2. Academic Validation
  3. The G4 resolvase Dhx36 modulates cardiomyocyte differentiation and ventricular conduction system development

The G4 resolvase Dhx36 modulates cardiomyocyte differentiation and ventricular conduction system development

  • Nat Commun. 2024 Oct 4;15(1):8602. doi: 10.1038/s41467-024-52809-1.
Pablo Gómez-Del Arco 1 2 3,  Joan Isern 4 5,  Daniel Jimenez-Carretero 6,  Dolores López-Maderuelo 7 8,  Rebeca Piñeiro-Sabarís 9 10,  Fadoua El Abdellaoui-Soussi 11 7 12,  Carlos Torroja 6,  María Linarejos Vera-Pedrosa 13,  Mercedes Grima-Terrén 4 5,  Alberto Benguria 14,  Ana Simón-Chica 15,  Antonio Queiro-Palou 11 7 16,  Ana Dopazo 14,  Fátima Sánchez-Cabo 6,  José Jalife 13 17,  José Luis de la Pompa 9 10,  David Filgueiras-Rama 9 15 18,  Pura Muñoz-Cánoves 19 20 21 22,  Juan Miguel Redondo 23 24 25
Affiliations

Affiliations

  • 1 Institute for Rare Diseases Research, Instituto de Salud Carlos III (ISCIII). Majadahonda, Madrid, Spain. pgomez@isciii.es.
  • 2 Gene Regulation in Cardiovascular Remodelling and Inflammation Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain. pgomez@isciii.es.
  • 3 Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain. pgomez@isciii.es.
  • 4 Altos Labs, Inc., San Diego Institute of Science, San Diego, CA, USA.
  • 5 Tissue Regeneration Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
  • 6 Bioinformatics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
  • 7 Gene Regulation in Cardiovascular Remodelling and Inflammation Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
  • 8 Microscopy and Dynamic Imaging Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
  • 9 Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain.
  • 10 Intercellular Signaling in Cardiovascular Development and Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
  • 11 Institute for Rare Diseases Research, Instituto de Salud Carlos III (ISCIII). Majadahonda, Madrid, Spain.
  • 12 Center for Stem Cells and Organoid Medicine (CuSTOM), Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • 13 Cardiac Arrhythmia Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
  • 14 Genomics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
  • 15 Novel Arrhythmogenic Mechanisms Program, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
  • 16 Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
  • 17 University of Michigan, Ann Arbor, MI, USA.
  • 18 Cardiovascular Institute, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
  • 19 Altos Labs, Inc., San Diego Institute of Science, San Diego, CA, USA. pmunozcanoves@altoslabs.com.
  • 20 Tissue Regeneration Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain. pmunozcanoves@altoslabs.com.
  • 21 Department of Experimental & Health Sciences, University Pompeu Fabra (UPF)/CIBERNED, Barcelona, Spain. pmunozcanoves@altoslabs.com.
  • 22 Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain. pmunozcanoves@altoslabs.com.
  • 23 Gene Regulation in Cardiovascular Remodelling and Inflammation Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain. jmredondo@cbm.csic.es.
  • 24 Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain. jmredondo@cbm.csic.es.
  • 25 Cell-Cell Communication & Inflammation Unit, Centro de Biología Molecular Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain. jmredondo@cbm.csic.es.
PMID: 39366945 DOI: 10.1038/s41467-024-52809-1
Abstract

Extensive genetic studies have elucidated cardiomyocyte differentiation and associated gene networks using single-cell RNA-seq, yet the intricate transcriptional mechanisms governing cardiac conduction system (CCS) development and working cardiomyocyte differentiation remain largely unexplored. Here we show that mice deleted for Dhx36 (encoding the Dhx36 helicase) in the embryonic or neonatal heart develop overt dilated cardiomyopathy, surface ECG alterations related to cardiac impulse propagation, and (in the embryonic heart) a lack of a ventricular conduction system (VCS). Heart snRNA-seq and snATAC-seq reveal the role of Dhx36 in CCS development and in the differentiation of working cardiomyocytes. Dhx36 deficiency directly influences cardiomyocyte gene networks by disrupting the resolution of promoter G-quadruplexes in key cardiac genes, impacting cardiomyocyte differentiation and CCS morphogenesis, and ultimately leading to dilated cardiomyopathy and atrioventricular block. These findings further identify crucial genes and pathways that regulate the development and function of the VCS/Purkinje fiber (PF) network.

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