Lau-Corona Dana, Suvorov Alexander, Waxman David J
Department of Biology and Bioinformatics Program, Boston University, Boston, Massachusetts, USA.
Department of Biology and Bioinformatics Program, Boston University, Boston, Massachusetts, USA
Mol Cell Biol. 2017 Sep 12;37(19). doi: 10.1128/MCB.00301-17. Print 2017 Oct 1.
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. 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.
垂体生长激素（GH）的分泌模式存在性别差异——雄性为脉冲式分泌，雌性为持续性分泌——这种差异调节了小鼠肝脏中数百种基因的性别偏向性、依赖信号转导和转录激活因子5（STAT5）的表达，在肝脏药物/脂质代谢及疾病风险方面产生了性别差异。在此，我们研究了连续输注生长激素（cGH）在雄性小鼠中诱导的转录和表观遗传变化，cGH能迅速使肝脏中STAT5活性的时间模式呈现雌性化。cGH在4天内抑制了86%的雄性偏向性基因，并诱导了68%的雌性偏向性基因；然而，即使在cGH处理14天后，一些高度雌性特异性基因的雌性化程度仍较弱或未发生雌性化。在雄性肝脏中已处于活跃染色质状态的雌性偏向性基因通常对cGH有早期反应；处于非活跃染色质状态的基因往往反应较晚。早期对cGH有反应的基因包括那些编码两种受GH/STAT5调节的转录抑制因子的基因：被抑制的雄性偏向性基因B细胞淋巴瘤6（BCL6）和被诱导的雌性特异性基因CUX2。被STAT5激活和/或被CUX2抑制的雄性偏向性基因在早期cGH抑制中富集。雌性偏向性基因BCL6的靶标在早期cGH去抑制中富集。性别特异性染色质可及性和组蛋白修饰的变化伴随着这些cGH诱导的性别偏向性基因表达变化。因此，对持续GH刺激的时间性、性别偏向性基因反应由排列在分层网络中的GH/STAT5调节转录因子以及性别偏向性表观遗传状态变化的动力学所决定。
