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

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• dc.contributor.author Gómez del Arco, Pablo
• dc.contributor.author Muñoz Cánoves, Pura, 1962-
• dc.contributor.author Redondo, Juan Miguel
• dc.date.accessioned 2025-04-07T06:15:19Z
• dc.date.available 2025-04-07T06:15:19Z
• dc.date.issued 2024
• dc.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.
• dc.description.sponsorship This work was supported by the Spanish Ministerio de Ciencia e Innovación (MICINN; grant RTI2018-096068), ERC-2016-AdG-741966, LaCaixa-HEALTH-HR17-00040, MDA, UPGRADE-H2020-825825, AFM, DPP-Spain, SGR, Fundació La MaratóTV3-80/19-202021, and MWRF; María-de-Maeztu Program for Units of Excellence to UPF (MDM-2014-0370) and the Severo-Ochoa Program for Centers of Excellence to CNIC (SEV-2015-0505) to P.M-C. The grants SAF2016-77816-P and PID2020-114773GB-I00 from MCIN/AEI/10.13039/501100011033 supported P.G-A. The grants PID2021-122388OB-100 from MCIN/AEI/10.13039/501100011033; and RED2024-154025-T; the Comunidad de Madrid and European Social Fund (ESF) grant AORTASANA-CM (B2017/BMD-3676); Fundació La Marató 2023 grant 202334-30-31; La Caixa Banking Foundation (project code HR18-00068); the MICINN – to JFN and JMR –; and the Instituto de Salud Carlos III (ISCIII) (CIBER-CVCB16/11/00264) supported JMR. The grants PID2022-104776RB-100 and CB16/11/00399 (CIBER CV) from MCIN/AEI/10.13039/501100011033, and La Caixa Research Health Foundation (Ref. HR23-00084) supported J.L.P. La Caixa Banking Foundation (HR18-00304); Severo Ochoa CNIC Intramural Project 12-2016 IGP; Fundació La MaratóTV3 (Ayudas a la investigación en enfermedades raras 2020: LAMARATO-2020); the ISCIII; and the European Commission (MAESTRIA H2020) supported J.J. The European Union Horizon 2020 research and innovation program under Grant Agreement#965286; the MCIN (grant#PID2019-109329RB-I00); Fondo Europeo de Desarrollo Regional (CB16/11/00458) and the Heart Rhythm Association of the Spanish Society of Cardiology supported DF. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation). The CBMSO is supported by Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid. CBMSO and CNIC are Severo Ochoa Centers of Excellence (grants CEX2021-001154-S and CEX2020-001041-S, respectively) funded by MCIN/AEI/10.13039/501100011033. FAS was supported by a Science and Innovation Fellowship (BES-2017-080629).
• dc.format.mimetype application/pdf
• dc.identifier.citation Gómez-Del Arco P, Isern J, Jimenez-Carretero D, López-Maderuelo D, Piñeiro-Sabarís R, El Abdellaoui-Soussi F, et al. 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
• dc.identifier.doi http://dx.doi.org/10.1038/s41467-024-52809-1
• dc.identifier.issn 2041-1723
• dc.identifier.uri http://hdl.handle.net/10230/70097
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nat Commun. 2024 Oct 4;15(1):8602
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/741966
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-096068
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/825825
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2016-77816-P
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-114773GB-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-122388OB-100
• dc.relation.projectID info:eu-repo/grantAgreement/ES/4PE/RED2024-154025-T
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2022-104776RB-100
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/965286
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-109329RB-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/CEX2021-001154-S
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/CEX2020-001041-S
• dc.rights © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
• dc.subject.keyword Arrhythmias
• dc.subject.keyword Cardiac hypertrophy
• dc.subject.keyword Gene regulation
• dc.subject.keyword Heart development
• dc.title The G4 resolvase Dhx36 modulates cardiomyocyte differentiation and ventricular conduction system development
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion