Super-Enhancer-Mediated RNA Processing Revealed by Integrative MicroRNA Network Analysis
Open accessAbstract
Super-enhancers are an emerging subclass of regulatory regions controlling cell identity and disease genes. However, their biological function and impact on miRNA networks are unclear. Here, we report that super-enhancers drive the biogenesis of master miRNAs crucial for cell identity by enhancing both transcription and Drosha/DGCR8-mediated primary miRNA (pri-miRNA) processing. Super-enhancers, together with broad H3K4me3 domains, shape a tissue-specific and evolutionarily conserved atlas of miRNA expression and function. CRISPR/Cas9 genomics revealed that super-enhancer constituents act cooperatively and facilitate Drosha/DGCR8 recruitment and pri-miRNA processing to boost cell-specific miRNA production. The BET-bromodomain inhibitor JQ1 preferentially inhibits super-enhancer-directed cotranscriptional pri-miRNA processing. Furthermore, super-enhancers are characterized by pervasive interaction with DGCR8/Drosha and DGCR8/Drosha-regulated mRNA stability control, suggesting unique RNA regulation at super-enhancers. Finally, super-enhancers mark multiple miRNAs associated with cancer hallmarks. This study presents principles underlying miRNA biology in health and disease and an unrecognized higher-order property of super-enhancers in RNA processing beyond transcription.
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Super-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 [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 Suzuki et al. 2017
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“…recent reports have explored the contribution of the constituent enhancers of SEs to expression of mRNA transcripts, with varying results (Hay et al., 2016; Hnisz et al., 2015; Shin et al., 2016); it remains unclear whether multiple SE constituents have redundant or non-redundant…”
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- Authors
- Suzuki, H. I., Young, R. A., & Sharp, P. A.
- Affiliations
- Koch Institute for Integrative Cancer Research At MIT (US)
- Whitehead Institute for Biomedical Research (US)
- Corresponding author
- Sharp, Phillip A.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-03
- Volume
- 168
- Issue
- 6
- Pages
- 1000-1014.e15
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5350633
- OpenAlex
- W2593459113
- Cited by
- 284
- References
- 11
- Citations by year
- 2026: 12 · 2025: 21 · 2024: 28 · 2023: 26 · 2022: 30 · 2021: 42 · 2020: 41 · 2019: 34 · 2018: 30 · 2017: 19 · 2015: 1
- FWCI
- 11.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- PMC
- Funders
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (P30-CA14051)
- National Institutes of Health
- U.S. Public Health Service (P30-CA14051, R01CA133404)
- Japan Society for the Promotion of Science
- National Human Genome Research Institute (R01HG002668)
- National Cancer Institute (R01CA133404, P01CA042063, CA14051, P30CA014051, P30-CA-14051)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Keywords
- super-enhancers, microRNA biogenesis, pri-miRNA processing, H3K4me3, cell identity, JQ1, BET bromodomain inhibition, mRNA stability, cancer hallmarks, RNA processing
- MeSH terms
- Animals, Azepines, Enhancer Elements, Genetic, Gene Expression Regulation, Humans, Neoplasms, Organ Specificity, RNA Processing, Post-Transcriptional, Transcription Factors, Transcription, Genetic, Triazoles, MicroRNAs, Histone Code, Mice
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