigations so far have dealt with Erk activation, not message induction.
      ll Interim symbol and name.
      mm The gene studied now appears to be the ortholog of Msx2, not Msx1 (as thought at the time).
      nn Mm symbol and name.
      oo Interim symbol and name.
      pp Induced in 3-dimensional systems but not in 2-dimensional cultures of keratinocytes and fibroblasts.
      qq The effects of 9-cis, which are not covered here, have also been investigated. Cf. PMID 10403834 and PMID 0009717711 for example.
      rr Interim Hs symbol and name.
      ss SPRR1A, SPRR2, and SPRR3 are covered in some of these papers; the RA situation is basically the same.
      tt Probable name, see PMID 11416019.
      uu Hs DNA in Rn cells.
      vv Suppression at 8 hours (100 nM) is discussed in PMID 10502285, but Figure 1B suggests it is significant by 4 h.
      ww Both TOP2A and TOP2B have been studied, but most of the RA work has concentrated on 2A.
      xx The statistical significance of a slight decrease at 6 h in PMID 11146166 is not clear.
      yy An RARE half site seems to be marked in a GenBank entry but neither the site nor RA is mentioned in the associated paper.
      zz No official name or symbol; no curated orthologs.
      aaa Aggrecanase-1 is an alias for ADAMTS4; some of the papers listed here cover ADAMTS5 (aggrecanse-2) as well. MMP3 and MMP13 (q.v.) may also be involved.
      bbb Probable Mm ortholog; no Rn assignment.
      ccc High consentrations of retinoic acid inhibit BGLAP induction by vitamin D, but a well-characterized AP-1 response element is contained in the VDRE. Some experiments found neither induction nor suppression by RA alone.
      ddd There is no evidence that RA has different effects on the expression of the splicing alternates, calcitonin and calcitonin gene related peptide (CGRP).
      eee Several studies have also been done in Rn and Hs using 9-cis. No good d/t data there, either.
      fff Rn sequences in HepG2 cells; no RA regulation seen in hamster.
      ggg Interim symbol and name.
      hhh An altered transcription rate could not be shown in nuclear run-on experiments (although controls worked as expected); this was attributed to the highly stable mRNA.
      iii Symbol and name pending.
      jjj Interim symbol and name.
      kkk Mm symbol and name.
      lll Interim symbol and name.
      continued
      Gene Table—Continued
      mmm Very long exposure may induce expression in some systems.
      nnn Promoter constructs from Hs used in Rn cells.
      ooo Mm symbol and name.
      ppp The older articles study enzyme activity without distinguishing OAS1, -2, and -3.
      qqq An altered transcription rate could not be shown in nuclear run-on experiments (although controls worked as expected); this was attributed to the highly stable mRNA.
      rrr Many studies have looked at mechanisms by which RA influences RB phosphorylation. They are not included here.
      sss Interim symbol and name.
      ttt An altered transcription rate could not be shown in nuclear run-on experiments (although controls worked as expected); this was attributed to the highly stable mRNA.
      uuu An altered transcription rate could not be shown in nuclear run-on experiments (although controls worked as expected); this was attributed to the highly stable mRNA.
      vvv Interim Mm symbol and name.
      www Probable Mm ortholog; no Rn assignment.
      xxx It is not clear whether the repressed gene was Shmt1 or Shmt2.
      yyy An altered transcription rate could not be shown in nuclear run-on experiments (although controls worked as expected); this was attributed to the highly stable mRNA.
      zzz Interim symbol and name.
      aaaa Studies do not necessarily distinguish members of the TIMP family.

