Sex modulates the human genome regulatory network during heart failure and aging.

Abstract

Heart failure and other cardiomyopathies have distinct presentations in males versus females that are often overlooked, leading to ineffective treatment and the growing mortality from heart diseases. Understanding the sex dimorphism in the pathogenesis of heart disease can guide improved diagnostics and sex-specific therapy. Thus, we aimed to investigate the sex dimorphism of promoter and enhancer activity in the pathogenesis of heart failure and aging. We applied cap analysis of gene expression (CAGE) to characterize the sex-specific activity of transcribed regulatory elements (TRE) in 17 male and 14 female healthy and failing hearts. We show that TREs exhibit significant sex dimorphism spread throughout the entire genome in healthy and failing atria and ventricles and are related to the immune system, metabolic, cardiomyocyte function, and developmental pathways. Moreover, we found 720 genes with sex-dependent promoter switching, of which 40 switched dominant promoters. One example 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 heart failure, hypertrophy, and arrhythmia. Furthermore, we identified that aging in the female and male hearts is associated with metabolic and developmental pathways, respectively. 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. In conclusion, we report evidence of significant sex dimorphism exhibited in hundreds of transcribed genome regulatory elements in health, heart failure pathogenesis, and aging.