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

Manon Baudic, Hiroshige Murata, Fernanda M. Bosada, Uirá Souto Melo, Takanori Aizawa, Pierre Lindenbaum, Lieve E. Maarel, Amaury Guedon, Estelle Baron, Enora Fremy, Adrien Foucal, Taisuke Ishikawa, Hiroya Ushinohama, Sean J. Jurgens, Seung Hoan Choi, Florence Kyndt, Solena 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 Deleuze, Richard Redon, Hervé Marec, Thierry Tourneau, Jean-Baptiste Gourraud, Yoshinori Yoshida, Naomasa Makita, Claude Vieyres, Takeru Makiyama, Stephan Mundlos, Vincent M. Christoffels, Vincent Probst, Jean-Jacques Schott () and Julien Barc ()
Additional contact information
Manon Baudic: l’institut du Thorax
Hiroshige Murata: Nippon Medical School Hospital
Fernanda M. Bosada: University of Amsterdam
Uirá Souto Melo: RG Development and Disease
Takanori Aizawa: Kyoto University Graduate School of Medicine
Pierre Lindenbaum: l’institut du Thorax
Lieve E. Maarel: University of Amsterdam
Amaury Guedon: l’institut du Thorax
Estelle Baron: l’institut du Thorax
Enora Fremy: l’institut du Thorax
Adrien Foucal: l’institut du Thorax
Taisuke Ishikawa: National Cerebral and Cardiovascular Center
Hiroya Ushinohama: Fukuoka Children’s Hospital
Sean J. Jurgens: Broad Institute of MIT and Harvard
Seung Hoan Choi: Broad Institute of MIT and Harvard
Florence Kyndt: l’institut du Thorax
Solena Scouarnec: l’institut du Thorax
Vincent Wakker: University of Amsterdam
Aurélie Thollet: l’institut du Thorax
Annabelle Rajalu: l’institut du Thorax
Tadashi Takaki: Kyoto University
Seiko Ohno: National Cerebral and Cardiovascular Center Research Institute
Wataru Shimizu: Nippon Medical School Hospital
Minoru Horie: Shiga University of Medical Science
Takeshi Kimura: Kyoto University Graduate School of Medicine
Patrick T. Ellinor: Broad Institute of MIT and Harvard
Florence Petit: Hôpital Jeanne de Flandre
Yves Dulac: Hôpital des Enfants
Paul Bru: GH La Rochelle
Anne Boland: Centre National de Recherche en Génomique Humaine (CNRGH)
Jean-François Deleuze: Centre National de Recherche en Génomique Humaine (CNRGH)
Richard Redon: l’institut du Thorax
Hervé Marec: l’institut du Thorax
Thierry Tourneau: l’institut du Thorax
Jean-Baptiste Gourraud: l’institut du Thorax
Yoshinori Yoshida: Kyoto University
Naomasa Makita: National Cerebral and Cardiovascular Center
Claude Vieyres: Clinique St. Joseph
Takeru Makiyama: Kyoto University Graduate School of Medicine
Stephan Mundlos: RG Development and Disease
Vincent M. Christoffels: University of Amsterdam
Vincent Probst: l’institut du Thorax
Jean-Jacques Schott: l’institut du Thorax
Julien Barc: l’institut du Thorax

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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 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.

Date: 2024
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DOI: 10.1038/s41467-024-47739-x

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