The G4 resolvase Dhx36 modulates cardiomyocyte differentiation and ventricular conduction system development
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 unexplo...
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| Format: | Article |
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Nature Portfolio
2024-10-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-52809-1 |
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| author | 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 de la Pompa David Filgueiras-Rama Pura Muñoz-Cánoves Juan Miguel Redondo |
| author_facet | 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 de la Pompa David Filgueiras-Rama Pura Muñoz-Cánoves Juan Miguel Redondo |
| author_sort | Pablo Gómez-del Arco |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-6e6e018aa0f54c20af7b9385311cf831 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-6e6e018aa0f54c20af7b9385311cf8312025-08-20T03:43:11ZengNature PortfolioNature Communications2041-17232024-10-0115112010.1038/s41467-024-52809-1The G4 resolvase Dhx36 modulates cardiomyocyte differentiation and ventricular conduction system developmentPablo Gómez-del Arco0Joan Isern1Daniel Jimenez-Carretero2Dolores López-Maderuelo3Rebeca Piñeiro-Sabarís4Fadoua El Abdellaoui-Soussi5Carlos Torroja6María Linarejos Vera-Pedrosa7Mercedes Grima-Terrén8Alberto Benguria9Ana Simón-Chica10Antonio Queiro-Palou11Ana Dopazo12Fátima Sánchez-Cabo13José Jalife14José Luis de la Pompa15David Filgueiras-Rama16Pura Muñoz-Cánoves17Juan Miguel Redondo18Institute for Rare Diseases Research, Instituto de Salud Carlos III (ISCIII). MajadahondaAltos Labs, Inc., San Diego Institute of ScienceBioinformatics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)Gene Regulation in Cardiovascular Remodelling and Inflammation Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV)Institute for Rare Diseases Research, Instituto de Salud Carlos III (ISCIII). MajadahondaBioinformatics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)Cardiac Arrhythmia Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)Altos Labs, Inc., San Diego Institute of ScienceGenomics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)Novel Arrhythmogenic Mechanisms Program, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)Institute for Rare Diseases Research, Instituto de Salud Carlos III (ISCIII). MajadahondaGenomics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)Bioinformatics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)Cardiac Arrhythmia Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV)Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV)Altos Labs, Inc., San Diego Institute of ScienceGene Regulation in Cardiovascular Remodelling and Inflammation Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)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.https://doi.org/10.1038/s41467-024-52809-1 |
| spellingShingle | 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 de la Pompa David Filgueiras-Rama Pura Muñoz-Cánoves Juan Miguel Redondo The G4 resolvase Dhx36 modulates cardiomyocyte differentiation and ventricular conduction system development Nature Communications |
| title | The G4 resolvase Dhx36 modulates cardiomyocyte differentiation and ventricular conduction system development |
| title_full | The G4 resolvase Dhx36 modulates cardiomyocyte differentiation and ventricular conduction system development |
| title_fullStr | The G4 resolvase Dhx36 modulates cardiomyocyte differentiation and ventricular conduction system development |
| title_full_unstemmed | The G4 resolvase Dhx36 modulates cardiomyocyte differentiation and ventricular conduction system development |
| title_short | The G4 resolvase Dhx36 modulates cardiomyocyte differentiation and ventricular conduction system development |
| title_sort | g4 resolvase dhx36 modulates cardiomyocyte differentiation and ventricular conduction system development |
| url | https://doi.org/10.1038/s41467-024-52809-1 |
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