Combinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve split-hand/foot malformation type 3.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
17 03 2023
17 03 2023
Historique:
received:
21
03
2022
accepted:
01
03
2023
entrez:
17
3
2023
pubmed:
18
3
2023
medline:
22
3
2023
Statut:
epublish
Résumé
Split-Hand/Foot Malformation type 3 (SHFM3) is a congenital limb malformation associated with tandem duplications at the LBX1/FGF8 locus. Yet, the disease patho-mechanism remains unsolved. Here we investigate the functional consequences of SHFM3-associated rearrangements on chromatin conformation and gene expression in vivo in transgenic mice. We show that the Lbx1/Fgf8 locus consists of two separate, but interacting, regulatory domains. Re-engineering of a SHFM3-associated duplication and a newly reported inversion in mice results in restructuring of the chromatin architecture. This leads to ectopic activation of the Lbx1 and Btrc genes in the apical ectodermal ridge (AER) in an Fgf8-like pattern induced by AER-specific enhancers of Fgf8. We provide evidence that the SHFM3 phenotype is the result of a combinatorial effect on gene misexpression in the developing limb. Our results reveal insights into the molecular mechanism underlying SHFM3 and provide conceptual framework for how genomic rearrangements can cause gene misexpression and disease.
Identifiants
pubmed: 36928426
doi: 10.1038/s41467-023-37057-z
pii: 10.1038/s41467-023-37057-z
pmc: PMC10020157
doi:
Substances chimiques
Fgf8 protein, mouse
0
Fibroblast Growth Factor 8
148997-75-5
Homeodomain Proteins
0
Lbx1h protein, mouse
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1475Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2023. The Author(s).
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