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

Di Micco R, Fontanals-Cirera B, Low V, Ntziachristos P, Yuen SK, Lovell CD, Dolgalev I, Yonekubo Y, Zhang G, Rusinova E, Gerona-Navarro G, CaƱamero M, Ohlmeyer M, Aifantis I, Zhou MM, Tsirigos A, Hernando E - Cell Rep (2014)

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.

View Article: PubMed Central - PubMed

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.

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Model Depicting the Effects of BET Inhibition on the Binding of MED, BRD4, CDK9, and Pol II at SE-Associated Stem Cell Genes and Non-SE-Associated Genes(A) SE-associated stem cell genes depend on the cooperative binding of BRD4, MED, and CDK9 at their SEs for productive transcription elongation (Pol II pS2 and H3K36me3). BRD4 also localizes in the gene body, most likely to help the traveling of Pol II through nucleosomes. Compound treatment displaces, together with BRD4, MED, and CDK9, resulting in Pol II stalling at TSSs and reduced elongating Pol II in the gene body of stem cell genes.(B) The vast majority of TE-associated genes does not rely on BRD4 binding for their elongation and are insensitive to BRD4 inhibition. Transcription factors and chromatin remodelers rather than BRD4 may be responsible for the expression of TE-associated genes.
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Figure 7: Model Depicting the Effects of BET Inhibition on the Binding of MED, BRD4, CDK9, and Pol II at SE-Associated Stem Cell Genes and Non-SE-Associated Genes(A) SE-associated stem cell genes depend on the cooperative binding of BRD4, MED, and CDK9 at their SEs for productive transcription elongation (Pol II pS2 and H3K36me3). BRD4 also localizes in the gene body, most likely to help the traveling of Pol II through nucleosomes. Compound treatment displaces, together with BRD4, MED, and CDK9, resulting in Pol II stalling at TSSs and reduced elongating Pol II in the gene body of stem cell genes.(B) The vast majority of TE-associated genes does not rely on BRD4 binding for their elongation and are insensitive to BRD4 inhibition. Transcription factors and chromatin remodelers rather than BRD4 may be responsible for the expression of TE-associated genes.

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.


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

Di Micco R, Fontanals-Cirera B, Low V, Ntziachristos P, Yuen SK, Lovell CD, Dolgalev I, Yonekubo Y, Zhang G, Rusinova E, Gerona-Navarro G, CaƱamero M, Ohlmeyer M, Aifantis I, Zhou MM, Tsirigos A, Hernando E - Cell Rep (2014)

Model Depicting the Effects of BET Inhibition on the Binding of MED, BRD4, CDK9, and Pol II at SE-Associated Stem Cell Genes and Non-SE-Associated Genes(A) SE-associated stem cell genes depend on the cooperative binding of BRD4, MED, and CDK9 at their SEs for productive transcription elongation (Pol II pS2 and H3K36me3). BRD4 also localizes in the gene body, most likely to help the traveling of Pol II through nucleosomes. Compound treatment displaces, together with BRD4, MED, and CDK9, resulting in Pol II stalling at TSSs and reduced elongating Pol II in the gene body of stem cell genes.(B) The vast majority of TE-associated genes does not rely on BRD4 binding for their elongation and are insensitive to BRD4 inhibition. Transcription factors and chromatin remodelers rather than BRD4 may be responsible for the expression of TE-associated genes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4317728&req=5

Figure 7: Model Depicting the Effects of BET Inhibition on the Binding of MED, BRD4, CDK9, and Pol II at SE-Associated Stem Cell Genes and Non-SE-Associated Genes(A) SE-associated stem cell genes depend on the cooperative binding of BRD4, MED, and CDK9 at their SEs for productive transcription elongation (Pol II pS2 and H3K36me3). BRD4 also localizes in the gene body, most likely to help the traveling of Pol II through nucleosomes. Compound treatment displaces, together with BRD4, MED, and CDK9, resulting in Pol II stalling at TSSs and reduced elongating Pol II in the gene body of stem cell genes.(B) The vast majority of TE-associated genes does not rely on BRD4 binding for their elongation and are insensitive to BRD4 inhibition. Transcription factors and chromatin remodelers rather than BRD4 may be responsible for the expression of TE-associated genes.
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.

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.

View Article: PubMed Central - PubMed

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.

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Related in: MedlinePlus