       The species designations column

      The third column of the Gene Table lists the “species” studied in the papers cited. Although we made no systematic attempt to classify animals below the genus level, most of the designations are accurate. The following abbreviations are used: Bt, Bos taurus (cattle); Cf, Canis familiaris (dogs); Cj, Coturnix japonica (quails); Cp, Cavia porcellus (guinea pigs); Dm, Drosophila melanogaster (fruit flies); Dr, Danio rerio (zebrafish); Gc, Geodia cydonium (Geodia sponges); Gg, Gallus gallus (chickens); Hs, Homo sapiens (people); Ma, Mesocricetus auratus (hamsters); Mf, Macaca fascicularis (macaques); Mm, Mus musculus (mice); Oc, Oryctolagus cuniculus (rabbits); Rn, Rattus norvegicus (rats); Ss, Sus scrofa (pigs); Tr, Takifugu rubripes; (puffer fish); Xl, Xenopus laevis (frogs).

       The regulatory directions column

      For each gene, we have noted the predominant regulatory direction attributed to RA, up or down. This can be problematic in situations where, intuitively, RA can effect opposite actions in different cellular contexts: up during differentiation, for example, and down during growth inhibition. Again, we concentrated on what was most frequently reported. Genes are marked ‘vrs’ (various) when there is no obvious predominant direction. For all such genes, it should be clear from our comments whether the category rating is based on a single regulatory direction or on the data taken as a whole. For example, there are several clear demonstrations that the rapid down-regulation of Myc is indirect in the cell types in which this has been investigated. This seems likely to apply whenever Myc is down-regulated. Its rapid up-regulation in other contexts, however, has not convincingly been shown to be indirect anywhere. Myc‘s Category 2 rating therefore refers to its rapid up-regulation following a moderate dose of RA in certain situations. The comments column should make this clear. Everything in the table is based on currently available data, of course, and as additional contexts are studied, more cell types, different developmental stages, unusual environmental situations, and so forth, the picture will only get more complex.

       Stock phrases used in the summary column

      Every phrase in the Gene Table and every category rating should be read with the implicit qualification, “in the cell types or at the developmental stages studied.” Even the paradigm of classical RA regulation, RARβ, is not under RA control at all times or in all cell types. To keep the table as concise as possible, and to make comparisons easier, we used the following stock phrases when applicable: 1) “No good d/t data” means we found no experiments using dose and time conditions within our limits for suggestive data. The phrase does not impugn the work referred to but was chosen for its brevity. In particular, minute-by-minute observations using physiological doses of ligand are only rarely relevant in clinical research or developmental work. In fact, pharmacological doses may be the only effective therapies in certain clinical situations and teratological doses have been indispensable in some truly seminal developmental studies. In ordinary circumstances, however, it is generally assumed that direct transcriptional modulation is rapid and that it can be initiated with a physiologically moderate dose of ligand. Ideally, unless there is a transport problem, one would like to see experiments using nanomolar concentrations of RA and making observations within minutes. However, the number of experiments conforming to these standards is very small, so we set 1 μM × 6 h as the upper limit for “suggestive” data. This was a necessary compromise given the range of scientific questions addressed in the papers consulted. 2) “Specific ligands” refers to either receptor-selective ligands or ligands that do not have the full complement of biological effects associated with all-trans retinoic acid (for example, ligands that help sort out AP-1 events). 3) The phrase “functional binding site” implies that a whole range of thoughtfully-designed tests has been performed, and that a more or less recognizable response element has been identified. The phrase is distinguished from such other notations as “functional motifs” (for which no dimer binding or native transcriptional verification has been made), “binding sites” (from which heterologous promoters can be driven), “motifs” (which are supported by sequence analysis only), and so forth. The phrase “no motif found” says that a promoter or other presumed control region was inspected in at least one of the papers cited, but that no candidate motif was found. 4) “Other NRs” indicates that other nuclear receptors are known to be involved in the gene's regulation in some cells. The importance of noting this stems from the cross-talk that can occur between nuclear receptors, and from the similarity of nuclear receptor binding sites (which can be confounding when extreme dose conditions are used). 5) “During differentiation” (or a similar phrase) indicates that the gene has only been studied during differentiation, growth control, proliferation control, cell cycle arrest, apoptosis, wound healing, hypertrophy, or any of the other wholesale cellular or phenotypic changes RA can effect. We did not always include such an annotation. 6) “ … not for RA … ” or “ … not for RA alone … ” means that the referenced experiments, or parts of them, have been done with ligands other than all-trans RA, usually 9-cis or a synthetic, or with RA plus an additional factor. 7) “d/t borderline” signals that while at least some data fall within our dose/time limits, they are right on the borderline. This is meant to draw attention to the compromise inherent in the limits imposed for “suggestive” data. 8) “Probably indirect” is more specific than it sounds. It indicates that a transcriptional intermediary, as opposed to another indirect mechanism, is most likely involved: RA regulates X and X regulates Y. The particular intermediary is noted in some cases.

