title: Coactivators p300 and CBP maintain the identity of mouse embryonic stem cells by mediating long-range chromatin structure.
abstract: Master transcription factors Oct4, Sox2, and Nanog are required to maintain the pluripotency and self-renewal of embryonic stem cells (ESCs) by regulating a specific transcriptional network. A few other transcription factors have been shown to be important in ESCs by interacting with these master transcription factors; however, little is known about the transcriptional mechanisms regulated by coregulators (coactivators and corepressors). In this study, we examined the function of two highly homologous coactivators, p300 and CREB-binding protein (CBP), in ESCs. We find that these two coactivators play redundant roles in maintaining the undifferentiated state of ESCs. They are recruited by Nanog through physical interaction to Nanog binding loci, mediating the formation of long-range chromatin looping structures, which is essential to maintain ESC-specific gene expression. Further functional studies reveal that the p300/CBP binding looping fragments contain enhancer activities, suggesting that the formation of p300/CBP-mediated looping structures may recruit distal enhancers to create a concentration of factors for the transcription activation of genes that are involved in self-renewal and pluripotency. Overall, these results provide a total new insight into the transcriptional regulation mechanism of coactivators p300 and CBP in ESCs, which is important in maintaining self-renewal and pluripotency, by mediating the formation of higher order chromosome structures.
authors.affiliation: Computation and Systems Biology, Singapore-MIT Alliance, Singapore, Singapore.
authors.forename: Fang
authors.initials: F
authors.lastname: Fang
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Xu
authors.forename: Kai-Khen
authors.initials: KK
authors.lastname: Chew
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Huck-Hui
authors.initials: HH
authors.lastname: Ng
authors.forename: Paul
authors.initials: P
authors.lastname: Matsudaira
mesh_terms: D000818:Animals; D001665:Binding Sites; D050882:CREB-Binding Protein / Q000502:physiology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics*; D042002:Chromatin Assembly and Disassembly; D050881:E1A-Associated p300 Protein / Q000502:physiology*; D053595:Embryonic Stem Cells / Q000378:metabolism*; D004843:Epistasis, Genetic; D006801:Humans; D051379:Mice; D005810:Multigene Family; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015533:Transcriptional Activation
chemical_list: D002843:Chromatin; D050882:CREB-Binding Protein; D050881:E1A-Associated p300 Protein
keywords: Chromatin looping; Coactivator; Embryonic stem cells; Self-renewal; Transcription factors