Virtual Issue: Lipids in transcription and chromatin biology

Assembled by Ray Blind

Ever since chromatin was first purified in the middle of the 20th century, this nuclear fraction has been found associated with lipids.

Although early biochemical studies suggested lipids associated with chromatin and other sub-nuclear fractions, it was not impossible those results were trivial biochemical artifacts reflecting the "stickiness" of hydrophobic lipids. Later studies examining lipid association with nuclear compartments toward the end of the 20th century, however, took advantage of ectopic nuclear localization of lipid metabolic enzymes, novel immunofluorescent reagents and the discovery of complete lipid signaling pathways within the nucleus. These studies added significant confidence to the initial observations that lipids were structurally and functionally associated with chromatin and the intranuclear compartment. Subsequent X-ray crystallographic analyses of specific transcription factors bound in one-to-one stoichiometry with specific signaling phospholipids unequivocally defined direct, important roles for lipids in the regulation of transcription, revealing how lipids can exist in the nucleoplasm bound-up by nuclear proteins. It is now well established that phospholipids, sterols and fatty acids directly participate in non-membrane nuclear events, such as transcription, RNA-processing and nuclear export of mRNAs.

JLR cover

Raymond Blind is an assistant professor at Vanderbilt University School of Medicine. His lab studies the structure, function and signaling properties of nuclear phosphoinositide lipids and soluble inositol phosphates.

The Journal of Lipid Research has published many studies over the years that expand our understanding of the function of lipids in control of nuclear events even further. We now have evidence that lipids actively participate in epigenetic reprogramming, chromatin modifications and nucleosome structure, in addition to the more well-established roles in splicing, RNA export and transcriptional regulation. This virtual issue highlights some of the most recent JLR papers in these areas.

Nuclear phospholipids: Although many lipid-signaling enzymes are known to shuttle into the nuclear compartment, nuclear phosphoinositide-specific phospholipase C (Ratti, et al) has been implicated broadly in many human disease states, as recently reviewed in a JLR thematic series. However, what has remained far less clear is how the lipid substrates of phospholipases and other lipid signaling enzymes might participate in nuclear processes. Recently, researchers coupled endonuclear lipidomic mass spectrometry (Tribble, et al) with a rigorous biochemical purification of membrane-free nuclei to not only determine that the lipid content of the endonuclear compartment is different than that of other cellular compartments, but also that soluble nuclear proteins have the capacity to stoichiometrically "soak up" the entire glycerophospholipid content within the nuclear matrix, consistent with a regulatory role for intranuclear non-membrane phospholipids. Another recent study of cholesterol in chromatin provided evidence that cholesterol may alter histone interaction with DNA (Silva, et al), perturb chromatin fiber formation and increase chromatin compaction in vitro. Molecular dynamics simulations identified potential cholesterol docking sites in the nucleosome core particle, opening the door for genetic testing of this intriguing model. Together, these studies highlight the potential for endonuclear lipids to regulate genomic events.

Histone control of lipid biology:  All-trans retinoic acid (ATRA) activates the gene encoding neutral sphingomyelinase-2 (nSMase2), phenocopying histone deacetylase (HDAC) inhibitor-mediated activation of this same locus. Further evidence supporting a histone-acetylation mediated mechanism (Clarke, et al) of nSMase2 activation is suggested by the requirement of histone-acetyltransferases to elicit full response to ATRA. Thus, it appears likely that ATRA elicits an epigenetic change to the nSMase2 locus, resulting in altered transcription. HDACs, however, do not always repress gene expression.  HDAC inhibitors were shown to attenuate expression (Fork, et al) of the gene encoding the key prostaglandin synthesis enzyme microsomal prostaglandin E2 synthase-1 (PTGES1), suggesting an activating role for HDACs. Genomic ChIP-seq analyses revealed HDACs help recruit the histone acetyltransferase p300 to the PTGES1 locus, resulting in activated transcription. HDAC5 was recently shown to mediate liver transcriptional responses to fasting glucagon, through a mechanism whereby HDAC5 trans-activates PPARa. The HDAC5-mediated PPARa responses (Qiu, et al) improved liver lipid homeostasis, while loss of HDAC5 promoted fatty liver, suggesting HDAC5 is an important new player in controlling fatty acid oxidation in the liver. Thus, HDACs and histone modifications actively participate in regulating genes important for lipid biology.