       The citations column

      We have attempted to evaluate RA's role in the control of 532 genes and could not possibly cite every relevant paper. Each paper we do cite makes a point directly connected to the Gene Table: a first assertion of RA control, a regulatory direction, a time or dose curve, a binding site, a species, or something else. In addition, we have cited a (very) few papers of particular historical importance even though the research described may have preceded the experimental techniques or genetic models that underpin today's RA work. To save space, we have used PubMed Unique Identifiers (PMIDs) rather than traditional citations.
      PMIDs are the unique record numbers assigned to journal articles at the National Library of Medicine. They can be used in PubMed, National Library of Medicine Gateway, and other National Institutes of Health databases to retrieve citations, abstracts, cross-links to GenBank sequences or other sequence-based information, external links to full-text articles where available, and so forth. Unmodified identifiers are valid queries, type or paste the number(s) into the Search Box, at all appropriate National Library of Medicine front ends, but in complex queries or in other databases the tag “[PMID]” may be required.

       The category ratings column

      The ratings reflect overall assessments. Experimental evidence varies from gene to gene and there is no algorithm that can assign a category automatically. Investigators use different techniques and have different scientific questions in mind; the quality of figures varies, and the threshold of “proof” varies from lab to lab. For each gene then, the rating expresses our overall reading of the evidentiary situation based on all the work considered. Again, not all of the studies were designed to investigate mechanisms, so we are imposing extrinsic considerations in some cases.

       Category 0.

      There is no particular reason to believe that this gene is directly regulated through the classical RA pathway.

       Case 1

      Indirect regulation has been demonstrated in a context that seems likely to apply generally and no other data suggest that direct regulation is likely in other contexts. Indirect regulation can include the existence of RA-regulated transcriptional intermediaries, non-transcriptional or post-transcriptional effects, and so forth.

       Case 2

      Hexamer motifs have been found in a location that might represent a regulatory unit, but no other evidence of RA involvement has been offered in any paper we know of.

       Case 3

      An historical correction has been made and the gene is no longer thought to be under RA control.

       Category 1.

      There is solid evidence that the gene is controlled by RA and no indirect mechanism has been demonstrated experimentally. At the same time, the available data do not justify a prediction, or even suggest which way a prediction should go: direct or indirect regulation.

       Case 1

      Induction or suppression has been shown, but the dose and/or time conditions exceed our limits for “suggestive” data.

       Case 2

      Physiological, clinical, or dietary information (or evidence from transgenics, knock-ins, or knockouts) strongly implicates RA, but there is no particular reason to posit direct regulation through the classical RA pathway.

       Case 3

      mRNA studies are lacking but protein studies or other evidence suggests that further work should be done.

       Category 2.

      The gene is a strong candidate for direct regulation, but specific data are lacking.

       Case 1

      Transcriptional effects have been demonstrated under suggestive dose and time conditions but i) no binding site connection has been made, or ii) the involvement of an RAR.RXR dimer is not clear.

       Case 2

      There is highly promising binding site information plus basic inductive or suppressive data.

       Category 3.

      A persuasive case has been made, or can be made based on currently available data, that the gene is directly regulated by RA in at least one genetically “normal” cell type.

       Requirement 1

      Transcription-based induction or suppression (within the limits of 1 μM or less × 6 h or less) has been confirmed in some reasonably general context.

       Requirement 2

      Evidence of RAR.RXR involvement has been produced or strongly implied.

       Requirement 3

      A functional binding site, preferably conserved, has been found and tested in a broad panel of experiments.

