title: DNA methylation alters transcriptional rates of differentially expressed genes and contributes to pathophysiology in mice fed a high fat diet.
abstract: Overnutrition can alter gene expression patterns through epigenetic mechanisms that may persist through generations. However, it is less clear if overnutrition, for example a high fat diet, modifies epigenetic control of gene expression in adults, or by what molecular mechanisms, or if such mechanisms contribute to the pathology of the metabolic syndrome. Here we test the hypothesis that a high fat diet alters hepatic DNA methylation, transcription and gene expression patterns, and explore the contribution of such changes to the pathophysiology of obesity.
  
  
  
  RNA-seq and targeted high-throughput bisulfite DNA sequencing were used to undertake a systematic analysis of the hepatic response to a high fat diet. RT-PCR, chromatin immunoprecipitation andin vivoknockdown of an identified driver gene,Phlda1, were used to validate the results.
  
  
  
  A high fat diet resulted in the hypermethylation and decreased transcription and expression ofPhlda1and several other genes. A subnetwork of genes associated withPhlda1was identified from an existing Bayesian gene network that contained numerous hepatic regulatory genes involved in lipid and body weight homeostasis. Hepatic-specific depletion ofPhlda1in mice decreased expression of the genes in the subnetwork, and led to increased oil droplet size in standard chow-fed mice, an early indicator of steatosis, validating the contribution of this gene to the phenotype.
  
  
  
  We conclude that a high fat diet alters the epigenetics and transcriptional activity of key hepatic genes controlling lipid homeostasis, contributing to the pathophysiology of obesity.
authors.affiliation: Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Pili
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA; Center for Fetal Medicine, Magee-Women's Research Institute, Pittsburgh, PA, USA.
authors.forename: Tianjiao
authors.initials: T
authors.lastname: Chu
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Dedousis
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Benjamin S
authors.initials: BS
authors.lastname: Mantell
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Sipula
authors.affiliation: Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Lucy
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA; Center for Fetal Medicine, Magee-Women's Research Institute, Pittsburgh, PA, USA.
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: Bunce
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA; Center for Fetal Medicine, Magee-Women's Research Institute, Pittsburgh, PA, USA.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Shaw
authors.affiliation: Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Liora S
authors.initials: LS
authors.lastname: Katz
authors.affiliation: Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Carmen
authors.initials: C
authors.lastname: Argmann
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: O'Doherty
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA; Center for Fetal Medicine, Magee-Women's Research Institute, Pittsburgh, PA, USA. Electronic address: dgp6@pitt.edu.
authors.forename: David G
authors.initials: DG
authors.lastname: Peters
authors.affiliation: Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: donald.scott@mssm.edu.
authors.forename: Donald K
authors.initials: DK
authors.lastname: Scott
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D019175:DNA Methylation; D059305:Diet, High-Fat / Q000009:adverse effects*; D044127:Epigenesis, Genetic; D022781:Hepatocytes / Q000378:metabolism; D066292:Lipid Droplets / Q000378:metabolism; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000209:etiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: C114072:Phlda1 protein, mouse; D012333:RNA, Messenger; D014157:Transcription Factors
keywords: DNA methylation; High fat diet; Liver; Phlda1; RNA-seq; Transcription