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Cell Rep. 2014 Oct 9;9(1):234-247. doi: 10.1016/j.celrep.2014.08.055. Epub 2014 Sep 26.

Control of embryonic stem cell identity by BRD4-dependent transcriptional elongation of super-enhancer-associated pluripotency genes.

Author information

1
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.
2
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.
3
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.
4
Genome Technology Center, Office for Collaborative Science, NYU Medical Center, New York, NY 10016, USA.
5
Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
6
Histopathology Core Unit, Biotechnology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain.
7
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.
8
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.

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.

PMID:
25263550
PMCID:
PMC4317728
DOI:
10.1016/j.celrep.2014.08.055
[Indexed for MEDLINE]
Free PMC Article

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