Activation of Galectin-3 (LGALS3) Transcription by Injurious Stimuli in the Liver Is Commonly Mediated by BRG1
Activation of Galectin-3 (LGALS3) Transcription by Injurious Stimuli in the Liver Is Commonly Mediated by BRG1
复制标题
肝脏中有害刺激引起的半乳糖凝集素 3 (LGALS3) 转录激活通常由 BRG1 介导。
DOI：
10.3389/fcell.2019.00310
复制
发表时间：
2019-11-26
影响因子：
5.5
通讯作者：
Xu, Yong
中科院分区：
文献类型：
--
作者：
Li, Zilong;Lv, Fangqiao;Xu, Yong
半乳糖凝集素-3（由LGALS 3编码）是一种聚糖结合蛋白，其调节有助于人类疾病发病机制的多种病理生理过程。先前的研究已经发现，半乳糖凝集素-3水平在肝脏中被许多不同的有害刺激上调。然而，潜在的表观遗传机制尚不清楚。在这里，我们报告了条件性敲除Brahma相关基因（BRG 1），一种染色质重塑蛋白，在肝细胞中减弱了几种不同的肝损伤动物模型中半乳糖凝集素-3表达的诱导。类似地，培养的肝细胞中的BRG 1消耗或药物抑制抑制通过用LPS加游离脂肪酸（棕榈酸酯）处理来抑制半乳糖凝集素-3表达的诱导。进一步的分析表明，BRG 1与AP-1相互作用，结合到近端半乳糖凝集素3启动子并激活转录。从机制上讲，半乳糖凝集素-3启动子周围的DNA去甲基化似乎是BRG 1介导的半乳糖凝集素-3转录激活的限速步骤。BRG 1将DNA 5-甲基胞嘧啶双加氧酶TET 1募集到半乳糖凝集素-3以促进活性DNA去甲基化，从而激活半乳糖凝集素-3转录。最后，TET 1沉默废除了LPS加棕榈酸在培养的肝细胞中对半乳糖凝集素-3表达的诱导。总之，我们的数据揭示了一种新的表观遗传途径，有助于肝细胞中半乳糖凝集素-3转录的损伤相关激活。
Galectin-3 (encoded by LGALS3) is a glycan-binding protein that regulates a diverse range of pathophysiological processes contributing to the pathogenesis of human diseases. Previous studies have found that galectin-3 levels are up-regulated in the liver by a host of different injurious stimuli. The underlying epigenetic mechanism, however, is unclear. Here we report that conditional knockout of Brahma related gene (BRG1), a chromatin remodeling protein, in hepatocytes attenuated induction of galectin-3 expression in several different animal models of liver injury. Similarly, BRG1 depletion or pharmaceutical inhibition in cultured hepatocytes suppressed the induction of galectin-3 expression by treatment with LPS plus free fatty acid (palmitate). Further analysis revealed that BRG1 interacted with AP-1 to bind to the proximal galectin-3 promoter and activate transcription. Mechanistically, DNA demethylation surrounding the galectin-3 promoter appeared to be a rate-limiting step in BRG1-mediated activation of galectin-3 transcription. BRG1 recruited the DNA 5-methylcytosine dioxygenase TET1 to the galectin-3 to promote active DNA demethylation thereby activating galectin-3 transcription. Finally, TET1 silencing abrogated induction of galectin-3 expression by LPS plus palmitate in cultured hepatocytes. In conclusion, our data unveil a novel epigenetic pathway that contributes to injury-associated activation of galectin-3 transcription in hepatocytes.