Single-nucleus RNA/ATAC-seq in early-stage HCM models predicts SWI/SNF-activation in mutant-myocytes, and allele-specific differences in fibroblasts.

Autor:	Thottakara T; Department of Medicine, University of California San Francisco, Division of Cardiology, San Francisco.; Department of Cardiology, University Heart and Vascular Center Hamburg, Germany., Padmanabhan A; Department of Medicine, University of California San Francisco, Division of Cardiology, San Francisco.; Gladstone Institutes, San Francisco, CA, USA., Tanriverdi T; Department of Medicine, University of California San Francisco, Division of Cardiology, San Francisco., Thambidurai T; Department of Medicine, University of California San Francisco, Division of Cardiology, San Francisco., Diaz-Rg JA; Department of Medicine, University of California San Francisco, Division of Cardiology, San Francisco., Amonkar SR; Department of Medicine, University of California San Francisco, Division of Cardiology, San Francisco., Olgin JE; Department of Medicine, University of California San Francisco, Division of Cardiology, San Francisco., Long CS; Department of Medicine, University of California San Francisco, Division of Cardiology, San Francisco., Roselle Abraham M; Department of Medicine, University of California San Francisco, Division of Cardiology, San Francisco.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Apr 24. Date of Electronic Publication: 2024 Apr 24.
DOI:	10.1101/2024.04.24.589078
Abstrakt:	Hypertrophic cardiomyopathy (HCM) is associated with phenotypic variability. To gain insights into transcriptional regulation of cardiac phenotype, single-nucleus linked RNA-/ATAC-seq was performed in 5-week-old control mouse-hearts (WT) and two HCM-models (R92W-TnT, R403Q-MyHC) that exhibit differences in heart size/function and fibrosis; mutant data was compared to WT. Analysis of 23,304 nuclei from mutant hearts, and 17,669 nuclei from WT, revealed similar dysregulation of gene expression, activation of AP-1 TFs (FOS, JUN) and the SWI/SNF complex in both mutant ventricular-myocytes. In contrast, marked differences were observed between mutants, for gene expression/TF enrichment, in fibroblasts, macrophages, endothelial cells. Cellchat predicted activation of pro-hypertrophic IGF-signaling in both mutant ventricular-myocytes, and profibrotic TGFβ-signaling only in mutant-TnT fibroblasts. In summary, our bioinformatics analyses suggest that activation of IGF-signaling, AP-1 TFs and the SWI/SNF chromatin remodeler complex promotes myocyte hypertrophy in early-stage HCM. Selective activation of TGFβ-signaling in mutant-TnT fibroblasts contributes to genotype-specific differences in cardiac fibrosis. Competing Interests: Competing Interests statement The authors declare no competing interests.
Databáze:	MEDLINE
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