Sex-specific control of human heart maturation by the progesterone receptor [bulk_ATACseq_human]

The physiological adaptation of the heart to the postnatal environment is one of the most critical developmental transitions in the life of mammals. Despite in depth knowledge of the molecular mechanisms controlling embryonic heart development, little is known about the signals that govern postnatal maturation of the heart in humans. Here, we analyse the transcriptome of more than 50,000 single cells in the developing human heart from early gestation to adulthood, which enabled mapping of developmental trajectories across 7 main classes of cardiac cells over time. Striking sex-specific differences in cardiomyocyte maturation were identified and subsequently confirmed via deep RNA sequencing of purified cardiomyocytes. To identify transcriptional drivers of these changes, ATAC-seq was used to assay the open chromatin landscape, which unveiled the progesterone receptor as a key mediator of sex-dependent transcriptional changes during cardiomyocyte maturation. Functional studies in mice, as well as human pluripotent stem cell-derived cardiomyocytes and organoids, validated the progesterone receptor as a mediator of sex-specific metabolic programs and as a cardiac inotrope, consistent with a role in developmental maturation. These datasets provide a blueprint for understanding sex-specific mechanisms governing human heart development and unveil an important role for the progesterone receptor in cardiomyocyte maturation. Chromatin landscape analysis of cardiomyocytes from 3 different human developmental stages and 2 induced human pluripotent stem cell differentiated cardiomyocyte lines.