EuroHPC AI in DAPHNE

Cardiovascular disease (CVD) manifests and progresses differently in men and women, a phenomenon known as sex bias. Understanding the mechanisms underlying this sex bias is critical to the development of sex-specific treatments. Hormonal differences have been suggested to account for the sex bias by the observation that younger women are routinely protected from CVD until postmenopause. However, hormone replacement therapies have not provided broad cardioprotection, suggesting that other biological factors contribute to the sex bias. One likely contributor is the set of genes that escape X-chromosome inactivation in females, resulting in higher gene dosage compared to males. Here, we characterized the escape landscape in major organs of the mouse to elucidate the functions of escape genes and the extent of organ- and lineage-specific escape. In addition, we captured gene escape in mouse models of cardiac disease at the celltype resolution and characterized the function of selected candidate genes. The overall goal is to identify novel sex-specific regulatory disease mechanisms with the perspective of developing RNA-based therapies for sex-specific treatment.