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.
“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
The Results report that super-enhancers have substantially higher H3K27ac levels than typical enhancers, and the Discussion links super-enhancers to genes that establish and maintain cellular identity. The paper does not say that mammalian cellular identity is established prenatally; its statement about establishment and maintenance is conditional. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSuper-enhancers commonly drive high-level expression of tissue-specific genes, including miRNA genes, with evolutionarily conserved cell type-specific function.
“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]
The Results sections on functional attributes and cell identity report higher expression of super-enhancer-associated genes, cell type-specific associations, and an ESC miRNA locus among those genes. The Discussion says these regulatory clusters evolved, but our copy does not establish that their cell type-specific functions are evolutionarily conserved. (LLM, conf=0.87)
Experimental — accuracy not yet measuredSome enhancers reside in clusters of a handful to even hundreds ('super enhancers'), whereas many are solo.
“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]
The Results section describes super-enhancers as clusters of constituent enhancers and says the vast majority of enhancers in the studied embryonic stem cells are typical enhancers. The passages do not establish that a super-enhancer contains hundreds of enhancers or that the typical enhancers are necessarily solo; no page numbers are available in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measuredMediator 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 [72]
The Results sections on large genomic domains and functional attributes describe super-enhancers as unusually long, highly occupied by Mediator, and associated with higher gene expression than typical enhancers. The passages have no page numbers in our copy. They do not establish that BRD4 co-localises with Mediator at super-enhancers. (LLM, conf=0.88)
Experimental — accuracy not yet measuredA catalog of 748 large enhancers was assembled from scATAC-seq data from diseased TAC hearts.
“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]
Numerous publications have demonstrated that super-enhancers activate high levels of gene expression with a tendency to regulate lineage-specific genes.
“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]
SEs in both HCC and TAN are associated with GO terms related to metabolic genes (e.g. CYP3A4, SLC38A4, IGFBP1).
“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]
The Results section, “Super-enhancers are cell type-specific and mark key cell identity genes” (page unavailable), reports GO analysis across several cell types, but not HCC or TAN. Searches for HCC, TAN, the three named genes, and liver metabolism found no passage supporting the specific association claimed. (LLM, conf=0.76)
Experimental — accuracy not yet measuredLiver-restricted TFs (C/EBPα/β, HNF1A, HNF4A), pioneering TFs (CEBPα/β, FOXA2, FOXA3), and Wnt-signaling TFs (TCF7) bind at individual GPC3 constituent enhancers.
“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]
The Introduction and Results discuss transcription-factor binding at enhancers generally, including constituent enhancers in embryonic stem and pro-B cells (page unavailable). Searches for GPC3 and the named liver, pioneering, and Wnt-signaling factors found no passage reporting their binding at GPC3 constituent enhancers. (LLM, conf=0.76)
Experimental — accuracy not yet measuredIntragenic large differentially methylated regions can overlap tissue-defining signature genes and predicted super-enhancers.
“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]
Superenhancers are dense genomic regions of transcription factor binding sites that have a multiplicative effect on increasing adjacent gene expression.
“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 used ROSE (https://bitbucket.org/young_computation/rose) for identification of super-enhancers according to previous reports 12,13 .”
- 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 · 2012: 1
- 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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