Jmjd3 Activates Mash1 Gene in RA-Induced Neuronal Differentiation of P19 Cells
Jmjd3 Activates Mash1 Gene in RA-Induced Neuronal Differentiation of P19 Cells
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Jmjd3 在 RA 诱导的 P19 细胞神经元分化中激活 Mash1 基因
DOI：
10.1002/jcb.22703
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发表时间：
2010-08-15
影响因子：
4
通讯作者：
Shen, Yu-fei
中科院分区：
文献类型：
--
作者：
Dai, Jin-po;Lu, Jian-yi;Shen, Yu-fei
组蛋白尾部的共价修饰对染色质的结构和功能具有重要作用。组蛋白H3的27位赖氨酸(H3K27me3)的三甲基修饰通常与基因抑制有关，而基因抑制在细胞谱系承诺和发育中起着重要作用。Mash1是一种基本的螺旋-环-螺旋调节蛋白，在神经发生中发挥关键作用，它作为早期标志物表达。在这项研究中，我们发现在RA处理的P19细胞中，Mash1启动子上H3K27me3的减少和H3K27me3的去甲基酶(Jmjd3)的增加可以显著地诱导Mash1的高效表达。Jmjd3在P19细胞中的过表达也显著增强了RA诱导的Mash1的表达和启动子活性。相反，当Jmjd3 siRNA或显性负突变Jmjd3被导入P19细胞后，Mash1的mRNA表达和启动子活性显著降低。染色质免疫沉淀分析表明，在RA诱导的细胞中，Jmjd3被有效地募集到Mash1启动子的上游近端区域，该区域与Hes1的特异性结合部位重叠。此外，免疫共沉淀试验显示了Jmjd3和Hes1之间的关联。因此，Jmjd3很可能通过Hes1被招募到Mash1启动子。我们的结果表明，在RA诱导P19细胞神经分化的早期阶段，Jmjd3增强Mash1基因高效表达所必需的去甲基酶活性及其与Mash1启动子结合的介体Hest都是必需的。J.细胞。生物化学。110：1457-1463,2010。(C)2010年Wiley-Liss公司
Covalent modifications of histone tails have fundamental roles in chromatin structure and function. Tri-methyl modification on lysine 27 of histone H3 (H3K27me3) usually correlates with gene repression that plays important roles in cell lineage commitment and development. Mash1 is a basic helix-loop-helix regulatory protein that plays a critical role in neurogenesis, where it expresses as an early marker. In this study, we have shown a decreased H3K27me3 accompanying with an increased demethylase of H3K27me3 (Jmjd3) at the promoter of Mash1 can elicit a dramatically efficient expression of Mash1 in RA-treated P19 cells. Over-expression of Jmjd3 in P19 cells also significantly enhances the RA-induced expression and promoter activity of Mash1. By contrast, the mRNA expression and promoter activity of Mash1 are significantly reduced, when Jmjd3 siRNA or dominant negative mutant of Jmjd3 is introduced into the P19 cells. Chromatin immunoprecipitation assays show that Jmjd3 is efficiently recruited to a proximal upstream region of Mash1 promoter that is overlapped with the specific binding site of Hes1 in RA-induced cells. Moreover, the association between Jmjd3 and Hes1 is shown in a co-Immunoprecipitation assay. It is thus likely that Jmjd3 is recruited to the Mash1 promoter via Hes1. Our results suggest that the demethylase activity of Jmjd3 and its mediator Hest for Mash1 promoter binding are both required for Jmjd3 enhanced efficient expression of Mash1 gene in the early stage of RA-induced neuronal differentiation of P19 cells. J. Cell. Biochem. 110: 1457-1463, 2010. (C) 2010 Wiley-Liss, Inc.