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

The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.

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·2025·Nature Communications
DOI 10.1101/2025.03.27.645641

Preprint — published as 10.1038/s41467-026-71220-6 · Paper page

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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 EEs 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 EEs in the cis-regulation of host and distal gene expression. Through large-scale cancer genome analyses, we reveal that EE mutations correlate with dysregulated target-gene expression and clinical outcomes, highlighting their potential relevance in disease. Evolutionary comparisons show that EEs exhibit both strong sequence constraint and lineage-specific plasticity, suggesting that they serve ancient regulatory functions while also contributing to species divergence. Our findings redefine the landscape of functional elements by establishing EEs 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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Research works printed but not linked: 51

  1. 10.1038/nrg2957 · DOI · Paper page
  2. 10.1126/science.1243490 · DOI
  3. 10.1101/gr.133546.111 · DOI
  4. 10.1371/journal.pgen.1004592 · DOI
  5. 10.1093/nar/gkab996 · DOI
  6. 10.1038/s41586-020-2493-4 · DOI · Paper page
  7. 10.1038/s41586-020-2559-3 · DOI · Paper page
  8. 10.1093/NAR/GKAE358 · DOI
  9. 10.1038/nature13182 · DOI · Paper page
  10. 10.1038/nature12787 · DOI · Paper page
  11. 10.1038/nature11232 · DOI · Paper page
  12. 10.1126/science.1232542 · DOI · Paper page
  13. 10.1038/ng.2677 · DOI
  14. 10.1038/s41580-020-0236-x · DOI
  15. 10.1038/s41588-023-01437-4 · DOI
  16. 10.1101/gr.275901.121 · DOI
  17. 10.1101/2023.11.09.563812 · DOI · Paper page
  18. 10.1038/s41586-020-2308-7 · DOI · Paper page
  19. 10.1093/NAR/GKAB1113 · DOI · Paper page
  20. 10.1038/s41467-021-26861-0 · DOI
  21. 10.1038/ng.2653 · DOI · Paper page
  22. 10.1016/j.cell.2018.03.022 · DOI · Paper page
  23. 10.1126/science.1186176 · DOI · Paper page
  24. 10.7554/eLife.02626 · DOI · Paper page
  25. 10.1093/nar/gkae974 · DOI
  26. 10.1093/nar/gkae969 · DOI
  27. 10.1093/nar/gkac1071 · DOI
  28. 10.1093/NAR/GKAA942 · DOI
  29. 10.1126/science.1198374 · DOI
  30. 10.1105/tpc.114.125617 · DOI
  31. 10.1101/gr.239202.118 · DOI
  32. 10.1105/tpc.19.00815 · DOI
  33. 10.1093/NAR/GKZ1020 · DOI
  34. 10.1016/j.xgen.2023.100411 · DOI
  35. 10.1093/nar/gku365 · DOI · Paper page
  36. 10.1093/nar/gkz179 · DOI
  37. 10.1093/nar/gkac393 · DOI
  38. 2009, The Sequence Alignment/Map format and SAMtools, Bioinforma. Oxf. Engl, 25, 2078
  39. 10.1016/j.ajhg.2022.11.006 · DOI
  40. 10.1093/nar/gky354 · DOI
  41. 2010, BEDTools: a flexible suite of utilities for comparing genomic features, Bioinforma. Oxf. Engl, 26, 841
  42. 10.1126/science.aaz1776 · DOI · Paper page
  43. 10.1016/j.cels.2018.03.002 · DOI
  44. 2023, PyDESeq2: a python package for bulk RNA-seq differential expression analysis, Bioinforma. Oxf. Engl, 39, btad547
  45. 10.1093/bib/bbac090 · DOI
  46. 10.1093/NAR/GKAC1010 · DOI · Paper page
  47. 10.1038/nature15393 · DOI · Paper page
  48. 10.1101/gr.076554.108 · DOI
  49. 2015, The khmer software package: enabling efficient nucleotide sequence analysis, F1000Research, 4, 900, 10.12688/f1000research.6924.1 · DOI
  50. 10.1073/pnas.1617743114 · DOI
  51. 10.1515/jib-2018-0090 · DOI

Metadata

Authors
Mouren, J.-C., Torres, M., van Ouwerkerk, A., Manosalva, I., Gallardo, F., Spicuglia, S., & Ballester, B.
Affiliations
  • Inserm (FR)
  • Aix Marseille University, INSERM, TAGC, UMR 1090 Marseille, France
ORCID
Venue
Nature Communications
Publisher
openRxiv
Published
2025-04-01
Volume
17
Issue
1
ISSN
2041-1723 (ISSN-L)
DOI
10.1101/2025.03.27.645641
OpenAlex
W7147689203
Cited by
4
References
1
Citations by year
2026: 4
FWCI
8.21
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
  • Agence Nationale de la Recherche (ANR-23-CE12-0008)
  • Ministère de l'Enseignement Supérieur, de la Recherche, de la Science et de la Technologie
  • Horizon 2020 Framework Programme (Eprom-101065610)
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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