HIF-1 alpha coordinates epigenetic activation of SIAH1 in hepatocytes in response to nutritional stress
HIF-1 alpha coordinates epigenetic activation of SIAH1 in hepatocytes in response to nutritional stress
复制标题
HIF-1 α 协调肝细胞中 SIAH1 的表观遗传激活以响应营养应激
DOI：
10.1016/j.bbagrm.2017.08.002
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发表时间：
2017
影响因子：
4.7
通讯作者：
Xu Yong
中科院分区：
文献类型：
--
作者：
Fan Zhiwen;Li Zilong;Yang Yuyu;Liu Shuai;Guo Junli;Xu Yong
缺氧诱导因子1 α（HIF-1α）调节多种病理生理过程。以前已经证明，HIF-1α在脂肪变性的发病机制中起作用，介导过度营养损伤的作用。在本研究中，我们研究了HIF-1α在SIAH 1基因反式激活中的作用及其机制。我们报告说，在响应营养应激，SIAH 1表达上调，在小鼠的肝脏和培养的肝细胞。与此同时，HIF-1α开始占据SIAH 1启动子。用siRNA去除HIF-1α或用chetomin抑制HIF-1α可消除SIAH 1表达的诱导。HIF-1α敲低或抑制SIAH 1启动子周围的表观遗传改变，其特征在于乙酰化组蛋白H3和三甲基化H3 K4的丢失以及二甲基化H3 K9的获得。进一步的分析显示HIF-1α与组蛋白去甲基化酶KDM 3A相互作用并将其募集到SIAH 1启动子上以激活转录。HIF-1α还介导KDM 3A与p300之间的串扰。KDM 3A的耗尽与SIAH 1诱导的丧失和SIAH 1启动子周围二甲基化H3 K9的积累一致。有趣的是，KDM 3A表达也以HIF-1α依赖的方式被营养应激上调。总之，我们的数据揭示了一种新的表观遗传途径，可能有助于调节SIAH 1表达和脂肪变性的发病机制。
Hypoxia inducible factor 1 alpha (HIF-1α) regulates a diverse range of pathophysiological processes. It has been demonstrated previously that HIF-1α plays a role in the pathogenesis of steatosis mediating the effects of excessive nutritional insults. In the present study we investigated the role of HIF-1α in trans‑activating the sevenin absentiahomolog 1 (SIAH1) gene and the underlying mechanism. We report that in response to nutritional stress, SIAH1 expression was up-regulated in the liver in mice and in cultured hepatocytes. In the meantime, HIF-1α started to occupy the SIAH1 promoter. Depletion of HIF-1α with siRNA or inhibition of HIF-1α with chetomin abrogated the induction of SIAH1 expression. HIF-1α knockdown or inhibition paralleled epigenetic alterations surrounding the SIAH1 promoter characterized by the loss of acetylated histone H3 and trimethylated H3K4 as well as the acquisition of dimethylated H3K9. Further analyses revealed that HIF-1α interacted with and recruited the histone demethylase KDM3A to the SIAH1 promoter to activate transcription. HIF-1α also mediated the crosstalk between KDM3A and p300. Depletion of KDM3A coincided with the loss of SIAH1 induction and the accumulation of dimethylated H3K9 surrounding the SIAH1 promoter. Interestingly, KDM3A expression was also up-regulated by nutritional stress in a HIF-1α dependent manner. Together, our data uncover a novel epigenetic pathway that may contribute to the regulation of SIAH1 expression and the pathogenesis of steatosis.