2026-04-13T07:15:21Zhttps://recercat.cat/oai/request

oai:recercat.cat:10230/700972025-10-03T00:08:25Zcom_2072_6col_2072_452952

00925njm 22002777a 4500 dc Gómez del Arco, Pablo author Muñoz Cánoves, Pura, 1962- author Redondo, Juan Miguel author 2025-04-07T06:15:19Z 2025-04-07T06:15:19Z 2024 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. 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). Arrhythmias Cardiac hypertrophy Gene regulation Heart development The G4 resolvase Dhx36 modulates cardiomyocyte differentiation and ventricular conduction system development