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

• Published in: Nature communications Vol. 15; no. 1; pp. 3380 - 15
• Main Authors: Baudic, Manon, Murata, Hiroshige, Bosada, Fernanda M., Melo, Uirá Souto, Aizawa, Takanori, Lindenbaum, Pierre, van der Maarel, Lieve E., Guedon, Amaury, Baron, Estelle, Fremy, Enora, Foucal, Adrien, Ishikawa, Taisuke, Ushinohama, Hiroya, Jurgens, Sean J., Choi, Seung Hoan, Kyndt, Florence, Le Scouarnec, Solena, Wakker, Vincent, Thollet, Aurélie, Rajalu, Annabelle, Takaki, Tadashi, Ohno, Seiko, Shimizu, Wataru, Horie, Minoru, Kimura, Takeshi, Ellinor, Patrick T., Petit, Florence, Dulac, Yves, Bru, Paul, Boland, Anne, Deleuze, Jean-François, Redon, Richard, Le Marec, Hervé, Le Tourneau, Thierry, Gourraud, Jean-Baptiste, Yoshida, Yoshinori, Makita, Naomasa, Vieyres, Claude, Makiyama, Takeru, Mundlos, Stephan, Christoffels, Vincent M., Probst, Vincent, Schott, Jean-Jacques, Barc, Julien
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.04.2024; Nature Publishing Group; Nature Portfolio
• Series: Nature Communications
• Subjects: 38/15; 38/39; 38/47; 38/91; 45/100; 45/23; 631/208/176; 64/60; 692/4019/592/2727; Binding sites; Cardiomyocytes; Chromatin remodeling; Conformation; Gene deletion; Gene regulation; Genomes; Heart; Hereditary diseases; Homeobox; Humanities and Social Sciences; Life Sciences; multidisciplinary; Phenotypes; Pluripotency; Science; Science (multidisciplinary); Stem cells; Ventricle
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-47739-x

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. This study identifies an altered chromatin conformation associated to a cardiac disorder observed in 7 independent families. A deletion of 2 diverging CTCF binding sites on 4q25 induces TAD fusion and leads to PITX2 expression dysregulation.