Epigenetic responses to lipids: Epigenetics often refers simply to chromatin modifications, but it also can be defined as heritable, non-sequence based changes to the genome, which allow environmental perturbations in the parental generation to alter genomic expression patterns of offspring. Prenatal high-fat diet (HFD) alters metabolism in the offspring of mice, but the mechanisms driving that prenatal response are not fully understood. A recent study showed prenatal HFD leads to hypermethylation of the lipin-1 gene locus (Rouschop, et al) altering expression of that important lipid metabolic gene. It will be interesting to determine the degree to which this hypermethylation phenotype is heritable to the next generation in this model.  Also, an epigenomewide association study (Lai, et al) showed increased methylation of five genomic loci associated with lipid-metabolic-enzyme–encoding genes correlates with increased triglyceride postprandial lipemia response, suggesting epigenetic gene modifications contribute to lipid physiological responses. Another study showed the a-ketoglutarate-dependent dioxygenase (Fto) gene controls adipocyte differentiation, in part by promoting demethylation of the promoter region (Martin Carli, et al) of the gene encoding the Cebpd bZIP transcription factor, again suggesting lipid metabolism imparts epigenetic changes to specific loci within the genome. Polymorphisms in the human fatty acid desaturase (Hang Su, et al) gene alter expression of FADS in response to diets with differing levels of poly-unsaturated fatty acids (PUFA), while another study showed polymorphisms in the CD36 gene associate with methylation of the CD36 locus (Love-Gregory, et al), revealing a new way epigenetic changes to a locus can participate in the regulation of lipid metabolism. Together, these insights suggest lipids can have important functions in regulating epigenetic changes to chromatin.

Unique lipid-based mechanisms: Newly discovered aspects of RNA biology have been shown to influence lipid biology, particularly in the liver. A recent genome-wide RNA profiling study identified and characterized the long-noncoding RNAs (lncRNAs) differentially expressed in the liver upon high-fat diet (Qian Chen, et al) challenge in mice.  Some classical transcriptional mediators of lipid responses can also have effects on cytoplasmic membranes, highlighted by a recent study that identified a variant of the transcription factor and nuclear receptor ERa (Maczis, et al) that acts through rapid, nongenomic membrane signaling, inducing secretion of sphingosine 1-phosphate (S1P) and dihydro-S1P from breast cancer cells. These functions of lipids highlight just a few of the diverse mechanisms lipids can use to elicit important changes to cell physiology.

Genome-wide association studies: Genome-wide association studies (GWAS) have reshaped our understanding of lipid action in patients. Fenofibrates have been used widely as lipid-lowering drugs, but how polymorphisms in patients receiving this therapy might influence clinical response had not been evaluated.  A recent study used exome-wide sequencing association (Xin Geng, et al) to identify several rare coding variants in lipid metabolic genes that significantly associate with the low-density lipoprotein cholesterol clinical response to fenofibrate therapy. This study highlights the power of genome-wide association to identify new precision-medicine targets for the treatment of metabolic disorders, predicting which patients are most likely to respond favorably to a drug and which are not.

The Journal of Lipid Research welcomes cutting-edge research of lipid function in chromatin and the nucleus. These new functions in epigenetics, nucleosome biology and histone identity inform our understanding of human disease, the first steps needed for precision medicine to tailor specific therapies to each patient.  More broadly, these insights also permit development of new therapies based on basic science discoveries published in JLR.

Cover Image

The cover art, by Luciana Giono, is an abstract representation of nuclear lipids participating in the regulation of transcription and chromatin biology.

Featured research and reviews

Nuclear phospholipase C isoenzyme imbalance leads to pathologies in brain, hematologic, neuromuscular, and fertility disorders

Stefano Ratti, Matilde Y. Follo, Giulia Ramazzotti, Irene Faenza, Roberta Fiume, Pann-Ghill Suh, James A. McCubrey, Lucia Manzoli, Lucio Cocco
First published on October 4, 2018

Matilde Y. Follo

Matilde Y. Follo is an associate professor the University of Bologna in Italy. Her research is focused on the translational relevance of nuclear inositide-dependent signaling pathways in hematopoiesis, namely in myelodysplastic syndromes and acute myeloid leukemia.

