ArticleNature communications2024
TAD boundary deletion causes PITX2-related cardiac electrical and structural defects.
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Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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23citing papers in PubMed
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23 citing papers in PubMed, 23 citations in OpenAlex.
- Mechanisms underlying disease-causing variants in promoters and enhancers.Nature genetics · 2026Review
- dicast: a machine learning method for accurate structural variant detection from short-read sequencing data.Genome biology · 2026Article
- The cardiac 4D nucleome: nuclear and chromatin dynamics across development, disease and ageing.Nature reviews. Cardiology · 2026Review
- Whole-genome sequencing implicates rare, low-frequency and structural non-coding variation at themedRxiv : the preprint server for health sciences · 2026Article
- CT-TADB predicts TAD boundaries without Hi-C by integrating DNA sequences and epigenomic features.NPJ systems biology and applications · 2026Article
- The cardiac conduction system: development, function and therapeutic targets.Nature reviews. Cardiology · 2026Review
- CD40/PI3K/FOXO1 axis rewiring drives microenvironment-dependent BIM silencing to sustain lymphoma growth and survival.Leukemia · 2026Article
- Structural variants in human congenital heart disease disrupt distal genomic regulatory contacts of developmental genes.bioRxiv : the preprint server for biology · 2026Article
- Unravelling the genetic architecture of cardiovascular disease through structural variant detection with whole-genome sequencing.Frontiers in genetics · 2026Review
- Spatial Reorganization of Chromatin Architecture Shapes the Expression Phenotype of Therapy-Induced Senescent Cells.Aging cell · 2026Article
- Functional architecture of cardiac TF regulatory landscapes in control of mammalian heart development.bioRxiv : the preprint server for biology · 2025Article
- PITX2 dosage-dependent changes in pacemaker cell state underlie sinus node dysfunction and atrial arrhythmias.Nature communications · 2025Article
- Structural variants in the 3D genome as drivers of disease.Nature reviews. Genetics · 2025Review
- Genetic and epigenetic architectures of stroke: Insights from GWAS to precision medicine.Neurochemistry international · 2025Review
- Nuclear FGF2 orchestrates phase separation-mediated rDNA chromatin architecture to control BMSCs cell fate.Bone research · 2025Article
- The Biological Function of Genome Organization.International journal of molecular sciences · 2025Review
- Bystander activation across a TAD boundary supports a cohesin-dependent transcription cluster model for enhancer function.Genes & development · 2025Article
- Evolution of the management of ultrarare inherited arrhythmias and cardiomyopathies.Future cardiology · 2025Article
- Deletion of a single CTCF motif at the boundary of a chromatin domain with three FGF genes disrupts gene expression and embryonic development.Developmental cell · 2025Article
- Cohesin in 3D: development, differentiation, and disease.Genes & development · 2025Review
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Authors and funding
44 authors at 14 institutions in 5 countries.
Manon Baudic *Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000, Nantes, France.ORCID http://orcid.org/0000-0001-6414-5012
Hiroshige Murata *The Department of Cardiovascular Medicine, Nippon Medical School Hospital, Tokyo, Japan.ORCID http://orcid.org/0000-0002-4627-7326
Fernanda M Bosada *Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
Uirá Souto Melo *Max Planck Institute for Molecular Genetics, RG Development and Disease, 13353, Berlin, Germany.ORCID http://orcid.org/0000-0003-4065-8635
Takanori Aizawa *Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Pierre Lindenbaum *Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000, Nantes, France.ORCID http://orcid.org/0000-0003-0148-9787
Lieve E van der Maarel *Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam Reproduction and Development, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.ORCID http://orcid.org/0000-0001-6686-4029
Amaury GuedonNantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000, Nantes, France.
Estelle BaronNantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000, Nantes, France.
Enora FremyNantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000, Nantes, France.
Adrien FoucalNantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000, Nantes, France.
Taisuke IshikawaOmics Research Center, National Cerebral and Cardiovascular Center, Suita, Japan.ORCID http://orcid.org/0000-0001-8195-4700
Hiroya UshinohamaDepartment of Cardiology, Fukuoka Children's Hospital, Fukuoka, Japan.
Sean J JurgensCardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-1605-9782
Seung Hoan ChoiCardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-2797-3190
Florence KyndtNantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000, Nantes, France.
Solena Le ScouarnecNantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000, Nantes, France.
Vincent WakkerDepartment of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
Aurélie TholletNantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000, Nantes, France.
