Activation of Male Liver Chromatin Accessibility and STAT5-Dependent Gene Transcription by Plasma Growth Hormone Pulses
Activation of Male Liver Chromatin Accessibility and STAT5-Dependent Gene Transcription by Plasma Growth Hormone Pulses
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DOI：
10.1210/en.2017-00060
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发表时间：
2017-05-01
期刊：
影响因子：
4.8
通讯作者：
Waxman, David J.
中科院分区：
文献类型：
--
作者：
Connerney, Jeannette;Lau-Corona, Dana;Waxman, David J.
垂体生长激素（GH）分泌的性别差异（雄性中的脉冲式与雌性中的近连续/持续性）赋予成年小鼠肝脏中数百个基因性别依赖性表达。信号转导子和转录激活子（STAT）5是一种GH激活的转录因子，对肝脏性别二型性至关重要，直接响应每个雄性血浆GH脉冲而动态激活。然而，GH诱导的STAT 5脉冲对肝脏染色质可及性和下游转录事件的影响是未知的。在这项研究中，我们研究了垂体切除小鼠单脉冲GH对局部肝染色质可及性（DNA酶超敏位点分析），转录率（异质核RNA分析）和基因表达（定量聚合酶链反应和RNA测序）的影响，确定30，90或240分钟后。STAT 5依赖性，但性别无关的早期GH反应基因Igf 1和Cish显示快速，GH脉冲诱导的染色质可及性和基因转录的增加，逆转垂体切除术的影响。在垂体切除的雄性小鼠中，一些（Ces 2b，Ugt 2b 38）也诱导了肝脏染色质可及性和转录活性的快速增加，但其他肝脏STAT 5依赖性雄性偏向基因（Cyp 7 b1）则没有。此外，在垂体完整的雄性小鼠中，Igf 1，Cish，Ces 2b和Ugt 2b 38都显示出显着的染色质开放和关闭周期，以及诱导基因转录的相关周期，这些周期密切关注肝脏STAT 5活性的每个内源性脉冲。因此，男性血浆GH脉动的内源性节律动态开放，然后关闭肝染色质在离散的，本地化的监管网站在时间与Igf 1，Cish的转录激活，和一个子集的STAT 5依赖男性偏置基因。
Sex differences in pituitary growth hormone (GH) secretion (pulsatile in males vs near continuous/ persistent in females) impart sex-dependent expression to hundreds of genes in adult mouse liver. Signal transducer and activator of transcription (STAT) 5, a GH-activated transcription factor that is essential for liver sexual dimorphism, is dynamically activated in direct response to each male plasma GH pulse. However, the impact of GH-induced STAT5 pulses on liver chromatin accessibility and downstream transcriptional events is unknown. In this study, we investigated the impact of a single pulse of GH given to hypophysectomized mice on local liver chromatin accessibility (DNase hypersensitive site analysis), transcription rates (heterogeneous nuclear RNA analysis), and gene expression (quantitative polymerase chain reaction and RNA sequencing) determined 30, 90, or 240 minutes later. The STAT5-dependent but sex-independent early GH response genes Igf1 and Cish showed rapid, GH pulse-induced increases in chromatin accessibility and gene transcription, reversing the effects of hypophysectomy. Rapid increases in liver chromatin accessibility and transcriptional activity were also induced in hypophysectomized male mice for some (Ces2b, Ugt2b38) but not for other liver STAT5-dependent male-biased genes (Cyp7b1). Moreover, in pituitary-intact male mice, Igf1, Cish, Ces2b, and Ugt2b38 all showed remarkable cycles of chromatin opening and closing, as well as associated cycles of induced gene transcription, which closely followed each endogenous pulse of liver STAT5 activity. Thus, the endogenous rhythms of male plasma GH pulsation dynamically open and then close liver chromatin at discrete, localized regulatory sites in temporal association with transcriptional activation of Igf1, Cish, and a subset of STAT5-dependent male-biased genes.