Biophysical studies of cholesterol effects on chromatin

Isabel T. G. Silva, Vinícius Fernandes, Caio Souza, Werner Treptow, Guilherme M. Santos
First published on March 22, 2017

Vinicius Fernandes

Vinicius Fernandes is a pharmacist, holds a master’s degree in pharmaceutical science, and is a Ph.D. student under the supervision of Guilherme Santos and Werner Treptow at the University of Brasilia in Brazil. He works on computational biophysics applied to structure-function relationship of biological systems, focusing on how nucleosome binding molecules modulate chromatin architecture, and on the understanding of the basic principles of ion channels regulation. In his spare time, he enjoys playing soccer and table tennis.

HDAC5 integrates ER stress and fasting signals to regulate hepatic fatty acid oxidation

Xinchen Qiu, Jian Li, Sihan Lv, Jiamin Yu, Junkun Jiang, Jindong Yao, Yang Xiao, Bingxin Xu, Haiyan He, Fangfei Guo, Zhen-Ning Zhang, Chao Zhang, Bing Luan
First published on December 11, 2017

Xinchen Qiu

Xinchen Qiu earned her master’s degree in biochemistry at Tongji University. Her research is focused on the regulation of hepatic lipid metabolism and its contribution to hepatic steatosis. In her leisure time, she enjoys traveling with her family and friends.

Gene expression and DNA methylation as mechanisms of disturbed metabolism in offspring after exposure to a prenatal HF diet

Sven H. Rouschop, Tanja Karl, Angela Risch, Petronella A. van Ewijk, Vera B. Schrauwen-Hinderling, Antoon Opperhuizen, Frederik J. van Schooten, Roger W. Godschalk
First published on May 7, 2019

Sven Rouschop

Sven Rouschop is a Ph.D. candidate at the Department of Pharmacology and Toxicology at Maastricht University in the Netherlands. Rouschop’s scientific interests include maternal diet during pregnancy and its effect on the offspring’s immune system and metabolism. More specifically, he tries to unravel the epigenetic regulation of these effects. Outside the lab, he enjoys spending time with his family and playing the trumpet.

Epigenome-wide association study of triglyceride postprandial responses to a high-fat dietary challenge

Chao-Qiang Lai, Mary K. Wojczynski, Laurence D. Parnell, Bertha A. Hidalgo, Marguerite Ryan Irvin, Stella Aslibekyan, Michael A. Province, Devin M. Absher, Donna K. Arnett, José M. Ordovás
First published on October 24, 2016

Chao-Qiang Lai

Dr. Chao-Qiang Lai is a USDA ARS Research Molecular Biologist and Geneticist in the Nutrition and Genomics Laboratory at the Jean-Mayer USDA Human Nutrition Research Center on Aging at Tufts University. His research focuses on the relationship between nutrition, genetics, and healthy aging; in particular, epigenomics, metabolomics, gene-by-diet interactions, and risk prediction and prevention of heart and metabolic diseases.

FTO mediates cell-autonomous effects on adipogenesis and adipocyte lipid content by regulating gene expression via 6mA DNA modifications

Jayne F. Martin Carli, Charles A. LeDuc, Yiying Zhang, George Stratigopoulos, Rudolph L. Leibel
First published on June 22, 2018

Jayne Martin Carli

Jayne Martin Carli is a postdoctoral research fellow at the University of Colorado Anschutz Medical Campus in the section of Pediatric Nutrition. She investigates the molecular biology of lactation as it relates to the metabolic health of mothers and their children. Jayne studied the molecular genetics of adipocyte development and function as a graduate student with Rudolph Leibel at Columbia University Medical Center in New York.

