Growth hormone-activated STAT5b 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 STAT5a/STAT5b (collectively, STAT5)-deficient mouse liver. In male liver, many male-biased genes were downregulated in direct association with the loss of STAT5 binding; many female-biased genes, which show low STAT5 binding, were derepressed, indicating an indirect mechanism for repression by STAT5. Extensive changes in CpG methylation were seen in STAT5-deficient liver, where sex differences were abolished at 88% of ∼1,500 sex-differentially methylated regions, largely due to increased DNA methylation upon STAT5 loss. STAT5-dependent CpG hypomethylation was rarely found at proximal promoters of STAT5-dependent genes. Rather, STAT5 primarily regulated the methylation of distal enhancers, where STAT5 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]), STAT5 binding, and DNA motifs for STAT5 and other transcription factors implicated in liver sex differences. Thus, the sex-dependent binding of STAT5 to liver chromatin is closely linked to the sex-dependent demethylation of distal regulatory elements linked to STAT5-dependent genes important for liver sex bias.

中文翻译：

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STAT5调节性依赖的基因的远端调控元件上的性别依赖性肝CpG甲基化的调控

生长激素激活的STAT5b是小鼠肝脏中性别差异基因表达的重要调节剂。然而，其对肝基因表达和表观遗传反应的影响了解甚少。在这里，我们发现，肝细胞特异性STAT5a / STAT5b（统称STAT5）缺陷的小鼠肝脏中肝性别偏倚的丧失是完全的，尽管不完全。在男性肝脏中，许多男性偏向基因被下调，与STAT5结合的丧失直接相关。许多雌性偏倚的基因显示出低的STAT5结合，它们被抑制，这表明STAT5的间接抑制机制。在STAT5缺失的肝脏中观察到CpG甲基化的广泛变化，在大约1500个性别差异的甲基化区域中，有88％的性别差异被消除，这主要是由于STAT5缺失导致DNA甲基化增加所致。在STAT5依赖性基因的近端启动子上很少发现STAT5依赖性CpG甲基化不足。相反，STAT5主要调节远端增强子的甲基化，其中STAT5缺乏会导致在富含可及的染色质，增强子组蛋白标记（组蛋白H3赖氨酸4单甲基化[H3K4me1]和组蛋白H3赖氨酸27乙酰化[H3K27ac]）的基因组区域引起广泛的高甲基化。以及涉及肝性别差异的STAT5和其他转录因子的DNA基序。因此，STAT5与肝染色质的性别依赖性结合与远端调节元件的性别依赖性脱甲基紧密相关，而远端调节元件与对肝性别偏倚重要的STAT5依赖性基因相关。其中STAT5缺乏导致在富含可及的染色质，增强组蛋白标记（组蛋白H3赖氨酸4单甲基化[H3K4me1]和组蛋白H3赖氨酸27乙酰化[H3K27ac]）的基因组区域引起广泛的甲基化，STAT5结合，以及涉及STAT5和其他转录因子的DNA基序肝脏性别差异。因此，STAT5与肝染色质的性别依赖性结合与远端调节元件的性别依赖性脱甲基紧密相关，而远端调节元件与对肝性别偏倚重要的STAT5依赖性基因相关。其中STAT5缺乏导致在富含可及的染色质，增强组蛋白标记（组蛋白H3赖氨酸4单甲基化[H3K4me1]和组蛋白H3赖氨酸27乙酰化[H3K27ac]）的基因组区域引起广泛的甲基化，STAT5结合，以及涉及STAT5和其他转录因子的DNA基序肝脏性别差异。因此，STAT5与肝染色质的性别依赖性结合与远端调节元件的性别依赖性脱甲基紧密相关，而远端调节元件与对肝性别偏倚重要的STAT5依赖性基因相关。STAT5和其他转录因子的DNA基序与肝脏性别差异有关。因此，STAT5与肝染色质的性别依赖性结合与远端调节元件的性别依赖性脱甲基紧密相关，而远端调节元件与对肝性别偏倚重要的STAT5依赖性基因相关。STAT5和其他转录因子的DNA基序与肝脏性别差异有关。因此，STAT5与肝染色质的性别依赖性结合与远端调节元件的性别依赖性脱甲基紧密相关，而远端调节元件与对肝性别偏倚重要的STAT5依赖性基因相关。