STAT5 Regulation of Sex-Dependent Hepatic CpG Methylation at Distal Regulatory Elements Mapping to Sex-Biased Genes.

Growth hormone-activated is an essential regulator of sex-differential gene expression in mouse liver; however, its impact on hepatic gene expression and epigenetic responses is poorly understood. Here, we found a substantial, albeit incomplete loss of liver sex bias in hepatocyte-specific (collectively, mouse liver. In male liver, many male-biased genes were downregulated in direct association with the loss of binding; many female-biased genes, which show low duanyu18135 binding, were derepressed, indicating an indirect mechanism for repression by Extensive changes in CpG methylation were seen in liver, where sex differences were abolished at 88% of ∼1,500 sex-differentially methylated regions, largely due to increased DNA methylation upon duanyu18135 loss. CpG hypomethylation was rarely found at proximal promoters of duanyu18135-dependent genes. Rather, duanyu18135 primarily regulated the methylation of distal enhancers, where duanyu18135 deficiency induced widespread hypermethylation at genomic regions enriched for accessible chromatin, enhancer histone marks (histone H3 lysine 4 monomethylation [H3K4me1] and histone H3 lysine 27 acetylation [H3K27ac]), duanyu18135 binding, and DNA motifs for duanyu18135 and other transcription factors implicated in liver sex differences. Thus, the sex-dependent binding of duanyu18135 to liver chromatin is closely linked to the sex-dependent demethylation of distal regulatory elements linked to duanyu18135-dependent genes important for liver sex bias. Copyright © 2021 American Society for Microbiology.

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