STAT3 Targets the Regulatory Regions of Gluconeogenic Genes in Vivo
STAT3 Targets the Regulatory Regions of Gluconeogenic Genes in Vivo
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DOI：
10.1210/me.2008-0264
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发表时间：
2009-06-01
影响因子：
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通讯作者：
Hollenberg, Anthony N.
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文献类型：
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作者：
Ramadoss, Preeti;Unger-Smith, Nathan E.;Hollenberg, Anthony N.
葡萄糖-6-磷酸酶(G6Pase)和磷酸烯醇式丙酮酸羧激酶(PEPCK)等糖异生基因在肝脏中的表达调控在血糖稳态中起着重要作用，因为这些基因的异常表达参与了2型糖尿病的发生发展。以往的研究表明，信号转导和转录激活因子3(STAT3)在糖异生基因的表达调控中起着关键作用，但其机制尚不清楚。在此，我们证明了在HepG2细胞和小鼠肝脏中，需要磷酸化的STAT3来抑制IL-6对G6Pase的表达。有趣的是，PEPCK的表达是由STAT3调节的，而不是IL-6的激活。利用体内染色质免疫沉淀，我们证明了STAT3与G6Pase的启动子、PEPCK和细胞因子信号转导(SOCS)3的抑制子结合，并且在IL-6处理后它在G6Pase和SOCS3的启动子上的募集增加。与IL-6诱导的SOCS3启动子一致，RNA聚合酶II在SOCS3启动子上持续募集，而IL-6处理后G6Pase启动子上的聚合酶II募集和组蛋白H4乙酰化减少。因此，STAT3通过与这些基因的调节区相互作用，在体内介导对肝脏糖异生基因表达的负调控。(分子内分泌学23：827-837,2009)
The regulation of expression of gluconeogenic genes including glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) in the liver plays an important role in glucose homeostasis, because aberrant expression of these genes contributes to the development of type 2 diabetes. Previous reports demonstrate that signal transducer and activator of transcription 3 (STAT3) plays a key role in regulating gluconeogenic gene expression, but the mechanism remains unclear. Herein we demonstrate that phosphorylated STAT3 is required for repression of G6Pase expression by IL-6 in both HepG2 cells and mouse liver. Interestingly, PEPCK expression is regulated by STAT3 independent of IL-6 activation. Using in vivo chromatin immunoprecipitation, we demonstrate that STAT3 binds to the promoters of the G6Pase, PEPCK, and suppressor of cytokine signaling (SOCS) 3 genes, and its recruitment increases at the G6Pase and SOCS3 promoters with IL-6 treatment. Whereas persistent recruitment of RNA polymerase II is seen on the SOCS3 promoter, consistent with its induction by IL-6, a decrease in polymerase II recruitment and histone H4 acetylation is seen at the G6Pase promoter with IL-6 treatment. Thus STAT3 mediates negative regulation of hepatic gluconeogenic gene expression in vivo by interacting with regulatory regions of these genes. (Molecular Endocrinology 23: 827-837, 2009)