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Cited by 79Genomics and Chromatin DynamicsDevelopmental Biology and Gene RegulationChromosomal and Genetic Variations

Ultraconserved enhancer function does not require perfect sequence conservation

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Snetkova, Valentina, Ypsilanti, Athena R., Akiyama, Jennifer A., Mannion, Brandon J., Plajzer-Frick, Ingrid, Novak, Catherine S., Harrington, Anne N., Pham, Quan T. +13 more·2021·Nature Genetics
DOI 10.1038/s41588-021-00812-3PMC PMC8038972
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Abstract

Ultraconserved enhancer sequences show perfect conservation between human and rodent genomes, suggesting that their functions are highly sensitive to mutation. However, current models of enhancer function do not sufficiently explain this extreme evolutionary constraint. We subjected 23 ultraconserved enhancers to different levels of mutagenesis, collectively introducing 1,547 mutations, and examined their activities in transgenic mouse reporter assays. Overall, we find that the regulatory properties of ultraconserved enhancers are robust to mutation. Upon mutagenesis, nearly all (19/23, 83%) still functioned as enhancers at one developmental stage, as did most of those tested again later in development (5/9, 56%). Replacement of endogenous enhancers with mutated alleles in mice corroborated results of transgenic assays, including the functional resilience of ultraconserved enhancers to mutation. Our findings show that the currently known activities of ultraconserved enhancers do not necessarily require the perfect conservation observed in evolution and suggest that additional regulatory or other functions contribute to their sequence constraint.

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  • Even enhancers with extremely high evolutionary conservation may not require the exact preservation of their sequence for their correct function.

    “Furthermore, even enhancers with extremely high evolutionary conservation may not require the exact preservation of their sequence for their correct function, as was recently shown using CRISPR-mediated mutagenesis [112].”

    From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [112]

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Authors
Snetkova, V., Ypsilanti, A. R., Akiyama, J. A., Mannion, B. J., Plajzer-Frick, I., Novak, C. S., Harrington, A. N., Pham, Q. T., Kato, M., Zhu, Y., Godoy, J., Meky, E., Hunter, R. D., Shi, M., Kvon, E. Z., Afzal, V., Tran, S., Rubenstein, J. L. R., Visel, A., Pennacchio, L. A., & Dickel, D. E.
Affiliations
  • Lawrence Berkeley National Laboratory (US)
  • University of California, San Francisco (US)
Corresponding author
  • Visel, Axel
  • Pennacchio, Len A.
  • Dickel, Diane E.
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2021-03-29
Volume
53
Issue
4
Pages
521-528
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/s41588-021-00812-3
PMC
PMC8038972
OpenAlex
W3150031743
Cited by
79
References
2
Citations by year
2026: 10 · 2025: 18 · 2024: 21 · 2023: 11 · 2022: 11 · 2021: 7
FWCI
4.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion, other-oa)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion, other-oa)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • U.S. Department of Energy (DE-AC02-05CH11231)
  • Foundation Fyssen
  • U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (R01MH049428)
  • U.S. Department of Health & Human Services | National Institutes of Health (R01HG003988)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
Keywords
ultraconserved elements, enhancer function, sequence conservation, mutagenesis, evolutionary constraints, developmental gene regulation
MeSH terms
Alleles, Animals, Base Sequence, Embryo, Mammalian, Enhancer Elements, Genetic, Humans, Mutation, Transcription Factors, Mutagenesis, Site-Directed, Conserved Sequence, Gene Expression Regulation, Developmental, Mice, Rats

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