Ultraconserved enhancer function does not require perfect sequence conservation.
Journal
Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
received:
14
05
2020
accepted:
04
02
2021
pubmed:
31
3
2021
medline:
21
4
2021
entrez:
30
3
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33782603
doi: 10.1038/s41588-021-00812-3
pii: 10.1038/s41588-021-00812-3
pmc: PMC8038972
mid: NIHMS1674779
doi:
Substances chimiques
Transcription Factors
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
521-528Subventions
Organisme : NHGRI NIH HHS
ID : R01 HG003988
Pays : United States
Organisme : NHGRI NIH HHS
ID : R00 HG009682
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS034661
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH049428
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS099099
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH081880
Pays : United States
Commentaires et corrections
Type : CommentIn
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