TAD boundary deletion causes PITX2-related cardiac electrical and structural defects.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
20 Apr 2024
20 Apr 2024
Historique:
received:
17
02
2023
accepted:
08
04
2024
medline:
21
4
2024
pubmed:
21
4
2024
entrez:
20
4
2024
Statut:
epublish
Résumé
While 3D chromatin organization in topologically associating domains (TADs) and loops mediating regulatory element-promoter interactions is crucial for tissue-specific gene regulation, the extent of their involvement in human Mendelian disease is largely unknown. Here, we identify 7 families presenting a new cardiac entity associated with a heterozygous deletion of 2 CTCF binding sites on 4q25, inducing TAD fusion and chromatin conformation remodeling. The CTCF binding sites are located in a gene desert at 1 Mb from the Paired-like homeodomain transcription factor 2 gene (PITX2). By introducing the ortholog of the human deletion in the mouse genome, we recapitulate the patient phenotype and characterize an opposite dysregulation of PITX2 expression in the sinoatrial node (ectopic activation) and ventricle (reduction), respectively. Chromatin conformation assay performed in human induced pluripotent stem cell-derived cardiomyocytes harboring the minimal deletion identified in family#1 reveals a conformation remodeling and fusion of TADs. We conclude that TAD remodeling mediated by deletion of CTCF binding sites causes a new autosomal dominant Mendelian cardiac disorder.
Identifiants
pubmed: 38643172
doi: 10.1038/s41467-024-47739-x
pii: 10.1038/s41467-024-47739-x
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
3380Subventions
Organisme : Agence Nationale de la Recherche (French National Research Agency)
ID : R21006NN, RPV21014NNA
Informations de copyright
© 2024. The Author(s).
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