title: Integrative genomics identifies the corepressor SMRT as a gatekeeper of adipogenesis through the transcription factors C/EBPβ and KAISO.
abstract: The molecular role of corepressors is poorly understood. Here, we studied the transcriptional function of the corepressor SMRT during terminal adipogenesis. Genome-wide DNA-binding profiling revealed that this corepressor is predominantly located in active chromatin regions and that most distal SMRT binding events are lost after differentiation induction. Promoter-proximal tethering of SMRT in preadipocytes is primarily mediated by KAISO through the conserved TCTCGCGAGA motif. Further characterization revealed that KAISO, similar to SMRT, accelerates the cell cycle and increases fat accumulation upon knockdown, identifying KAISO as an adipogenic repressor that likely modulates the mitotic clonal expansion phase of this process. SMRT-bound promoter-distal sites tend to overlap with C/EBPβ-bound regions, which become occupied by proadipogenic transcription factors after SMRT clearance. This reveals a role for SMRT in masking enhancers from proadipogenic factors in preadipocytes. Finally, we identified SMRT as an adipogenic gatekeeper as it directly fine-tunes transcription of pro- and antiadipogenic genes.
authors.affiliation: Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Raghav
authors.forename: Sebastian M
authors.initials: SM
authors.lastname: Waszak
authors.forename: Irina
authors.initials: I
authors.lastname: Krier
authors.forename: Carine
authors.initials: C
authors.lastname: Gubelmann
authors.forename: Alina
authors.initials: A
authors.lastname: Isakova
authors.forename: Tarjei S
authors.initials: TS
authors.lastname: Mikkelsen
authors.forename: Bart
authors.initials: B
authors.lastname: Deplancke
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D050156:Adipogenesis / Q000235:genetics*; D000818:Animals; D001665:Binding Sites; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation; D055785:Gene Knockdown Techniques; D023281:Genomics; D051379:Mice; D041681:NIH 3T3 Cells; D056985:Nuclear Receptor Co-Repressor 2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D047495:PPAR gamma / Q000378:metabolism / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; C539131:Ncor2 protein, mouse; D056985:Nuclear Receptor Co-Repressor 2; D047495:PPAR gamma; D014157:Transcription Factors; C118822:Zbtb33 protein, mouse