Circadian Transcriptomic and Epigenomic Remodeling in Response to Lipid Overload and Human Obesity

Obesity and elevated circulating lipids may impair metabolism by disrupting the molecular circadian clock. We tested the hypothesis that lipid-overload may interact with the circadian clock and alter the rhythmicity of gene expression through epigenetic mechanisms.We determined the effect of the saturated fatty acid palmitate on circadian transcriptomics and examined the impact on histone H3 lysine K27 acetylation (H3K27ac) and the regulation of circadian rhythms in primary human skeletal muscle myotubes. Total H3 abundance and histone H3K27ac was assessed in vastus lateralis muscle biopsies from obese and normal weight men.Palmitate disrupted transcriptomic rhythmicity in myotubes. Genes that lost or gained rhythmicity after palmitate treatment were involved in metabolic processes, protein translation and transport, and transcriptional regulation. Histone H3K27ac, a marker of active gene enhancers, was modified by palmitate treatment in myotubes, but not in skeletal muscle from men with obesity.Palmitate disrupts transcriptomic rhythmicity and modifies histone H3K27ac in circadian manner, suggesting acute lipid-overload alters the epigenetic state of skeletal muscle. Our results indicate that dietary saturated fatty acids impart post-transcriptional modifications to histone proteins and regulate circadian transcriptomics.

[1]  T. Hansen,et al.  Skeletal muscle enhancer interactions identify genes controlling whole-body metabolism , 2020, Nature Communications.

[2]  M. Lazar,et al.  Transcriptional Control of Circadian Rhythms and Metabolism: A Matter of Time and Space. , 2020, Endocrine reviews.

[3]  F. Gachon,et al.  Proteomics in circadian biology. , 2019, Journal of molecular biology.

[4]  F. Scheer,et al.  Sex differences in the circadian misalignment effects on energy regulation , 2019, Proceedings of the National Academy of Sciences.

[5]  Z. Ju,et al.  Elevated H3K27ac in aged skeletal muscle leads to increase in extracellular matrix and fibrogenic conversion of muscle satellite cells , 2019, Aging cell.

[6]  O. Froy,et al.  Non-obesogenic doses of fatty acids modulate the functionality of the circadian clock in the liver , 2019, Cellular and Molecular Life Sciences.

[7]  O. Froy,et al.  Non-obesogenic doses of palmitate disrupt circadian metabolism in adipocytes , 2019, Adipocyte.

[8]  V. Fuster,et al.  Association of Sleep Duration and Quality With Subclinical Atherosclerosis. , 2019, Journal of the American College of Cardiology.

[9]  K. Yasuda,et al.  Genome-wide profiling of histone H3K27 acetylation featured fatty acid signalling in pancreatic beta cells in diet-induced obesity in mice , 2018, Diabetologia.

[10]  M. W. Young.  Time Travels: A 40-Year Journey from Drosophila's Clock Mutants to Human Circadian Disorders (Nobel Lecture). , 2018, Angewandte Chemie.

[11]  F. Scheer,et al.  Circadian misalignment induces fatty acid metabolism gene profiles and compromises insulin sensitivity in human skeletal muscle , 2018, Proceedings of the National Academy of Sciences.

[12]  A. Klip,et al.  Sphingolipid changes do not underlie fatty acid-evoked GLUT4 insulin resistance nor inflammation signals in muscle cells[S] , 2018, Journal of Lipid Research.

[13]  Kyoung-Jae Won,et al.  Rev-erbα dynamically modulates chromatin looping to control circadian gene transcription , 2018, Science.

[14]  Astrid Gall,et al.  Ensembl 2018 , 2017, Nucleic Acids Res..

[15]  Mark S. Schmidt,et al.  Circadian Reprogramming in the Liver Identifies Metabolic Pathways of Aging , 2017, Cell.

[16]  H. Koistinen,et al.  Palmitate and oleate exert differential effects on insulin signalling and glucose uptake in human skeletal muscle cells , 2017, Endocrine connections.

[17]  A. Conesa,et al.  RGmatch: matching genomic regions to proximal genes in omics data integration , 2016, BMC Bioinformatics.

[18]  Scott B. Crown,et al.  Lipids Reprogram Metabolism to Become a Major Carbon Source for Histone Acetylation. , 2016, Cell reports.

[19]  M. Aznar,et al.  Ionizing Radiation Potentiates High-Fat Diet–Induced Insulin Resistance and Reprograms Skeletal Muscle and Adipose Progenitor Cells , 2016, Diabetes.

[20]  A. Kalsbeek,et al.  Nutrition in the spotlight: metabolic effects of environmental light , 2016, Proceedings of the Nutrition Society.

[21]  F. Scheer,et al.  Circadian misalignment increases cardiovascular disease risk factors in humans , 2016, Proceedings of the National Academy of Sciences.

[22]  D. Moore,et al.  Circadian Dysfunction Induces Leptin Resistance in Mice. , 2015, Cell metabolism.

