Global analyses of genomic and epigenomic influences on gene expression reveal Serpina3n as a major regulator of cardiac gene expression in response to catecholamine challenge during heart failure

Abstract

Heart failure arises from maladaptive remodelling driven by genetic and epigenetic networks. Using a systems genetics framework, we mapped how DNA variants and CpG methylation shape cardiac transcriptomes during beta adrenergic stress in the Hybrid Mouse Diversity Panel, a cohort of over 100 fully inbred mouse strains. Expression QTLs (eQTLs), methylation QTLs (mQTLs) and methylation-driven eQTLs (emQTLs) were generated from over 13k expressed genes and 200k hypervariable CpGs in left ventricles. We discovered hundreds of regulatory 'hotspots' that control large portions of the genome, including several that regulate over 10% of the transcriptome and/or methylome. Approximately 16% of these hotspots overlapped with prior GWAS or EWAS signals. We focus on a hotspot on chromosome 12 and identify the serpine peptidase inhibitor Serpina3n, as the most likely driver gene in this hotspot. Experimental knockdown of Serpina3n in neonatal rat ventricular cardiomyocytes blunted hypertrophy induced by a variety of hypertrophic signals, while altering predicted target expression and modulating the activity of Nppa and Nppb. Together, these findings position Serpina3n as a major regulator of stress-responsive cardiac gene programs, highlighting how integration of genetic and epigenetic signals can pinpoint key drivers of heart failure.

What are the key findings of this study?

Gene expression is how our DNA tells cells what to do. In heart failure, certain genes behave differently due to changes in DNA and chemical markers. This study highlights a gene called Serpina3n, which helps regulate heart functions under stress. Understanding these genetic factors is important because it can lead to better treatments for heart failure. ❤️

Key Points