Hepatic transcriptome analysis from HFD-fed mice defines a long noncoding RNA regulating cellular cholesterol levels

Qian Chen, Chaoliang Xiong, Kunyun Jia, Jing Jin, Ziyang Li, Yazhou Huang, Yewen Liu, Lingling Wang, Haitao Luo, Haiyan Li, Qing H. Meng, Wei Li
First published on November 30, 2018

Chaoliang Xiong

Chaoliang Xiong is a Ph.D. candidate at Institute of Biophysics, Chinese Academy of Sciences. His postgraduate research in Wei Li’s lab at Wenzhou Medical University focused on the pathogenesis of nonalcoholic fatty liver disease. He is interested in identifying and studying new risk factors related to diseases such as diabetes mellitus and cancer based on sequencing data. In his spare time, he enjoys cooking and hiking.

Sphingosine kinase 1 activation by estrogen receptor a36 contributes to tamoxifen resistance in breast cancer

Melissa A. Maczis, Michael Maceyka, Michael R. Waters, Jason Newton, Manjulata Singh, Madisyn F. Rigsby, Tia H. Turner, J. Chuck Harrell, Sheldon Milstien, Sarah Spiegel
First published on October 12, 2018

Melissa Maczis

Melissa Maczis is a Ph.D. student in the lab of Sarah Spiegel. Maczis is examining the role of sphingosine kinases, the enzymes that phosphorylate sphingosine to the bioactive sphingolipid metabolite sphingosine-1-phosphate in triple negative breast cancer metastasis, and the involvement of the tumor microenvironment in breast cancer.

An exome-wide sequencing study of lipid response to high-fat meal and fenofibrate in Caucasians from the GOLDN cohort

Xin Geng, Marguerite R. Irvin, Bertha Hidalgo, Stella Aslibekyan, Vinodh Srinivasasainagendra, Ping An, Alexis C. Frazier-Wood, Hemant K. Tiwari, Tushar Dave, Kathleen Ryan, Jose M. Ordovas, Robert J. Straka, Mary F. Feitosa, Paul N. Hopkins, Ingrid Borecki, Michael A. Province, Braxton D. Mitchell, Donna K. Arnett, Degui Zhi
First published on February 20, 2018

Xin Geng

Xin Geng completed his postdoctoral training at the niversity of Alabama at Birmingham and at the University of Texas Health Science Center at Houston, mentored by Degui Zhi, Marguerite Ryan Irvin and Donna Arnett. Xin earned his master’s degree in statistics and his doctorate in genetics at Auburn University. He is devoted to studying the molecular mechanisms of human health problems using multiomics data and contributing to public health. Xin likes playing soccer and outdoor activities, such as hiking in the mountains.

Compensatory induction of Fads1 gene expression in heterozygous Fads2-null mice and by diet with a high n-6/n-3 PUFA ratio

Hang Su, Dan Zhou, Yuan-Xiang Pan, Xingguo Wang, Manabu T. Nakamura
First published on September 9, 2016

Higher chylomicron remnants and LDL particle numbers associate with CD36 SNPs and DNA methylation sites that reduce CD36

Latisha Love-Gregory, Aldi T. Kraja, Fiona Allum, Stella Aslibekyan, Åsa K. Hedman, Yanan Duan, Ingrid B. Borecki, Donna K. Arnett, Mark I. McCarthy, Panos Deloukas, Jose M. Ordovas, Paul N. Hopkins, Elin Grundberg, Nada A. Abumrad
First published on October 11, 2016

ATRA transcriptionally induces nSMase2 through CBP/p300-mediated histone acetylation

Christopher J. Clarke, Achraf A. Shamseddine, Joseph J. Jacob, Gabrielle Khalife, Tara A. Burns, Yusuf A. Hannun
First published on March 24, 2016

Epigenetic control of microsomal prostaglandin E synthase-1 by HDAC-mediated recruitment of p300

Christian Fork, Andrea E. Vasconez, Patrick Janetzko, Carlo Angioni, Yannick Schreiber, Nerea Ferreirós, Gerd Geisslinger, Matthias S. Leisegang, Dieter Steinhilber, Ralf P. Brandes
First published on December 2, 2016

Quantitative profiling of the endonuclear glycerophospholipidome of murine embryonic fibroblasts

Emily K. Tribble, Pavlina T. Ivanova, Aby Grabon, James G. Alb, Jr., Irene Faenza, Lucio Cocco, H. Alex Brown, Vytas A. Bankaitis
First published on June 2, 2016