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Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes
Open accessAbstract
Master transcription factors Oct4, Sox2, and Nanog bind enhancer elements and recruit Mediator to activate much of the gene expression program of pluripotent embryonic stem cells (ESCs). We report here that the ESC master transcription factors form unusual enhancer domains at most genes that control the pluripotent state. These domains, which we call super-enhancers, consist of clusters of enhancers that are densely occupied by the master regulators and Mediator. Super-enhancers differ from typical enhancers in size, transcription factor density and content, ability to activate transcription, and sensitivity to perturbation. Reduced levels of Oct4 or Mediator cause preferential loss of expression of super-enhancer-associated genes relative to other genes, suggesting how changes in gene expression programs might be accomplished during development. In other more differentiated cells, super-enhancers containing cell-type-specific master transcription factors are also found at genes that define cell identity. Super-enhancers thus play key roles in the control of mammalian cell identity.
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“In mammals, cellular identity is established prenatally and maintained by H3K27ac-enriched super-enhancers (Hnisz et al., 2013; Whyte et al., 2013).”
From Loss of epigenetic information as a cause of mammalian aging (2023) · cites this paper as Whyte et al., 2013
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“Super-enhancers commonly drive high-level expression of tissue-specific genes, including miRNA genes, with evolutionarily conserved cell type-specific function11–13.”
From Gain-of-function mutation of microRNA-140 in human skeletal dysplasia (2019) · cites this paper as [12]
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In the citing paper
“Some enhancers reside in clusters of a handful116 to even hundreds (‘super enhancers’76,117), whereas many are solo.”
From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [76]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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 [72]
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“Superenhancers are dense genomic regions of transcription factor binding sites that have a multiplicative effect on increasing adjacent gene expression (Whyte et al. 2013; Suzuki et al. 2017).”
From Toward the human cellular microRNAome (2017) · cites this paper as Whyte et al. 2013
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“we assembled a catalog of 748 large enhancers28 using scATAC-seq data from diseased hearts (TAC) (Extended Data Fig. 6A).”
From Chromatin remodelling drives immune cell–fibroblast communication in heart failure (2024) · cites this paper as [28]
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“Numerous publications have demonstrated that SEs activate high levels of gene expression with a tendency to regulate lineage-specific genes.4,11,14,18”
From Super-enhancers include classical enhancers and facilitators to fully activate gene expression (2023) · cites this paper as [4]
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“SEs in both HCC and TAN were associated with GO terms related to metabolic genes (e.g. CYP3A4, SLC38A4, and IGFBP1) (Fig. 2c)20,21,58.”
From Multi-omic analysis of hepatocellular carcinoma reveals aberrant cis-regulatory changes and dysregulated retrotransposons with prognostic potential (2025) · cites this paper as [21]
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“we detected binding of liver-restricted TFs (C/EBPα/β, HNF1A, and HNF4A), pioneering TFs (CEBPα/β, FOXA2, and FOXA3), and Wnt-signaling TFs (TCF7) at individual constituent enhancers (Fig. 3b)20,21.”
From Multi-omic analysis of hepatocellular carcinoma reveals aberrant cis-regulatory changes and dysregulated retrotransposons with prognostic potential (2025) · cites this paper as [21]
Experimental — accuracy not yet measuredIn the citing paper
“Intragenic DMRs that stretch for kilobases (large-DMRs) can overlap with tissue defining “signature genes” as well as with predicted super-enhancers, which are clusters of enhancers that function cooperatively (4, 10, 11).”
From Dynamic DNA methylation: In the right place at the right time (2018) · cites this paper as [11]
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Metadata
- Authors
- Whyte, W. A., Orlando, D. A., Hnisz, D., Abraham, B. J., Lin, C. Y., Kagey, M. H., Rahl, P. B., Lee, T. I., & Young, R. A.
- Affiliations
- Whitehead Institute for Biomedical Research (US)
- Dana-Farber Cancer Institute (US)
- Corresponding author
- Young, Richard A.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-04
- Volume
- 153
- Issue
- 2
- Pages
- 307-319
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3653129
- OpenAlex
- W1971578941
- Cited by
- 4,143
- References
- 95
- Citations by year
- 2026: 226 · 2025: 346 · 2024: 384 · 2023: 380 · 2022: 376 · 2021: 449 · 2020: 360 · 2019: 343 · 2018: 308 · 2017: 267 · 2016: 248 · 2015: 225 · 2014: 169 · 2013: 54
- FWCI
- 103.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- PMC
- Funders
- National Institutes of Health
- National Human Genome Research Institute (HG002668, R01HG002668)
- National Cancer Institute (CA146445, R01CA146445, P30CA014051)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- super-enhancers, Mediator complex, Oct4, SOX2, Nanog, pluripotency, embryonic stem cells, cell identity genes, transcriptional regulation, cell differentiation, enhancer recruitment
- MeSH terms
- Animals, B-Lymphocytes, Cell Line, Enhancer Elements, Genetic, Gene Expression Regulation, Humans, Transcription Factors, Transcription, Genetic, Cell Lineage, Mice, Embryonic Stem Cells, Gene Knockdown Techniques, Mediator Complex
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