Sex modulates genome regulatory system in heart failure in humans 

ABSTRACT: Heart failure and other cardiomyopathies have distinct presentations in males versus females that are often overlooked, leading to ineffective treatment, and contributing to the growing mortality from heart diseases. Understanding the differences in the pathogenesis of heart disease in males and females can guide early diagnostics and sex-specific therapy. Thus, there is a pressing need to investigate the sex-specificity of promoter and enhancer activity in the pathogenesis of heart failure. Here, using cap analysis of gene expression we characterize the sex-specific activity of transcriptional regulatory elements in 17 male and 14 female healthy and failing hearts. We show that differentially expressed transcribed regulatory elements between two sexes are spread throughout the entire genome in healthy and failing atria and ventricles, and are related to immune system, metabolic, cardiomyocyte function, and developmental pathways. Moreover, we found 720 genes with sex-dependent promoter switching of which 40 switched dominant promoters. Among those was CREM, a transcription factor, with a short repressive dominant isoform exclusive for males. CREM is related to extensive β-adrenergic receptor stimulation that leads to elevated arrhythmic activity, hypertrophy and heart dysfunction. Furthermore, we identified metabolic pathways being more responsible for female aging and developmental pathways for male aging. We also showed sex-specific aging patterns, such as age-specific promoter usage of 1,100 genes that behaved differently depending on sex, including UCKL1 and HAND2 linked to uridine metabolism and cardiac development, respectively.

ORGANISM(S): Homo sapiens

PROVIDER: GSE212695 | GEO | 2023/04/27

REPOSITORIES: GEO