Intragenic Enhancers Attenuate Host Gene Expression
Open accessAbstract
Eukaryotic gene transcription is regulated at many steps, including RNA polymerase II (Pol II) recruitment, transcription initiation, promoter-proximal Pol II pause release, and transcription termination; however, mechanisms regulating transcription during productive elongation remain poorly understood. Enhancers, which activate gene transcription, themselves undergo Pol II-mediated transcription, but our understanding of enhancer transcription and enhancer RNAs (eRNAs) remains incomplete. Here we show that transcription at intragenic enhancers interferes with and attenuates host gene transcription during productive elongation. While the extent of attenuation correlates positively with nascent eRNA expression, the act of intragenic enhancer transcription alone, but not eRNAs, explains the attenuation. Through CRISPR/Cas9-mediated deletions, we demonstrate a physiological role for intragenic enhancer-mediated transcription attenuation in cell fate determination. We propose that intragenic enhancers not only enhance transcription of one or more genes from a distance but also fine-tune transcription of their host gene through transcription interference, facilitating differential utilization of the same regulatory element for disparate functions.
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Enhancers may have complex relationships with promoters, including feedback loops or competition with neighbouring genes.
“Enhancers may have complex relationships with promoters, including feedback loops or competition with neighbouring genes121,122.”
From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [122]
The Discussion (page unavailable) proposes an intrinsic negative feedback mechanism between an intragenic enhancer and its host-gene promoter. It also reports that the enhancer can activate distant genes while attenuating its host gene, but it does not describe competition with neighbouring genes. (LLM, conf=0.84)
Experimental — accuracy not yet measuredMPRAs would fail to recapitulate complex gene-enhancer networks.
“Finally, MPRAs would fail to recapitulate complex gene–enhancer networks121,122.”
From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [122]
The Results section reports that enhancer location affects activity in a double-reporter assay, and the Methods describe that assay. Neither passage assesses massively parallel reporter assays (MPRAs) or says they fail to recapitulate complex gene–enhancer networks. Searches for MPRA and for reporter-assay limitations found no passage establishing that claim. (LLM, conf=0.72)
Experimental — accuracy not yet measured
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- Authors
- Cinghu, S., Yang, P., Kosak, J. P., Conway, A. E., Kumar, D., Oldfield, A. J., Adelman, K., & Jothi, R.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Jothi, Raja
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2017-10
- Volume
- 68
- Issue
- 1
- Pages
- 104-117.e6
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC5683415
- OpenAlex
- W2763907932
- Cited by
- 100
- References
- 11
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 5 · 2023: 13 · 2022: 8 · 2021: 10 · 2020: 20 · 2019: 14 · 2018: 10 · 2017: 3
- FWCI
- 5.25
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH, National Institute of Environmental Health Sciences (1ZIAES102625)
- Topics
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- intragenic enhancers, transcriptional attenuation, enhancer transcription, enhancer RNA, RNA polymerase II, cell fate determination, enhancer function
- MeSH terms
- Mouse Embryonic Stem Cells, Gene Editing, Animals, Cell Line, Chromatin, Enhancer Elements, Genetic, Gene Expression Regulation, Promoter Regions, Genetic, RNA, RNA Polymerase II, Mice, Embryoid Bodies, Transcription Elongation, Genetic, CRISPR-Cas Systems
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