title: Extensive chromatin remodelling and establishment of transcription factor 'hotspots' during early adipogenesis.
abstract: Adipogenesis is tightly controlled by a complex network of transcription factors acting at different stages of differentiation. Peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein (C/EBP) family members are key regulators of this process. We have employed DNase I hypersensitive site analysis to investigate the genome-wide changes in chromatin structure that accompany the binding of adipogenic transcription factors. These analyses revealed a dramatic and dynamic modulation of the chromatin landscape during the first hours of adipocyte differentiation that coincides with cooperative binding of multiple early transcription factors (including glucocorticoid receptor, retinoid X receptor, Stat5a, C/EBPβ and -δ) to transcription factor 'hotspots'. Our results demonstrate that C/EBPβ marks a large number of these transcription factor 'hotspots' before induction of differentiation and chromatin remodelling and is required for their establishment. Furthermore, a subset of early remodelled C/EBP-binding sites persists throughout differentiation and is later occupied by PPARγ, indicating that early C/EBP family members, in addition to their well-established role in activation of PPARγ transcription, may act as pioneering factors for PPARγ binding.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
authors.forename: Rasmus
authors.initials: R
authors.lastname: Siersbæk
authors.forename: Ronni
authors.initials: R
authors.lastname: Nielsen
authors.forename: Sam
authors.initials: S
authors.lastname: John
authors.forename: Myong-Hee
authors.initials: MH
authors.lastname: Sung
authors.forename: Songjoon
authors.initials: S
authors.lastname: Baek
authors.forename: Anne
authors.initials: A
authors.lastname: Loft
authors.forename: Gordon L
authors.initials: GL
authors.lastname: Hager
authors.forename: Susanne
authors.initials: S
authors.lastname: Mandrup
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D050156:Adipogenesis / Q000502:physiology*; D000465:Algorithms; D000818:Animals; D015153:Blotting, Western; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D042002:Chromatin Assembly and Disassembly; D047369:Chromatin Immunoprecipitation; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D022782:CCAAT-Enhancer-Binding Protein-beta; D012333:RNA, Messenger; D047488:Retinoid X Receptors; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins