Control of Embryonic Stem Cell Identity by BRD4-Dependent Transcriptional Elongation of Super-Enhancer-Associated Pluripotency Genes
Open accessAbstract
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.
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Mediator and BRD4 co-localise at very high levels at super-enhancers, long stretches of sequences with gene regulatory activity that generally drive greater levels of gene expression than regular enhancers.
“In particular, Mediator and BRD4 co-localise at very high levels at “super-enhancers” (SEs): long stretches of sequences with gene regulatory activity that generally drive greater levels of gene expression than regular enhancers [69–72].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [71]
The Results sections (page unavailable) report that BRD4 and Mediator subunits localize at super-enhancers of stem-cell genes in human embryonic stem cells, and describe super-enhancers as large enhancer domains. The copy does not establish that super-enhancers generally drive higher gene expression than regular enhancers. It also reports that BRD4 peak signal intensity was similar at super-enhancers and typical enhancers in these cells, although BRD4-binding peaks were more frequent at super-enhancers. (LLM, conf=0.85)
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Cites
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Transcriptional enhancers and their communication with gene promoters
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- Authors
- 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.
- Affiliations
- NYU Langone Health (US)
- Howard Hughes Medical Institute (US)
- Icahn School of Medicine at Mount Sinai (US)
- Spanish National Cancer Research Centre (ES)
- Corresponding author
- Tsirigos, Aristotelis
- Hernando, Eva
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 9
- Issue
- 1
- Pages
- 234-247
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC4317728
- OpenAlex
- W2027773301
- Cited by
- 217
- References
- 6
- Citations by year
- 2026: 11 · 2025: 13 · 2024: 11 · 2023: 16 · 2022: 17 · 2021: 16 · 2020: 26 · 2019: 22 · 2018: 23 · 2017: 21 · 2016: 23 · 2015: 17
- FWCI
- 8.34
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (acceptedVersion, cc-by-nc-nd)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Howard Hughes Medical Institute
- New York Stem Cell Foundation
- National Institutes of Health (RO1CA133379, RO1CA149655, RO1CA105129)
- National Human Genome Research Institute (R01HG004508)
- National Cancer Institute (R01CA155234, K99CA188293, R01CA087658, R01CA163891, R01CA149655, R01CA133379, R01CA169784, R01CA87658, R01CA173636, R01CA105129, P30CA016087)
- National Institute of General Medical Sciences (R01GM088847)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R21AR062239)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- BRD4, BET proteins, super-enhancers, transcription elongation, P-TEFb, CDK9, Mediator complex, pluripotency genes, Oct4, PRDM14, self-renewal, epithelial-mesenchymal transition, neuroectodermal differentiation, stem cell differentiation, chromatin remodeling
- MeSH terms
- Bromodomain Containing Proteins, Animals, Humans, Nuclear Proteins, Transcription Factors, Transcription, Genetic, Gene Expression Regulation, Developmental, Cell Cycle Proteins, Pluripotent Stem Cells, Positive Transcriptional Elongation Factor B, Mice, Embryonic Stem Cells
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