      RESULTS AND DISCUSSION

       The number of genes per category

      We have evaluated published data pertaining to RA's regulation of 532 genes and have summarized the data in the Gene Table. Based on current research, 27 of these genes are unquestionably controlled through the classical RA pathway in some cellular context(s). Genes falling into this category were subjected to a high level of scrutiny in order to ensure, as far as possible, that they would never have to be removed, although indirect mechanisms may be used in other contexts as well. They are marked as Category 3 genes. Another 105 genes are in Category 2. They can be modulated at the transcriptional level in less than 6 h following an administration of 1 μM RA or less, but other indicators of direct regulation have not yet been explored. In most cases, the data still lacking relate to response elements or RAR.RXR involvement.
      Category 0 encompasses two cases. First, there are 124 genes that seem to be regulated indirectly in the contexts studied. We are aware of no data or arguments suggesting that these genes might be directly regulated through the classical RA pathway in other cellular contexts. Nine other genes (Adh1, BTK, FSCN2, Htf9c, IBSP, Itgb7, Lpl, Ranbp1, and Slc9a2) were also put into Category 0. They are discussed in the literature, but there is no strong reason to believe that they are regulated by RA at the transcriptional level. In two cases, Adh1 and Lpl, suspected or predicted mRNA changes were not confirmed, and while most of the others contain motifs resembling RA response elements, there is no evidence suggesting that these motifs, which can be highly ambiguous in the best of circumstances, represent biologically active retinoic acid response elements.
      The remaining 267 genes, slightly more than half of those we evaluated, fall into Category 1. They are regulated by RA in some way, but the data available at present do not allow us to predict direct versus indirect control. Most have not yet been studied except in long-term or high-dose contexts, and for many, the ultimate interest has been clinical, developmental, or diagnostic rather than mechanistic. Additional work will need to be done to push these genes into more informative categories.
      In fact, future research may change the classification status of any gene in the table. The method used to select Category 3 genes was designed to be sufficiently rigorous that no gene would easily be struck from the group, but there is no reason why any one of them might not be regulated indirectly in other contexts as well. Beyond that, we expect future research to find that many of the Category 2 genes are direct targets, and that some of the Category 1 genes are as well. In fact, some of the Category 0 genes may turn out to be direct targets too, but in contexts that have not yet been studied.

       Regulatory direction

      In terms of regulatory direction, 311 genes are always or almost always up-regulated in the contexts studied, 109 are always or almost always down-regulated, and the rest are quite variable. Most investigators now believe that direct regulation through the classical RA pathway is always inductive, although there is no theoretical reason why this should be so (and it is not true of some other transcription factors). Nevertheless, all the Category 3 genes are up-regulated and only three of the Category 2 genes are usually down-regulated. One Category 3 gene, Hoxb1, is marked “various” because it can be directly up-regulated in some contexts, but down-regulated, probably indirectly, in others. Given that many transcriptional events seem to be regulated cyclically, a “various” regulatory direction should probably be much more common than the data imply; most likely this is due to a lack of measurements taken along a fine enough time continuum. Table 2 summarizes category and direction data for the 532 genes. (The reader is reminded that gene expression in the presence of RA is the topic here. The repression of basal transcription by RAR.RXR in the absence of RA is an entirely different matter.)
      TABLE 2Category and direction summary
      Category/Regulatory Direction0123Total
      Up631309226311
      Down40663109
      Variable2171101103
      NA99
      Total13326710527532
      Genes regulated by retinoic acid, predominant regulatory direction versus gene ratings (see text). NA, direction not determined in the literature or no mRNA regulation found.

