Key Laboratory of Cardiovascular Disease, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
Cardiovascular Disease and Research Institute, Affiliated Hospital of Hainan Medical College, Haikou, Hainan, China.
Biochim Biophys Acta Gene Regul Mech. 2017 Oct;1860(10):1037-1046. doi: 10.1016/j.bbagrm.2017.08.002. Epub 2017 Aug 24.
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 seven in absentia homolog 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.
缺氧诱导因子 1 阿尔法（HIF-1α）调节多种病理生理过程。先前已经证明，HIF-1α 在介导过量营养损伤的脂肪变性发病机制中起作用。在本研究中，我们研究了 HIF-1α 在转激活七缺失同源物 1（SIAH1）基因中的作用及其潜在机制。我们报告说，在营养应激下，SIAH1 在小鼠和培养的肝细胞中的肝脏中表达上调。与此同时，HIF-1α 开始占据 SIAH1 启动子。用 siRNA 耗尽 HIF-1α 或用 chetomin 抑制 HIF-1α 可消除 SIAH1 表达的诱导。HIF-1α 敲低或抑制与 SIAH1 启动子周围的表观遗传改变平行，其特征为乙酰化组蛋白 H3 和三甲基化 H3K4 的丢失以及二甲基化 H3K9 的获得。进一步的分析表明，HIF-1α 与组蛋白去甲基酶 KDM3A 相互作用并募集到 SIAH1 启动子上以激活转录。HIF-1α 还介导了 KDM3A 和 p300 之间的串扰。KDM3A 的耗竭伴随着 SIAH1 诱导的丧失和 SIAH1 启动子周围二甲基化 H3K9 的积累。有趣的是，KDM3A 的表达也以 HIF-1α 依赖的方式受到营养应激的上调。总之，我们的数据揭示了一种可能有助于调节 SIAH1 表达和脂肪变性发病机制的新的表观遗传途径。
