title: BRD4 regulates Nanog expression in mouse embryonic stem cells and preimplantation embryos.
abstract: Bromodomain-containing protein 4 (BRD4) is an important epigenetic reader implicated in the pathogenesis of a number of different cancers and other diseases. Brd4-null mouse embryos die shortly after implantation and are compromised in their ability to maintain the inner cell mass, which gives rise to embryonic stem cells (ESCs). Here we report that BRD4 regulates expression of the pluripotency factor Nanog in mouse ESCs and preimplantation embryos, as well as in human ESCs and embryonic cancer stem cells. Inhibition of BRD4 function using a chemical inhibitor, small interfering RNAs, or a dominant-negative approach suppresses Nanog expression, and abolishes the self-renewal ability of ESCs. We also find that BRD4 associates with BRG1 (brahma-related gene 1, aka Smarca4 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4)), a key regulator of ESC self-renewal and pluripotency, in the Nanog regulatory regions to regulate Nanog expression. Our study identifies Nanog as a novel BRD4 target gene, providing new insights for the biological function of BRD4 in stem cells and mouse embryos. Knowledge gained from these non-cancerous systems will facilitate future investigations of how Brd4 dysfunction leads to cancers.
authors.affiliation: Department of Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Stein
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: X
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Yang
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: N-Y
authors.initials: NY
authors.lastname: Shao
authors.affiliation: Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: E E
authors.initials: EE
authors.lastname: Morrisey
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Schultz
authors.affiliation: Department of Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: J
authors.initials: J
authors.lastname: You
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000166:cytology / Q000378:metabolism*; D002454:Cell Differentiation; D004265:DNA Helicases / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D000071317:Nanog Homeobox Protein; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D000092468:Bromodomain Containing Proteins
chemical_list: D004265:DNA Helicases; D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; D009687:Nuclear Proteins; D014157:Transcription Factors; C486694:Brd4 protein, mouse; D000092468:Bromodomain Containing Proteins; C475540:Nanog protein, mouse; C513194:Smarca4 protein, mouse