Abstract
ABSTRACTSex-dependent pituitary growth hormone (GH) secretory profiles—pulsatile in males and persistent in females—regulate the sex-biased, STAT5-dependent expression of hundreds of genes in mouse liver, imparting sex differences in hepatic drug/lipid metabolism and disease risk. Here, we examine transcriptional and epigenetic changes induced by continuous GH infusion (cGH) in male mice, which rapidly feminizes the temporal profile of liver STAT5 activity. cGH repressed 86% of male-biased genes and induced 68% of female-biased genes within 4 days; however, several highly female-specific genes showed weak or no feminization, even after 14 days of cGH treatment. Female-biased genes already in an active chromatin state in male liver generally showed early cGH responses; genes in an inactive chromatin state often responded late. Early cGH-responsive genes included those encoding two GH/STAT5-regulated transcriptional repressors: male-biased BCL6, which was repressed, and female-specific CUX2, which was induced. Male-biased genes activated by STAT5 and/or repressed by CUX2 were enriched for early cGH repression. Female-biased BCL6 targets were enriched for early cGH derepression. Changes in sex-specific chromatin accessibility and histone modifications accompanied these cGH-induced sex-biased gene expression changes. Thus, the temporal, sex-biased gene responses to persistent GH stimulation are dictated by GH/STAT5-regulated transcription factors arranged in a hierarchical network and by the dynamics of changes in sex-biased epigenetic states.
Highlights
Sex-dependent pituitary growth hormone (GH) secretory profiles—pulsatile in males and persistent in females—regulate the sex-biased, STAT5-dependent expression of hundreds of genes in mouse liver, imparting sex differences in hepatic drug/lipid metabolism and disease risk
The female-biased BCL6 target genes are strongly enriched for early continuous GH infusion (cGH)-inducible genes and are depleted of late cGH-inducible genes (Fig. 4E), consistent with our earlier finding that BCL6 preferentially represses female-biased genes in male liver [29]. These findings indicate that the early induction of Cux2 and the early repression of Bcl6 by cGH infusion both contribute to the subsequent repression of male-biased genes and induction of female-biased genes in male liver
We found that cGH-responsive female-biased genes already in an active chromatin state in male liver are enriched for early cGH responses and depleted from the set of late response genes
Summary
Sex-dependent pituitary growth hormone (GH) secretory profiles—pulsatile in males and persistent in females—regulate the sex-biased, STAT5-dependent expression of hundreds of genes in mouse liver, imparting sex differences in hepatic drug/lipid metabolism and disease risk. CGH-responsive genes included those encoding two GH/STAT5-regulated transcriptional repressors: male-biased BCL6, which was repressed, and female-specific CUX2, which was induced. Females are more susceptible to acute liver failure, autoimmune hepatitis, and toxin-mediated hepatotoxicity [5], while males are more susceptible to liver fibrosis progression [6] and hepatocellular carcinoma [7,8,9] Underlying these phenotypic sex differences are sex differences in the expression of an unexpectedly large number of genes, as shown in mouse, rat, and human livers [10,11,12,13], including genes involved in lipid metabolism associated with dyslipidemia and cardiovascular disease risk in humans [13]. The sex-specific transcriptional actions of GH-activated STAT5 are enhanced by several GH/STAT5-regulated transcription factors, including BCL6 [30], a male-biased transcriptional repressor [31] that preferentially represses female-biased genes in male liver [29], and CUX2 [32], a female-specific repressor [33] that downregulates a subset of male-biased genes in female liver but can activate a subset of female-biased genes [34]
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