Mesomelic dysplasias associated with the HOXD locus are caused by regulatory reallocations.
Abnormalities, Multiple
/ embryology
Animals
Bone Diseases, Developmental
/ embryology
Disease Models, Animal
Female
Gene Deletion
Homeodomain Proteins
/ genetics
Humans
Limb Deformities, Congenital
/ embryology
Loss of Function Mutation
Male
Mice, Inbred C57BL
Multigene Family
Transcription Factors
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
18 08 2021
18 08 2021
Historique:
received:
12
02
2021
accepted:
05
08
2021
entrez:
19
8
2021
pubmed:
20
8
2021
medline:
15
9
2021
Statut:
epublish
Résumé
Human families with chromosomal rearrangements at 2q31, where the human HOXD locus maps, display mesomelic dysplasia, a severe shortening and bending of the limb. In mice, the dominant Ulnaless inversion of the HoxD cluster produces a similar phenotype suggesting the same origin for these malformations in humans and mice. Here we engineer 1 Mb inversion including the HoxD gene cluster, which positioned Hoxd13 close to proximal limb enhancers. Using this model, we show that these enhancers contact and activate Hoxd13 in proximal cells, inducing the formation of mesomelic dysplasia. We show that a secondary Hoxd13 null mutation in-cis with the inversion completely rescues the alterations, demonstrating that ectopic HOXD13 is directly responsible for this bone anomaly. Single-cell expression analysis and evaluation of HOXD13 binding sites suggests that the phenotype arises primarily by acting through genes normally controlled by HOXD13 in distal limb cells. Altogether, these results provide a conceptual and mechanistic framework to understand and unify the molecular origins of human mesomelic dysplasia associated with 2q31.
Identifiants
pubmed: 34408147
doi: 10.1038/s41467-021-25330-y
pii: 10.1038/s41467-021-25330-y
pmc: PMC8373931
doi:
Substances chimiques
Homeodomain Proteins
0
Hoxd13 protein, mouse
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5013Subventions
Organisme : NICHD NIH HHS
ID : F32 HD093555
Pays : United States
Informations de copyright
© 2021. The Author(s).
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