Unexpected XIST Expression in Male Hearts Associates with Disease

XIST is a long non-coding RNA that mediates the process of X chromosome inactivation in females, and has not been previously observed in males outside of developmental, pathological, and ectopic contexts. We report the unprecedented endogenous expression of XIST in 226 male heart samples across 15 single-cell RNA sequencing studies. The male expression of XIST is specific to a rare cell type typically annotated as neurons or glia. We investigate a variety of explanations and cross-reference the expression of XIST against age, sex, and pathology, finding signatures of a non-canonical inhibitory program, potentially mediated by a truncated transcript. Interestingly, the highest-powered datasets exhibit XIST upregulation in heart disease and comorbidity donors relative to healthier controls. Furthermore, in humans we identify a male-specific association of the XIST genomic locus with myocardial infarction (p = 1.3 x 10-4). Taken together, our findings suggest that the pathology of cardiomyopathy may involve uncharacterized, therapeutically actionable non-coding RNA pathways that operate through the cardiac nervous system, and underscore the importance of genomic investigations of the X chromosome.