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Cited by 47RNA Research and SplicingGenomics and Chromatin DynamicsCancer-related molecular mechanisms research

Enhancers regulate 3′ end processing activity to control expression of alternative 3′UTR isoforms

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Kwon, Buki, Fansler, Mervin M., Patel, Neil D., Lee, Jihye, Ma, Weirui, Mayr, Christine·2022·Nature Communications
DOI 10.1038/s41467-022-30525-yPMC PMC9114392

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Abstract

Multi-UTR genes are widely transcribed and express their alternative 3′UTR isoforms in a cell type-specific manner. As transcriptional enhancers regulate mRNA expression, we investigated if they also regulate 3′UTR isoform expression. Endogenous enhancer deletion of the multi-UTR gene PTEN did not impair transcript production but prevented 3′UTR isoform switching which was recapitulated by silencing of an enhancer-bound transcription factor. In reporter assays, enhancers increase transcript production when paired with single-UTR gene promoters. However, when combined with multi-UTR gene promoters, they change 3′UTR isoform expression by increasing 3′ end processing activity of polyadenylation sites. Processing activity of polyadenylation sites is affected by transcription factors, including NF-κB and MYC, transcription elongation factors, chromatin remodelers, and histone acetyltransferases. As endogenous cell type-specific enhancers are associated with genes that increase their short 3′UTRs in a cell type-specific manner, our data suggest that transcriptional enhancers integrate cellular signals to regulate cell type-and condition-specific 3′UTR isoform expression.

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  • Metrics that summarize post-transcriptional regulation inevitably struggle to describe complex splicing outcomes, unannotated de novo events or the intricate and sometimes competitive relationship between transcription, splicing and intronic polyadenylation.

    “However, such metrics inevitably struggle to describe complex splicing outcomes, unannotated de novo events or the intricate and sometimes competitive relationship between transcription, splicing and (intronic) polyadenylation24–26.”

    From Predicting RNA-seq coverage from DNA sequence as a unifying model of gene regulation (2025) · cites this paper as [26]

    The Introduction (page unavailable) says it is difficult to disentangle transcript production from processing when assessing expression of single-UTR genes. That supports a narrower version of the claimed complexity, but the paper does not establish that summary metrics inevitably fail to describe complex splicing, unannotated de novo events, or competition with intronic polyadenylation. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Authors
Kwon, B., Fansler, M. M., Patel, N. D., Lee, J., Ma, W., & Mayr, C.
Affiliations
Memorial Sloan Kettering Cancer Center (US)
Corresponding author
Mayr, Christine
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2022-05-17
Volume
13
Issue
1
Pages
2709-2709
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-022-30525-y
PMC
PMC9114392
OpenAlex
W4280517873
Cited by
47
References
114
Citations by year
2026: 7 · 2025: 12 · 2024: 8 · 2023: 13 · 2022: 6 · 2021: 1
FWCI
3.18
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Damon Runyon Cancer Research Foundation (P30 CA008748)
  • Pershing Square Sohn Cancer Research Alliance (P30 CA008748)
  • National Institutes of Health (CA008748)
  • National Cancer Institute (CA008748, P30CA008748)
  • National Institute of General Medical Sciences (DP1GM123454)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • 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
enhancers, 3' end processing, polyadenylation, PTEN, isoform switching, cell type-specific gene expression, NF-κB, c-Myc, transcription elongation, chromatin remodeling, histone acetyltransferase
MeSH terms
Gene Expression Regulation, Regulatory Sequences, Nucleic Acid, Protein Isoforms, 3' Untranslated Regions, Polyadenylation

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