Control of embryonic stem cell identity by BRD4-dependent transcriptional elongation of super-enhancer-associated pluripotency genes.
Bottom Line: Transcription factors and chromatin-remodeling complexes are key determinants of embryonic stem cell (ESC) identity.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.
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: firstname.lastname@example.org.Show MeSH
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Mentions: We envision a model in which BRD4 recruits SE-associated complexes at SEs of stem cell genes, thus allowing the progression of a promoter-proximal Pol II through the gene body to achieve productive elongation (Figure 7A). Meanwhile, the transcriptional elongation of non-SE-associated genes remains mostly unperturbed by BRD4 inhibition (Figure 7B). Downregulation of the small percentage of non-SE-associated genes following BRD4 inhibition is mainly due to increased Pol II at the TSS rather than to loss of elongating Pol II throughout the gene body. Collectively, our findings support a specific regulation of transcriptional elongation of stem cell genes that relies on BRD4-dependent binding of Mediator and CDK9 to SEs to sustain ESC identity.
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: email@example.com.