Plasma growth hormone pulses induce male-biased pulsatile chromatin opening and epigenetic regulation in adult mouse liver

Abstract

- Sex-differences in plasma growth hormone (GH) profiles, pulsatile in males and persistent in females, regulate sex differences in hepatic STAT5 activation linked to sex differences in gene expression and liver disease susceptibility, but little is understood about the fundamental underlying, GH pattern-dependent regulatory mechanisms. Here, DNase hypersensitivity site (DHS) analysis of liver chromatin accessibility in a cohort of 21 individual male mice established that the endogenous male rhythm of plasma GH pulse-stimulated liver STAT5 activation induces repeated cycles of chromatin opening and closing at several thousand liver DHS and comprises one of two distinct mechanisms conferring male bias to liver chromatin accessibility. Sex-dependent transcription factor binding patterns and chromatin state analysis identified key factors and epigenetic features distinguishing this dynamic, STAT5-driven mechanism of male-biased chromatin opening from that operative at static male-biased DHS, which are constitutively open in male but not female liver. Notably, dynamic but not static male-biased DHS adopt a bivalent epigenetic state in female liver, as do female-biased DHS in male liver, albeit using distinct repressive histone marks in each sex (H3K27me3 at female-biased DHS in male liver, H3K9me3 at male-biased DHS in female liver). Strikingly, a single physiological replacement dose of GH given to hypophysectomized male mice restored, within 30 min, liver STAT5 activity and chromatin accessibility at 83% of the dynamic male-biased DHS that closed following pituitary hormone ablation. Pulsatile chromatin opening stimulated by endogenous, physiological hormone pulses is thus a novel mechanism for establishing widespread sex differences in chromatin accessibility and transcription factor binding, which are closely linked to sex-biased gene expression and the sexual dimorphism of liver function.