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

Growth hormone-activated STAT5b is an essential regulator of sex-differential gene expression in mouse liver; however, its impact on hepatic and epigenetic responses poorly understood. Here, we found a substantial, albeit incomplete loss liver sex bias hepatocyte-specific STAT5a/STAT5b (collectively, STAT5)-deficient liver. In male liver, many male-biased genes were downregulated direct association with the STAT5 binding; female-biased genes, which show low binding, derepressed, indicating indirect mechanism for repression by STAT5. Extensive changes CpG methylation seen STAT5-deficient where differences abolished at 88% ?1,500 sex-differentially methylated regions, largely due to increased DNA upon loss. STAT5-dependent hypomethylation was rarely proximal promoters genes. Rather, primarily regulated distal enhancers, deficiency induced widespread hypermethylation genomic regions enriched accessible chromatin, enhancer histone marks (histone H3 lysine 4 monomethylation [H3K4me1] 27 acetylation [H3K27ac]), motifs other transcription factors implicated differences. Thus, sex-dependent binding chromatin closely linked demethylation regulatory elements important bias.