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

• DOI: 10.1038/s41467-024-47739-x
• Publication Date: 2024-04-21T02:41:25Z
• Authors: Manon Baudic; Hiroshige Murata; Fernanda M. Bosada; Uirá Souto Melo; Takanori Aizawa; Pierre Lindenbaum; Lieve E. van der ...; Amaury Guedon; Estelle Baron; Enora Fremy; Adrien Foucal; Taisuke Ishikawa; Hiroya Ushinohama; Sean J. Jurgens; Seung Hoan Choi; Florence Kyndt; Solena Le Scouarnec; Vincent Wakker; Aurélie Thollet; Annabelle Rajalu; Tadashi Takaki; Seiko Ohno; Wataru Shimizu; Minoru Horie; Takeshi Kimura; Patrick T. Ellinor; Florence Petit; Yves Dulac; Paul Bru; Anne Boland; Jean-François Del...; Richard Redon; Hervé Le Marec; Thierry Le Tourneau; Jean-Baptiste Gou...; Yoshinori Yoshida; Naomasa Makita; Claude Vieyres; Takeru Makiyama; Stephan Mundlos; Vincent M. Christ...; Vincent Probst; Jean-Jacques Schott; Julien Barc
• Keywords: CTCF

Abstract 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 human Mendelian disease largely unknown. Here, we identify 7 families presenting a new cardiac entity associated with heterozygous deletion 2 CTCF binding sites on 4q25, inducing TAD fusion conformation remodeling. The are located desert at 1 Mb from Paired-like homeodomain transcription factor ( PITX2 ). By introducing ortholog mouse genome, recapitulate patient phenotype characterize an opposite dysregulation expression sinoatrial node (ectopic activation) ventricle (reduction), respectively. Chromatin assay performed induced pluripotent stem cell-derived cardiomyocytes harboring minimal identified family#1 reveals remodeling TADs. We conclude that mediated by causes autosomal dominant disorder.