Annabelle RajaluNantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000, Nantes, France.
Tadashi TakakiDepartment of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
Seiko OhnoDepartment of Bioscience and Genetics, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan.ORCID http://orcid.org/0000-0003-1209-8896
Wataru ShimizuThe Department of Cardiovascular Medicine, Nippon Medical School Hospital, Tokyo, Japan.
Minoru HorieDepartment of Cardiovascular Medicine, Shiga University of Medical Science, Ohtsu, Japan.ORCID http://orcid.org/0000-0002-9029-2339
Takeshi KimuraDepartment of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Patrick T EllinorCardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-2067-0533
Florence PetitService de Génétique Clinique, CHU Lille, Hôpital Jeanne de Flandre, F-59000, Lille, France.ORCID http://orcid.org/0000-0002-1368-1023
Yves DulacUnité de Cardiologie Pédiatrique, Hôpital des Enfants, F-31000, Toulouse, France.
Paul BruService de Cardiologie, GH La Rochelle, F-17019, La Rochelle, France.
Anne BolandUniversité Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), 91057, Evry, France.
Jean-François DeleuzeUniversité Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), 91057, Evry, France.
Richard RedonNantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000, Nantes, France.ORCID http://orcid.org/0000-0001-7751-2280
Hervé Le MarecNantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000, Nantes, France.ORCID http://orcid.org/0000-0002-8288-8693
Thierry Le TourneauNantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000, Nantes, France.ORCID http://orcid.org/0000-0002-0110-9054
Jean-Baptiste GourraudNantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000, Nantes, France.
Yoshinori YoshidaDepartment of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.ORCID http://orcid.org/0000-0001-5511-9090
Naomasa MakitaOmics Research Center, National Cerebral and Cardiovascular Center, Suita, Japan.ORCID http://orcid.org/0000-0002-1807-672X
Claude VieyresCabinet Cardiologique, Clinique St. Joseph, F-16000, Angoulême, France.
Takeru MakiyamaDepartment of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Stephan MundlosMax Planck Institute for Molecular Genetics, RG Development and Disease, 13353, Berlin, Germany.
Vincent M ChristoffelsDepartment of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam Reproduction and Development, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.ORCID http://orcid.org/0000-0003-4131-2636
Vincent ProbstNantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000, Nantes, France.
Jean-Jacques SchottNantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000, Nantes, France. Jean-Jacques.Schott@univ-nantes.fr.
Julien BarcNantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000, Nantes, France. julien.barc@univ-nantes.fr.ORCID http://orcid.org/0000-0003-4106-5946
Centre National de la Recherche Scientifique · FRKyoto University · JPUniversity Medical Center · USBroad Institute · USNational Cerebral and Cardiovascular Center · JPCommissariat à l'Énergie Atomique et aux Énergies Alternatives · FRMax Planck Institute for Molecular Genetics · DENippon Medical School Hospital · JPCentre Hospitalier d'Angoulême · FRCentre Hospitalier de La Rochelle · FRCentre Hospitalier Universitaire de Toulouse · FRFukuoka Children's Hospital and Medical Center for Infectious Diseases · JPShiga University of Medical Science · JPUniversité de Lille · FR
Funding
IDENTIFICATION OF COMMON GENETIC VARIANTS FOR ATRIAL FIBRILLATION AND PR INTERVALR01HL092577 · NHLBI · MASSACHUSETTS GENERAL HOSPITAL · PI BENJAMIN, EMELIA J., ELLINOR, PATRICK THOMAS · 2009 to 2025
$20.6MGenomics of Cardiac ArrhythmiasR01HL139731 · NHLBI · MASSACHUSETTS GENERAL HOSPITAL · PI ELLINOR, PATRICK THOMAS · 2018 to 2022
$3.3MUsing Electrocardiogram Genetics to Inform Arrhythmia RiskR01HL157635 · NHLBI · MASSACHUSETTS GENERAL HOSPITAL · PI ELLINOR, PATRICK THOMAS, MIRSHAHI, TOORAJ · 2022 to 2025
$2.9MNHLBI NIH HHS R01 HL092577NHLBI NIH HHS R01 HL139731NHLBI NIH HHS R01 HL157635
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.
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Induced Pluripotent Stem CellsAnimalsCCCTC-Binding FactorChromatinDNA-Binding ProteinsGenomeHumansMiceCCCTC-Binding FactorChromatinDNA-Binding Proteins
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