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Cited by 4Genomics and Chromatin DynamicsCancer-related molecular mechanisms researchChromosomal and Genetic Variations

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Exonic enhancers are a widespread class of dual-function regulatory elements

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Mouren, Jean-Christophe, Torres, Magali, van Ouwerkerk, Antoinette, Manosalva, Iris, Gallardo, Frederic, Spicuglia, Salvatore, Ballester, Benoit·2026·Nature Communications
DOI 10.1038/s41467-026-71220-6

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Abstract

Exonic enhancers (EEs) occupy an under-appreciated niche in gene regulation. By integrating transcription factor binding, chromatin accessibility, and high-throughput enhancer-reporter assays, we demonstrate that many protein-coding exons possess enhancer activity across species. These candidate EEs (cEEs) exhibit characteristic epigenomic signatures, form long-range interactions with gene promoters, and can be altered by both nonsynonymous and synonymous variants. CRISPR-mediated inactivation demonstrated the involvement of cEEs in the cis-regulation of host and distal gene expression. Through large-scale cancer genome analyses, we reveal that cEE mutations correlate with dysregulated target-gene expression and clinical outcomes, highlighting their potential relevance in disease. Evolutionary comparisons show that cEEs exhibit both strong sequence constraint and lineage-specific plasticity, suggesting that they serve ancient regulatory functions while also contributing to species divergence. Our findings expand the landscape of functional elements by establishing cEEs as a component of gene regulation, while revealing how coding regions can simultaneously fulfil both protein-coding and cis-regulatory roles.

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Metadata

Authors
Mouren, J.-C., Torres, M., van Ouwerkerk, A., Manosalva, I., Gallardo, F., Spicuglia, S., & Ballester, B.
Affiliations
Inserm (FR)
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2026-04-02
Volume
17
Issue
1
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-026-71220-6
OpenAlex
W7147689203
Cited by
4
References
5
Citations by year
2026: 4
FWCI
8.27
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • HAL (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Ministère de l'Enseignement Supérieur, de la Recherche, de la Science et de la Technologie
  • EC | Horizon 2020 Framework Programme (Eprom-101065610)
  • Agence Nationale de la Recherche (ANR-23-CE12-0008-01)
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 › Genetics › Chromosomal and Genetic Variations
Keywords
cis-regulation, long-range chromatin interactions, transcription factor binding, chromatin accessibility, enhancer mutations, non-synonymous mutations, synonymous mutations, evolutionary constraints, sequence constraints
MeSH terms
Animals, Chromatin, Enhancer Elements, Genetic, Exons, Gene Expression Regulation, Humans, Mutation, Promoter Regions, Genetic, Transcription Factors, Evolution, Molecular

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