Feminization of Male Mouse Liver by Persistent Growth Hormone Stimulation: Activation of Sex-Biased Transcriptional Networks and Dynamic Changes in Chromatin States.
Feminization of Male Mouse Liver by Persistent Growth Hormone Stimulation: Activation of Sex-Biased Transcriptional Networks and Dynamic Changes in Chromatin States.
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DOI：
10.1128/mcb.00301-17
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发表时间：
2017-10-01
影响因子：
5.3
通讯作者：
Waxman DJ
中科院分区：
文献类型：
--
作者：
Lau-Corona D;Suvorov A;Waxman DJ
性别相关的垂体生长激素(GH)分泌谱--雄性为搏动性的，雌性为持续性的--调节小鼠肝脏中数百个基因的性别偏向、STAT5依赖的表达，赋予肝脏药物/脂肪代谢和疾病风险的性别差异。在这里，我们研究了持续GH输注(CGH)在雄性小鼠中诱导的转录和表观遗传学变化，它迅速女性化了肝脏STAT5活动的时间分布。CGH在4天内抑制了86%的雄性偏向基因，诱导了68%的雌性偏向基因；然而，即使在处理14天后，一些高度雌性特异的基因也表现出微弱的女性化或没有女性化。在男性肝脏中，已经处于活跃染色质状态的偏向女性的基因通常表现出早期的CGH反应；而处于非活跃染色质状态的基因通常反应较晚。早期的CGH反应基因包括编码两个GH/STAT5调节的转录抑制因子的基因：男性偏向的BCL6被抑制，女性特有的CUX2被诱导。被STAT5激活和/或被CUX2抑制的男性偏向基因为早期CGH抑制而富含。女性偏向的BCL6靶标被浓缩以用于早期CGH去抑制。性别特异性染色质可及性和组蛋白修饰的变化伴随着CGH诱导的性别偏见基因表达的变化。因此，对持续GH刺激的时间性、性别偏见的基因反应是由GH/STAT5调节的转录因子在分层网络中安排的，并由性别偏见表观遗传状态的变化动态决定的。
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.