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The G4 resolvase Dhx36 modulates cardiomyocyte differentiation and ventricular conduction system development
Pablo Gómez-Del Arco1,2,3, Joan Isern4,5, Daniel Jimenez-Carretero6
1Institute for Rare Diseases Research, Instituto de Salud Carlos III (ISCIII). Majadahonda, Madrid, Spain. pgomez@isciii.es.
Nature Communications
|October 4, 2024
Summary
Dhx36 helicase is crucial for heart development. Its deficiency in mice causes dilated cardiomyopathy and conduction system defects, impacting cardiac impulse propagation.
Area of Science:
- Cardiovascular Biology
- Molecular Genetics
- Developmental Biology
Background:
- Single-cell RNA-seq has advanced understanding of cardiomyocyte differentiation.
- Transcriptional mechanisms of cardiac conduction system (CCS) development are less understood.
Purpose of the Study:
- Investigate the role of Dhx36 helicase in CCS development and working cardiomyocyte differentiation.
- Elucidate the molecular mechanisms underlying Dhx36-dependent cardiac function.
Main Methods:
- Genetic deletion of Dhx36 in embryonic and neonatal mouse hearts.
- Single-nucleus RNA sequencing (snRNA-seq) and single-nucleus ATAC sequencing (snATAC-seq).
- Analysis of electrocardiogram (ECG) alterations and cardiac morphology.
Main Results:
- Dhx36 deficiency leads to dilated cardiomyopathy, ECG abnormalities, and absent ventricular conduction system (VCS).
- snRNA-seq and snATAC-seq reveal Dhx36's role in CCS development and cardiomyocyte differentiation.
- Dhx36 disruption impacts G-quadruplex resolution in cardiac genes, affecting differentiation and morphogenesis.
Conclusions:
- Dhx36 is essential for proper CCS development and working cardiomyocyte differentiation.
- Disruption of Dhx36 leads to severe cardiac dysfunction, including dilated cardiomyopathy and atrioventricular block.
- Identifies key genes and pathways regulating VCS/Purkinje fiber network development.