       The types of genes regulated

      Not surprisingly, the set of genes currently known to be regulated directly through the classical RA pathway does not form a unified or predictable group, either in function or in sequence. (For the record, the human versions of these 27 genes are spread over 13 autosomal chromosomes.) However, two subsets deserve special mention: i) genes that are somehow related to the handling, metabolism, function, or presumed evolutionary history of the retinoids, and ii) genes containing homeobox domains. Using symbols from the Gene Table, the first group includes RARA, RARB, RARG, Rbp1, and CRABP2, together with several more tenuous members: ADH1C (which can metabolize retinol), CRYAB (which is loosely related to photoreception), and Drd2 (which contains a rhodopsin family, 7 transmembrane receptor domain). The other subset, genes that contain homeobox domains, consists of Hoxa1, HOXA4, Hoxb1, Hoxb4, Hoxd4, Cdx1, and Pit1.
      Although no regulatory or evolutionary theory formally justifies it so far, it is tempting to see a certain logic in several other genes directly regulated by RA: HSD17B1 is involved in the function of other nuclear receptors; H1F0 is activated at differentiation and points of development; one of SFTPB's functions is developmental; IL2RA is involved in apoptosis; Ucp1 is expressed only in brown adipose tissue (and is therefore connected to dietary lipids); ETS1 ultimately derives from the E26 virus (and a number of viral control regions contain sequences that can respond to RA); Foxa1 and Egr1 are expressed early in differentiation. The other Category 3 genes are CD38 (which was originally identified as a differentiation antigen), Tgm2, and Pck1.
      We found 105 Category 2 genes that can be more or less rapidly up- or down-regulated at the transcriptional level in the presence of RA. Some of these genes are probably regulated directly. It would be surprising if there were a common thread among them, and there is not. They encode proteins of almost every imaginable type.
      However, several domain architectures turn up a number of times among the Category 2 and 3 genes and should probably be mentioned. Taking the 132 genes in these two categories together, 11 contain homeobox domains (Cdx1, GBX2, Hoxa1, HOXA4, Hoxb1, Hoxb4, Hoxd4, LHX1, Meis1, NCX, and Pit1) and six encode zinc finger proteins (NR2C2, NR4A3, RARA, RARB, RARG, and Egr1). Of those six, five are nuclear receptors with both c4 zinc finger domains and nuclear receptor ligand-binding domains. Five of the genes in the two categories are from the lipocalin/cytosolic fatty-acid binding protein family (APOD, Crabp1, CRABP2, Rbp1, and RBP4); and five contain tyrosine kinase catalytic, or eukaryotic protein kinase, domains (CSF1R, EGFR, LYN, Tgfbr1, and Tgfbr2). Three of the genes encode helix-loop-helix DNA-binding domain sequences (MYC, MYCN, and Srebf1); three encode short chain dehydrogenases (HSD17B1, HSD17B2, and RDHL); and three contain TGF-β propeptide domains (Ebaf, Gdf5, and Tgfb3).

