The G4 resolvase Dhx36 modulates cardiomyocyte differentiation and ventricular conduction system development.
Animals
Myocytes, Cardiac
/ metabolism
Cell Differentiation
/ genetics
Mice
DEAD-box RNA Helicases
/ genetics
Heart Conduction System
/ metabolism
Mice, Knockout
Cardiomyopathy, Dilated
/ genetics
Atrioventricular Block
/ genetics
G-Quadruplexes
Heart Ventricles
/ cytology
Promoter Regions, Genetic
/ genetics
Gene Regulatory Networks
Male
Female
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
04 Oct 2024
04 Oct 2024
Historique:
received:
03
05
2022
accepted:
19
09
2024
medline:
5
10
2024
pubmed:
5
10
2024
entrez:
4
10
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39366945
doi: 10.1038/s41467-024-52809-1
pii: 10.1038/s41467-024-52809-1
doi:
Substances chimiques
DEAD-box RNA Helicases
EC 3.6.4.13
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
8602Informations de copyright
© 2024. The Author(s).
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