Etv2 regulates enhancer chromatin status to initiate Shh expression in the limb bud.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
21 07 2022
21 07 2022
Historique:
received:
21
09
2019
accepted:
05
07
2022
entrez:
21
7
2022
pubmed:
22
7
2022
medline:
26
7
2022
Statut:
epublish
Résumé
Sonic hedgehog (Shh) is essential for limb development, and the mechanisms that govern the propagation and maintenance of its expression has been well studied; however, the mechanisms that govern the initiation of Shh expression are incomplete. Here we report that ETV2 initiates Shh expression by changing the chromatin status of the developmental limb enhancer, ZRS. Etv2 expression precedes Shh in limb buds, and Etv2 inactivation prevents the opening of limb chromatin, including the ZRS, resulting in an absence of Shh expression. Etv2 overexpression in limb buds causes nucleosomal displacement at the ZRS, ectopic Shh expression, and polydactyly. Areas of nucleosome displacement coincide with ETS binding site clusters. ETV2 also functions as a transcriptional activator of ZRS and is antagonized by ETV4/5 repressors. Known human polydactyl mutations introduce novel ETV2 binding sites in the ZRS, suggesting that ETV2 dosage regulates ZRS activation. These studies identify ETV2 as a pioneer transcription factor (TF) regulating the onset of Shh expression, having both a chromatin regulatory role and a transcriptional activation role.
Identifiants
pubmed: 35864091
doi: 10.1038/s41467-022-31848-6
pii: 10.1038/s41467-022-31848-6
pmc: PMC9304341
doi:
Substances chimiques
Chromatin
0
ER71 protein, mouse
0
ETV2 protein, human
0
Hedgehog Proteins
0
SHH protein, human
0
Shh protein, mouse
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
4221Subventions
Organisme : NIAMS NIH HHS
ID : R01 AR064195
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL100407
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL134764
Pays : United States
Informations de copyright
© 2022. The Author(s).
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