title: Peroxisome proliferator-activated receptor γ regulates genes involved in insulin/insulin-like growth factor signaling and lipid metabolism during adipogenesis through functionally distinct enhancer classes.
abstract: The nuclear receptor peroxisome proliferator-activated receptor (PPAR) is a transcription factor whose expression is induced during adipogenesis and that is required for the acquisition and control of mature adipocyte functions. Indeed, PPAR induces the expression of genes involved in lipid synthesis and storage through enhancers activated during adipocyte differentiation. Here, we show that PPAR also binds to enhancers already active in preadipocytes as evidenced by an active chromatin state including lower DNA methylation levels despite higher CpG content. These constitutive enhancers are linked to genes involved in the insulin/insulin-like growth factor signaling pathway that are transcriptionally induced during adipogenesis but to a lower extent than lipid metabolism genes, because of stronger basal expression levels in preadipocytes. This is consistent with the sequential involvement of hormonal sensitivity and lipid handling during adipocyte maturation and correlates with the chromatin structure dynamics at constitutive and activated enhancers. Interestingly, constitutive enhancers are evolutionary conserved and can be activated in other tissues, in contrast to enhancers controlling lipid handling genes whose activation is more restricted to adipocytes. Thus, PPAR utilizes both broadly active and cell type-specific enhancers to modulate the dynamic range of activation of genes involved in the adipogenic process.
authors.affiliation: From INSERM UMR U1011, F-59000 Lille, France.
authors.forename: Frédérik
authors.initials: F
authors.lastname: Oger
authors.forename: Julie
authors.initials: J
authors.lastname: Dubois-Chevalier
authors.forename: Céline
authors.initials: C
authors.lastname: Gheeraert
authors.forename: Stéphane
authors.initials: S
authors.lastname: Avner
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Durand
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.forename: Gilles
authors.initials: G
authors.lastname: Salbert
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.forename: Philippe
authors.initials: P
authors.lastname: Lefebvre
authors.forename: Jérôme
authors.initials: J
authors.lastname: Eeckhoute
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D050156:Adipogenesis / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D007328:Insulin / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics*; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D013002:Somatomedins / Q000378:metabolism; D059467:Transcriptome
chemical_list: D007328:Insulin; D047495:PPAR gamma; D013002:Somatomedins
keywords: Adipogenesis; Chromatin Modification; DNA Methylation; Epigenomics; Insulin/Insulin-like Growth Factor Signaling; Peroxisome Proliferator-activated Receptor (PPAR); Transcription Enhancers; Transcription Regulation