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

Pablo Gómez-del Arco (), Joan Isern, Daniel Jimenez-Carretero, Dolores López-Maderuelo, Rebeca Piñeiro-Sabarís, Fadoua El Abdellaoui-Soussi, Carlos Torroja, María Linarejos Vera-Pedrosa, Mercedes Grima-Terrén, Alberto Benguria, Ana Simón-Chica, Antonio Queiro-Palou, Ana Dopazo, Fátima Sánchez-Cabo, José Jalife, José Luis Pompa, David Filgueiras-Rama, Pura Muñoz-Cánoves () and Juan Miguel Redondo ()
Additional contact information
Pablo Gómez-del Arco: Instituto de Salud Carlos III (ISCIII). Majadahonda
Joan Isern: San Diego Institute of Science
Daniel Jimenez-Carretero: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Dolores López-Maderuelo: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Rebeca Piñeiro-Sabarís: Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV)
Fadoua El Abdellaoui-Soussi: Instituto de Salud Carlos III (ISCIII). Majadahonda
Carlos Torroja: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
María Linarejos Vera-Pedrosa: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Mercedes Grima-Terrén: San Diego Institute of Science
Alberto Benguria: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Ana Simón-Chica: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Antonio Queiro-Palou: Instituto de Salud Carlos III (ISCIII). Majadahonda
Ana Dopazo: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Fátima Sánchez-Cabo: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
José Jalife: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
José Luis Pompa: Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV)
David Filgueiras-Rama: Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV)
Pura Muñoz-Cánoves: San Diego Institute of Science
Juan Miguel Redondo: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52809-1

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