TAD boundary deletion causes PITX2-related cardiac electrical and structural defects. - Université de Lille Accéder directement au contenu
Article Dans Une Revue Nature Communications Année : 2024

TAD boundary deletion causes PITX2-related cardiac electrical and structural defects.

Hiroshige Murata
  • Fonction : Auteur
Taisuke Ishikawa
  • Fonction : Auteur
Hiroya Ushinohama
  • Fonction : Auteur
Wataru Shimizu
  • Fonction : Auteur
Naomasa Makita
  • Fonction : Auteur

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.
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hal-04630944 , version 1 (01-07-2024)

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Manon Baudic, Hiroshige Murata, Fernanda M. Bosada, Uira Souto Melo, Takanori Aizawa, et al.. TAD boundary deletion causes PITX2-related cardiac electrical and structural defects.. Nature Communications, 2024, Nature Communications, 15 (1), pp.3380. ⟨10.1038/s41467-024-47739-x⟩. ⟨hal-04630944⟩
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