       State of the science

      Intuitively, the number of Category 3 genes found in this work is surprisingly small, given the conservation of three RAR genes plus a triad of RXRs and multiple isoforms of all. The largest cohesive group of Category 2 or 3 genes consists of those somehow connected to the retinoids or nuclear receptors, the “infrastructure” of the regulatory system itself. And while evolution may not be particularly parsimonious, one suspects that the machinery of the classical RA pathway with all its complexities and autoregulatory loops has been conserved, not to regulate itself, but because it is uniquely useful in controlling, directly or indirectly, a particular range of genetic events in various cells and at different times of life. This suggests that the group of Category 3 genes will grow as new data become available on genes already in the table, and as new targets are discovered. There is circumstantial evidence for this, too. Since at least the mid-1980s, subtraction or differential-display experiments using RA have been turning up “novel” genes and there is no sign that this is slowing down. Many of these genes have not been investigated beyond the original paper mentioning them, and most are probably cases of indirect regulation. Nevertheless, this adds an exciting dimension to the RA field and points to quite a few experiments waiting to be done.
      In works that deal with a large number of genes, it has become customary to summarize functions, family memberships, and other quiddities, “ontologies” as they are now called in a puzzling use of the word. This is done as a first step in finding underlying biological regularities, and we have done it for that reason in this paper. However, its significance should not be overplayed. Duplications of whole genes, coding plus regulatory and non-coding regions, do not endure evolutionary time unchanged, and it is by now perfectly clear that non-coding regions are far more labile than coding regions. While some progress has been made in identifying regulatory elements analytically, see (
      • Stojanovic N.
      • Florea L.
      • Riemer C.
      • Gumucio D.
      • Slightom J.
      • Goodman M.
      • Miller W.
      • Hardison R.
      Comparison of five methods for finding conserved sequences in multiple alignments of gene regulatory regions.
      ) or (
      • Hardison R.C.
      Conserved noncoding sequences are reliable guides to regulatory elements.
      ), for example, intervening sequences seem to be highly variable. Indeed, the evolutionary comings and goings of regulatory signals remain almost completely mysterious, and RA response elements, which are almost always found in traditional promoters or extended, multi-function enhancers, are short, degenerate, ambiguous signals ripe for evolutionary experimentation. One would therefore expect only coincidental functional or formal resemblances among the complete set of genes controlled by RA. What this tells us is that many interesting and surprising results remain to be found: genes whose regulation by retinoic acid is not a priori predictable.
      Over the last quarter century, a substantial body of knowledge has been built up concerning gene expression regulation by RA. That work has contributed significantly to our understanding of context-regulated transcription, vertebrate development, and a host of important clinical issues. From the particular perspective of this paper, much of the work we consulted was tantalizingly close to helping answer the direct-versus-indirect question even though it was not originally designed to address that question at all. In other cases, elucidating a molecular pathway was a primary research goal and a clear answer was determined; and in a few cases, intriguing scientific issues have turned up when regulatory mechanisms do not seem to be as clear-cut as originally expected, as with LAMB1 (
      • Wang S.Y.
      • LaRosa G.J.
      • Gudas L.J.
      Molecular cloning of gene sequences transcriptionally regulated by retinoic acid and dibutyryl cyclic AMP in cultured mouse teratocarcinoma cells.
      ,
      • Wang S.Y.
      • Gudas L.J.
      Protein synthesis inhibitors prevent the induction of laminin B1, collagen IV (alpha 1), and other differentiation-specific mRNAs by retinoic acid in F9 teratocarcinoma cells.
      ,
      • Vasios G.W.
      • Gold J.D.
      • Petkovich M.
      • Chambon P.
      • Gudas L.J.
      A retinoic acid-responsive element is present in the 5′ flanking region of the laminin B1 gene.
      ,
      • Vasios G.
      • Mader S.
      • Gold J.D.
      • Leid M.
      • Lutz Y.
      • Gaub M.P.
      • Chambon P.
      • Gudas L.
      The late retinoic acid induction of laminin B1 gene transcription involves RAR binding to the responsive element.
      ,
      • Sharif K.A.
      • Li C.
      • Gudas L.J.
      cis-acting DNA regulatory elements, including the retinoic acid response element, are required for tissue specific laminin B1 promoter/lacZ expression in transgenic mice.
      ). Of course, many RA studies seek clinical or nutritional information, and the poignant need for such studies is beyond question; yet in the larger scheme, knowing which regulatory events are direct and which are indirect can perhaps lead to superior pharmacological and nutritional protocols as well as to progress in basic science.

      Endnote

      For many of the genes considered in this paper, there are entire labs with years of expertise and a broader interest than the gene's potential regulation by RA. People from these labs may see connections or alternatives that were not obvious to us. Similarly, the number of papers potentially relevant to a work of this sort is huge, and we were repeatedly reminded that neither titles nor abstracts need hint at all the results reported. Finally, while MeSH indexing and MEDLINE coding are invaluable tools and basic to virtually every biomedical research project now carried out, they are just as fallible as bench work. For all of these reasons, it would be surprising if we had not missed important ideas or papers.
      We think of this paper as a working document and hope that our errors and oversights will generously be pointed out by our colleagues so that the table can be updated, improved, and maintained, by us or by another group, as an evolving assessment of RA's genetic workings.

      Acknowledgments

      This work was supported by the Norwegian Cancer Society, the Research Council of Norway, and the Throne Holst Foundation.

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