TAD boundary deletion causes PITX2-related cardiac electrical and structural defects.
Manon Baudic
(1, 2)
,
Hiroshige Murata
,
Fernanda M. Bosada
(3, 4)
,
Uira Souto Melo
(5)
,
Takanori Aizawa
(6)
,
Pierre Lindenbaum
(2, 1)
,
Lieve E. van der Maarel
(4, 3)
,
Amaury Guedon
(2, 1)
,
Estelle Baron
(2, 1)
,
Enora Fremy
(2, 1)
,
Adrien Foucal
(2, 1)
,
Taisuke Ishikawa
,
Hiroya Ushinohama
,
Sean J. Jurgens
(7, 4, 3)
,
Seung Hoan Choi
(7, 4, 3)
,
Florence Kyndt
(2, 1)
,
Solena Le Scouarnec
(2, 1)
,
Vincent Wakker
(4, 3)
,
Aurélie Thollet
(2, 1)
,
Annabelle Rajalu
(2, 1)
,
Tadashi Takaki
(8, 9)
,
Seiko Ohno
(10)
,
Wataru Shimizu
,
Minoru Horie
(11)
,
Takeshi Kimura
(6)
,
Patrick T. Ellinor
(7, 12, 13)
,
Florence Petit
(14, 15)
,
Yves Dulac
(16)
,
Paul Bru
(17)
,
Anne Boland
(18, 19)
,
Jean-François Deleuze
(18, 19)
,
Richard Redon
(2, 1)
,
Hervé Le Marec
(2, 1)
,
Thierry Le Tourneau
(2, 1)
,
Jean-Baptiste Gourraud
(2, 1, 20)
,
Yoshinori Yoshida
(8)
,
Naomasa Makita
,
Claude Vieyres
(21)
,
Takeru Makiyama
(6)
,
Stephan Mundlos
(5)
,
Vincent M. Christoffels
(4, 3)
,
Vincent Probst
(2, 1, 20)
,
Jean-Jacques Schott
(2, 1, 20)
,
Julien Barc
(2, 1, 20)
1
ITX-lab -
ITX-lab unité de recherche de l'institut du thorax UMR1087 UMR6291
2 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
3 UvA - University of Amsterdam [Amsterdam] = Universiteit van Amsterdam
4 Amsterdam UMC - Amsterdam University Medical Centers
5 MPIMG - Max Planck Institute for Molecular Genetics
6 KUGSM - Kyoto University Graduate School of Medicine [Kyoto, Japan]
7 BROAD INSTITUTE - Broad Institute of MIT and Harvard
8 Kyoto University
9 NCGM - National Center for Global Health and Medicine [Japan]
10 National cerebral and cardiovascular center research institute
11 Shiga University of Medical Science
12 Massachusetts General Hospital [Boston]
13 HMS - Harvard Medical School [Boston]
14 RADEME - Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364
15 Hôpital Jeanne de Flandre [Lille]
16 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
17 Hôpitaux La Rochelle Ré Aunis [Groupe hospitalier littoral Atlantique]
18 CNRGH - Centre National de Recherche en Génomique Humaine
19 Université Paris-Saclay
20 ERN GUARD-Heart - European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart
21 CSJA - Clinique Saint-Joseph Angoulême
2 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
3 UvA - University of Amsterdam [Amsterdam] = Universiteit van Amsterdam
4 Amsterdam UMC - Amsterdam University Medical Centers
5 MPIMG - Max Planck Institute for Molecular Genetics
6 KUGSM - Kyoto University Graduate School of Medicine [Kyoto, Japan]
7 BROAD INSTITUTE - Broad Institute of MIT and Harvard
8 Kyoto University
9 NCGM - National Center for Global Health and Medicine [Japan]
10 National cerebral and cardiovascular center research institute
11 Shiga University of Medical Science
12 Massachusetts General Hospital [Boston]
13 HMS - Harvard Medical School [Boston]
14 RADEME - Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364
15 Hôpital Jeanne de Flandre [Lille]
16 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
17 Hôpitaux La Rochelle Ré Aunis [Groupe hospitalier littoral Atlantique]
18 CNRGH - Centre National de Recherche en Génomique Humaine
19 Université Paris-Saclay
20 ERN GUARD-Heart - European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart
21 CSJA - Clinique Saint-Joseph Angoulême
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.
Domaines
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