title: Control of embryonic stem cell identity by BRD4-dependent transcriptional elongation of super-enhancer-associated pluripotency genes.
abstract: Transcription factors and chromatin-remodeling complexes are key determinants of embryonic stem cell (ESC) identity. Here, we demonstrate that BRD4, a member of the bromodomain and extraterminal domain (BET) family of epigenetic readers, regulates the self-renewal ability and pluripotency of ESCs. BRD4 inhibition resulted in induction of epithelial-to-mesenchymal transition (EMT) markers and commitment to the neuroectodermal lineage while reducing the ESC multidifferentiation capacity in teratoma assays. BRD4 maintains transcription of core stem cell genes such as OCT4 and PRDM14 by occupying their super-enhancers (SEs), large clusters of regulatory elements, and recruiting to them Mediator and CDK9, the catalytic subunit of the positive transcription elongation factor b (P-TEFb), to allow Pol-II-dependent productive elongation. Our study describes a mechanism of regulation of ESC identity that could be applied to improve the efficiency of ESC differentiation.
authors.affiliation: Department of Pathology, New York University School of Medicine, and Perlmutter Cancer Center, New York, NY 10016, USA; Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU Langone Medical Center, New York, NY 10016, USA. Electronic address: raffaella.dimicco@nyumc.org.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Di Micco
authors.affiliation: Department of Pathology, New York University School of Medicine, and Perlmutter Cancer Center, New York, NY 10016, USA; Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU Langone Medical Center, New York, NY 10016, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Fontanals-Cirera
authors.affiliation: Department of Pathology, New York University School of Medicine, and Perlmutter Cancer Center, New York, NY 10016, USA; Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU Langone Medical Center, New York, NY 10016, USA.
authors.forename: Vivien
authors.initials: V
authors.lastname: Low
authors.affiliation: Department of Pathology, New York University School of Medicine, and Perlmutter Cancer Center, New York, NY 10016, USA; Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU Langone Medical Center, New York, NY 10016, USA; Howard Hughes Medical Institute and NYU Cancer Institute, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Ntziachristos
authors.affiliation: Department of Pathology, New York University School of Medicine, and Perlmutter Cancer Center, New York, NY 10016, USA; Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU Langone Medical Center, New York, NY 10016, USA.
authors.forename: Stephanie K
authors.initials: SK
authors.lastname: Yuen
authors.affiliation: Department of Pathology, New York University School of Medicine, and Perlmutter Cancer Center, New York, NY 10016, USA; Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU Langone Medical Center, New York, NY 10016, USA.
authors.forename: Claudia D
authors.initials: CD
authors.lastname: Lovell
authors.affiliation: Genome Technology Center, Office for Collaborative Science, NYU Medical Center, New York, NY 10016, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Dolgalev
authors.affiliation: Department of Pathology, New York University School of Medicine, and Perlmutter Cancer Center, New York, NY 10016, USA; Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU Langone Medical Center, New York, NY 10016, USA.
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Yonekubo
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Guangtao
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Rusinova
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Gerona-Navarro
authors.affiliation: Histopathology Core Unit, Biotechnology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Cañamero
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Ohlmeyer
authors.affiliation: Department of Pathology, New York University School of Medicine, and Perlmutter Cancer Center, New York, NY 10016, USA; Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU Langone Medical Center, New York, NY 10016, USA; Howard Hughes Medical Institute and NYU Cancer Institute, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Iannis
authors.initials: I
authors.lastname: Aifantis
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Zhou
authors.affiliation: Department of Pathology, New York University School of Medicine, and Perlmutter Cancer Center, New York, NY 10016, USA; Center for Health Informatics and Bioinformatics, NYU School of Medicine, New York, NY 10016, USA. Electronic address: aristotelis.tsirigos@nyumc.org.
authors.forename: Aristotelis
authors.initials: A
authors.lastname: Tsirigos
authors.affiliation: Department of Pathology, New York University School of Medicine, and Perlmutter Cancer Center, New York, NY 10016, USA; Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU Langone Medical Center, New York, NY 10016, USA. Electronic address: eva.hernando-monge@nyumc.org.
authors.forename: Eva
authors.initials: E
authors.lastname: Hernando
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D042925:Positive Transcriptional Elongation Factor B / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D042925:Positive Transcriptional Elongation Factor B; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C486694:Brd4 protein, mouse