title: The BET family member BRD4 interacts with OCT4 and regulates pluripotency gene expression.
abstract: Embryonic stem cell (ESC) pluripotency is controlled by defined transcription factors. During cellular differentiation, ESCs undergo a global epigenetic reprogramming. Female ESCs exemplify this process as one of the two X-chromosomes is globally silenced during X chromosome inactivation (XCI) to balance the X-linked gene disparity with XY males. The pluripotent factor OCT4 regulates XCI by triggering X chromosome pairing and counting. OCT4 directly binds Xite and Tsix, which encode two long noncoding RNAs (lncRNAs) that suppress the silencer lncRNA, Xist. To control its activity as a master regulator in pluripotency and XCI, OCT4 must have chromatin protein partners. Here we show that BRD4, a member of the BET protein subfamily, interacts with OCT4. BRD4 occupies the regulatory regions of pluripotent genes and the lncRNAs of XCI. BET inhibition or depletion of BRD4 reduces the expression of many pluripotent genes and shifts cellular fate showing that BRD4 is pivotal for transcription in ESCs.
authors: Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY 10605, USA; Departments of Neuroscience and Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA.
authors: Tao
authors: T
authors: Wu
authors: Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY 10605, USA; Departments of Neuroscience and Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA.
authors: Hugo Borges
authors: HB
authors: Pinto
authors: Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY 10605, USA; Departments of Neuroscience and Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA.
authors: Yasunao F
authors: YF
authors: Kamikawa
authors: Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY 10605, USA; Departments of Neuroscience and Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: med2008@med.cornell.edu.
authors: Mary E
authors: ME
authors: Donohoe
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D000066673:Cell Self Renewal / Q000235:genetics*; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005260:Female; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism*; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism; D011485:Protein Binding; D062085:RNA, Long Noncoding / Q000235:genetics; D016601:RNA-Binding Proteins; D012045:Regulatory Sequences, Nucleic Acid; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D049951:X Chromosome Inactivation / Q000235:genetics; D000092468:Bromodomain Containing Proteins; D000084622:Sestrins
chemical_list: D006360:Heat-Shock Proteins; D009687:Nuclear Proteins; D050814:Octamer Transcription Factor-3; D042925:Positive Transcriptional Elongation Factor B; D062085:RNA, Long Noncoding; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C486694:Brd4 protein, mouse; D000092468:Bromodomain Containing Proteins; C118642:Hexim1 protein, mouse; C549101:Sesn3 protein, mouse; D000084622:Sestrins; C077885:XIST non-coding RNA