Disruption of the Uty epigenetic regulator locus in hematopoietic cells phenocopies the profibrotic attributes of Y chromosome loss in heart failure

Heart failure is a prevalent condition that affects millions of people worldwide with men exhibiting a higher incidence than women. However, the mechanisms underlying this sex difference remain poorly understood. Our previous work has shown that the presence of mosaic loss of Y chromosome (LOY) in leukocytes is causally associated with increased risk for heart failure. In the current study, we show that LOY macrophages from the failing hearts of humans with dilated cardiomyopathy exhibit widespread changes in gene expression that correlate with fibroblast activation in the myocardium, and we identify the ubiquitously transcribed tetratricopeptide Y linked (Uty) gene in leukocytes as a causal locus for accelerated progression of heart failure in male mice with LOY. Using single-cell multiomics analysis, we demonstrate that Uty disruption leads to epigenetic alterations in both monocytes and macrophages, increasing the propensity of differentiation into pro-fibrotic macrophages that can contribute to cardiac fibrosis and dysfunction. These findings shed light on the mechanisms that contribute to the higher incidence of heart failure in males and suggest potential targets for treatment of heart failure patients with LOY in leukocytes. Overall design: Cardiac immune cells derived from BMT were isolated by tissue digestion and single cell dissociation of cardiac tissue 7 days post-TAC. Briefly, hearts from Control or UTYGT BMT mice were isolated 7 days post-TAC from three mice in each condition, cardiac tissue was digested using a digestion solution containing collagenase I (450 U/ml), collagenase XI (125 U/ml), hyaluronidase (450 U/ml), and DNAseI (60 U/ml) with subsequent homogenization, and live BMT-derived cardiac immune cells were isolated by FACS for the DAPI-CD45.2+ population. Single cell suspensions were then pooled between three mice at equal proportions.