Defining the Epigenetic Actions of Growth Hormone: Acute Chromatin Changes Accompany GH-Activated Gene Transcription
Defining the Epigenetic Actions of Growth Hormone: Acute Chromatin Changes Accompany GH-Activated Gene Transcription
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DOI：
10.1210/me.2010-0234
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发表时间：
2010-10-01
影响因子：
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通讯作者：
Rotwein, Peter
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文献类型：
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作者：
Chia, Dennis J.;Rotwein, Peter
生长激素的许多长期生理效应需要激素介导的基因表达变化。转录因子信号转导子和转录激活子5 b（Stat 5 b）通过不完全理解的机制调节大量GH依赖性基因，在GH对生长和代谢的作用中起关键作用。在这里，我们评估了生长激素启动和Stat 5 b介导的信号转导对垂体缺陷的年轻成年雄性大鼠肝脏中表达调节基因的染色质景观的影响。在没有GH的情况下，Socs 2、Cish、Igfals和Spi 2.1启动子处的持续转录最少，Stat 5 b在近端启动子位点处的占用最少，并且染色质相对封闭，如低水平的核心组蛋白乙酰化所证明的。与此相反，转录沉默Igf 1启动子1似乎准备被激活，基于结合的辅激活因子p300和Med 1/Trap 220，高水平的组蛋白乙酰化，和RNA聚合酶II的存在。GH处理导致所有五个基因的转录活性在30-60分钟内增加8- 20倍，并且伴随着Stat 5 b与近端Socs 2、Cish、Igfals和Spi 2.1启动子以及七个远端Igf 1 Stat 5 b元件的结合，通过增强所有五个启动子处的组蛋白乙酰化，通过募集RNA聚合酶II至Socs 2、Cish、Igfals和Spi 2.1启动子，和Spi 2.1启动子，以及Socs 2、Cish和Igf 1 Stat 5 b位点的转录抑制因子Bcl 6的缺失，但Igf 1 Stat 5 b结构域的缺失不影响Bcl 6的表达。我们的结论是，生长激素的行动诱导快速和显着的变化，在肝染色质的目标启动子，并建议染色质签名IgF 1不同于其他GH和Stat 5 b依赖基因。（分子内分泌学24：2038-2049，2010）
Many of the long-term physiological effects of GH require hormone-mediated changes in gene expression. The transcription factor signal transducer and activator of transcription 5b (Stat5b) plays a critical role in the actions of GH on growth and metabolism by regulating a large number of GH-dependent genes by incompletely understood mechanisms. Here we have assessed the impact of GH-initiated and Stat5b-mediated signaling on the chromatin landscape of hormone-regulated genes in the liver of pituitary-deficient young adult male rats. In the absence of GH there was minimal ongoing transcription at the Socs2, Cish, Igfals, and Spi 2.1 promoters, minimal occupancy of Stat5b at proximal promoter sites, and relatively closed chromatin, as evidenced by low levels of core histone acetylation. In contrast, transcriptionally silent Igf1 promoter 1 appeared poised to be activated, based on binding of coactivators p300 and Med1/Trap220, high levels of histone acetylation, and the presence of RNA polymerase II. GH treatment led to a 8- to 20-fold rise in transcriptional activity of all five genes within 30-60 min and was accompanied by binding of Stat5b to the proximal Socs2, Cish, Igfals, and Spi 2.1 promoters and to seven distal Igf1 Stat5b elements, by enhanced histone acetylation at all five promoters, by recruitment of RNA polymerase II to the Socs2, Cish, Igfals, and Spi 2.1 promoters, and by loss of the transcriptional repressor Bcl6 from Socs2, Cish, and Igfals Stat5b sites, but not from two Igf1 Stat5b domains. We conclude that GH actions induce rapid and dramatic changes in hepatic chromatin at target promoters and propose that the chromatin signature of Igf1 differs from other GH- and Stat5b-dependent genes. (Molecular Endocrinology 24: 2038-2049, 2010)