[23]  L. Yin,et al.  Palmitate Inhibits SIRT1-Dependent BMAL1/CLOCK Interaction and Disrupts Circadian Gene Oscillations in Hepatocytes , 2015, PloS one.

[24]  Matthew E. Ritchie,et al.  limma powers differential expression analyses for RNA-sequencing and microarray studies , 2015, Nucleic acids research.

[25]  R. Gomis,et al.  Altered Clock Gene Expression in Obese Visceral Adipose Tissue Is Associated with Metabolic Syndrome , 2014, PloS one.

[26]  Pål O. Westermark,et al.  Detecting Rhythms in Time Series with RAIN , 2014, Journal of biological rhythms.

[27]  C. Ling,et al.  Effects of palmitate on genome-wide mRNA expression and DNA methylation patterns in human pancreatic islets , 2014, BMC Medicine.

[28]  Björn Usadel,et al.  Trimmomatic: a flexible trimmer for Illumina sequence data , 2014, Bioinform..

[29]  Sara A. Grimm,et al.  Obesity, rather than diet, drives epigenomic alterations in colonic epithelium resembling cancer progression. , 2014, Cell metabolism.

[30]  R. Grunstein,et al.  Sleep loss and circadian disruption in shift work: health burden and management , 2013, The Medical journal of Australia.

[31]  Wei Shi,et al.  featureCounts: an efficient general purpose program for assigning sequence reads to genomic features , 2013, Bioinform..

[32]  J. Zierath,et al.  Weight loss after gastric bypass surgery in human obesity remodels promoter methylation. , 2013, Cell reports.

[33]  Satchidananda Panda,et al.  Circadian oscillations of protein-coding and regulatory RNAs in a highly dynamic mammalian liver epigenome. , 2012, Cell metabolism.

[34]  Steven L Salzberg,et al.  Fast gapped-read alignment with Bowtie 2 , 2012, Nature Methods.

[35]  S. Shimba,et al.  Obesity alters the expression profile of clock genes in peripheral blood mononuclear cells , 2011, Archives of medical science : AMS.

[36]  Tao Liu,et al.  A Circadian Rhythm Orchestrated by Histone Deacetylase 3 Controls Hepatic Lipid Metabolism , 2011, Science.

[37]  A. J. van der Beek,et al.  The effects of shift work on body weight change - a systematic review of longitudinal studies. , 2011, Scandinavian journal of work, environment & health.

[38]  H. Tseng,et al.  Abnormal expressions of circadian-clock and circadian clock-controlled genes in the livers and kidneys of long-term, high-fat-diet-treated mice , 2010, International Journal of Obesity.

[39]  Mark D. Robinson,et al.  edgeR: a Bioconductor package for differential expression analysis of digital gene expression data , 2009, Bioinform..

[40]  Gonçalo R. Abecasis,et al.  The Sequence Alignment/Map format and SAMtools , 2009, Bioinform..

[41]  Brad T. Sherman,et al.  Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists , 2008, Nucleic acids research.

[42]  Clifford A. Meyer,et al.  Model-based Analysis of ChIP-Seq (MACS) , 2008, Genome Biology.

[43]  Paolo Sassone-Corsi,et al.  The NAD+-Dependent Deacetylase SIRT1 Modulates CLOCK-Mediated Chromatin Remodeling and Circadian Control , 2008, Cell.

[44]  Paolo Sassone-Corsi,et al.  CLOCK-mediated acetylation of BMAL1 controls circadian function , 2007, Nature.

[45]  N. Dimopoulos,et al.  Differential effects of palmitate and palmitoleate on insulin action and glucose utilization in rat L6 skeletal muscle cells. , 2006, The Biochemical journal.

[46]  Paolo Sassone-Corsi,et al.  Circadian Regulator CLOCK Is a Histone Acetyltransferase , 2006, Cell.

[47]  Fred W. Turek,et al.  Obesity and Metabolic Syndrome in Circadian Clock Mutant Mice , 2005, Science.

[48]  Norio Iijima,et al.  Circadian and Light-Induced Transcription of Clock Gene Per1 Depends on Histone Acetylation and Deacetylation , 2004, Molecular and Cellular Biology.

[49]  Steven M. Reppert,et al.  Rhythmic histone acetylation underlies transcription in the mammalian circadian clock , 2003, Nature.

[50]  G. Orphanides,et al.  A Unified Theory of Gene Expression , 2002, Cell.

[51]  Rena R Wing,et al.  Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss. , 1999, American journal of physiology. Endocrinology and metabolism.

[52]  J. Zierath,et al.  Influence of Obesity, Weight Loss, and Free Fatty Acids on Skeletal Muscle Clock Gene Expression. , 2019, American journal of physiology. Endocrinology and metabolism.

[53]  Thomas R. Gingeras,et al.  STAR: ultrafast universal RNA-seq aligner , 2013, Bioinform..

[54]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[55]  Cheng Li,et al.  Adjusting batch effects in microarray expression data using empirical Bayes methods. , 2007, Biostatistics.