Control of Embryonic Stem Cell Identity by BRD4-Dependent Transcriptional Elongation of Super-Enhancer-Associated Pluripotency Genes
Raffaella Di Micco,
Barbara Fontanals-Cirera,
Vivien Low,
Panagiotis Ntziachristos,
Stephanie K. Yuen,
Claudia D. Lovell,
Igor Dolgalev,
Yoshiya Yonekubo,
Guangtao Zhang,
Elena Rusinova,
Guillermo Gerona-Navarro,
Marta Cañamero,
Michael Ohlmeyer,
Iannis Aifantis,
Ming-Ming Zhou,
Aristotelis Tsirigos,
Eva Hernando
Affiliations
Raffaella Di Micco
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; Corresponding author
Barbara Fontanals-Cirera
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
Vivien Low
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
Panagiotis Ntziachristos
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
Stephanie K. Yuen
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
Claudia D. Lovell
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
Igor Dolgalev
Genome Technology Center, Office for Collaborative Science, NYU Medical Center, New York, NY 10016, USA
Yoshiya Yonekubo
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
Guangtao Zhang
Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Elena Rusinova
Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Guillermo Gerona-Navarro
Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Marta Cañamero
Histopathology Core Unit, Biotechnology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain
Michael Ohlmeyer
Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Iannis Aifantis
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
Ming-Ming Zhou
Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Aristotelis Tsirigos
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; Corresponding author
Eva Hernando
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; Corresponding author
Summary: 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. : Di Micco et al. now dissect the mechanisms by which BRD4 regulates embryonic stem cell (ESC) identity by binding to super-enhancers of core pluripotency genes and recruiting active transcription complexes. BRD4 inhibition results in defective elongation of super-enhancer-associated gene transcripts, loss of ESC self-renewal/pluripotency, and commitment to the neuroectodermal lineage.