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

*Corresponding author for this work

Research output: Contribution to journalArticle

106 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)234-247
Number of pages14
JournalCell reports
Volume9
Issue number1
DOIs
StatePublished - Oct 9 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Di Micco, R., Fontanals-Cirera, B., Low, V., Ntziachristos, P., Yuen, S. K., Lovell, C. D., Dolgalev, I., Yonekubo, Y., Zhang, G., Rusinova, E., Gerona-Navarro, G., Cañamero, M., Ohlmeyer, M., Aifantis, I., Zhou, M. M., Tsirigos, A., & Hernando, E. (2014). Control of embryonic stem cell identity by brd4-dependent transcriptional elongation of super-enhancer-associated pluripotency genes. Cell reports, 9(1), 234-247. https://doi.org/10.1016/j.celrep.2014.08.055