Convergence of Developmental and Oncogenic Signaling Pathways at Transcriptional Super-Enhancers
Open accessAbstract
Super-enhancers and stretch enhancers (SEs) drive expression of genes that play prominent roles in normal and disease cells, but the functional importance of these clustered enhancer elements is poorly understood, so it is not clear why genes key to cell identity have evolved regulation by such elements. Here, we show that SEs consist of functional constituent units that concentrate multiple developmental signaling pathways at key pluripotency genes in embryonic stem cells and confer enhanced responsiveness to signaling of their associated genes. Cancer cells frequently acquire SEs at genes that promote tumorigenesis, and we show that these genes are especially sensitive to perturbation of oncogenic signaling pathways. Super-enhancers thus provide a platform for signaling pathways to regulate genes that control cell identity during development and tumorigenesis.
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Hnisz and colleagues previously showed that the E8 enhancer within Pri-miR-290-295 has very little enhancer activity measured by luciferase assay; nevertheless, deletion of E8 caused a large decrease in Pri-miR-290-295 expression.
“Similarly, Hnisz and colleagues previously showed that the E8 enhancer within the Pri-miR-290–295 has very little enhancer activity measured by luciferase assay; nevertheless, deletion of E8 caused a large decrease in Pri-miR-290–295 expression.18”
From Super-enhancers include classical enhancers and facilitators to fully activate gene expression (2023) · cites this paper as [18]
The Results section, “Perturbation of super-enhancer constituents” (page unavailable), reports that deleting miR-290-295 E8 caused a substantial reduction in gene expression—more than 50% versus wild type. The Results section, “Enhancer activity of super-enhancer constituents” (page unavailable), describes luciferase assays but does not state that E8 specifically had very little activity. That part of the attributed claim is unsupported by our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCurrent theories propose liquid-liquid phase separation and some form of transcription factor trapping or engagement of transcription factors in multivalent interactions independent of assembly into phase-separated liquid-like droplets.
“current theories propose liquid-liquid phase separation18,64–66 and some form of TF trapping22,67 or engagement of TFs in multivalent interactions independent of assembly into phase-separated liquid-like droplets.68”
From Super-enhancers include classical enhancers and facilitators to fully activate gene expression (2023) · cites this paper as [18]
The Results section (‘Signaling modules at super-enhancers’; page unavailable) reports that multiple transcription factors bind the same super-enhancers, and the Discussion describes physical and functional interactions among enhancer constituents. These findings support clustered TF engagement, but the paper does not establish multivalent TF interactions or address whether they occur independently of phase-separated droplets. Citation 68 is attached to that latter proposal, not to the sentence’s separate phase-separation or TF-trapping proposals. (LLM, conf=0.78)
Experimental — accuracy not yet measuredNumerous 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 [18]
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- Authors
- Hnisz, D., Schuijers, J., Lin, C. Y., Weintraub, A. S., Abraham, B. J., Lee, T. I., Bradner, J. E., & Young, R. A.
- Affiliations
- Whitehead Institute for Biomedical Research (US)
- Dana-Farber Cancer Institute (US)
- Corresponding author
- Young, Richard A.
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2015-04
- Volume
- 58
- Issue
- 2
- Pages
- 362-370
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC4402134
- OpenAlex
- W1969466735
- Cited by
- 476
- References
- 10
- Citations by year
- 2026: 17 · 2025: 31 · 2024: 44 · 2023: 61 · 2022: 40 · 2021: 47 · 2020: 31 · 2019: 44 · 2018: 46 · 2017: 44 · 2016: 48 · 2015: 22
- FWCI
- 23.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- 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 Institute of General Medical Sciences (T32GM007287)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- super-enhancers, developmental signaling pathways, oncogenic signaling, pluripotency genes, embryonic stem cells, cell identity, carcinogenesis, transcriptional regulation, enhancer evolution
- MeSH terms
- Animals, Cell Line, Enhancer Elements, Genetic, Humans, Neoplasms, Transcription Factors, Signal Transduction, Gene Expression Regulation, Neoplastic, Gene Expression Regulation, Developmental, HCT116 Cells, Mice, Embryonic Stem Cells, HEK293 Cells
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