Roles of the CSE1L-mediated nuclear import pathway in epigenetic silencing
Roles of the CSE1L-mediated nuclear import pathway in epigenetic silencing
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CSE1L介导的核输入途径在表观遗传沉默中的作用
DOI：
10.1073/pnas.1800505115
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发表时间：
2018-04-24
影响因子：
11.1
通讯作者：
Zhu, Bing
中科院分区：
文献类型：
--
作者：
Dong, Qiang;Li, Xiang;Zhu, Bing
表观遗传沉默可以通过多种机制介导，许多调节因子仍有待鉴定。在这里，我们报告了一个全基因组的siRNA筛选，以确定监管机构维持基因阻遏的CMV启动子沉默的DNA甲基化。我们确定CSE1L（chromosome segregation 1 like）是报告基因和许多内源性甲基化基因沉默的重要因素。CSE1L缺失不引起DNA去甲基化。另一方面，通过CSE1L消耗去抑制的甲基化基因与也通过组蛋白去乙酰化酶抑制剂（HDACi）处理再激活的甲基化基因在很大程度上重叠。在CSE1L消耗后观察到的基因沉默缺陷与其对某些蛋白质货物的核输入功能有关，因为参与相同核输入途径的其他因子（包括KPNAs和KPNB1蛋白）的消耗在全基因组水平上显示出相似的去阻遏谱。因此，CSE1L似乎对某些关键抑制蛋白的核输入至关重要。事实上，N0VA 1、HDAC 1、HDAC 2和HDAC 8（被称为沉默因子的基因）在CSE 1L耗尽后变得离域到胞质溶胶中。这项研究表明，蛋白质核输入系统的货物特异性可能会影响基因沉默的选择性。
Epigenetic silencing can be mediated by various mechanisms, and many regulators remain to be identified. Here, we report a genome-wide siRNA screening to identify regulators essential for maintaining gene repression of a CMV promoter silenced by DNA methylation. We identified CSE1L (chromosome segregation 1 like) as an essential factor for the silencing of the reporter gene and many endogenous methylated genes. CSE1L depletion did not cause DNA demethylation. On the other hand, the methylated genes derepressed by CSE1L depletion largely overlapped with methylated genes that were also reactivated by treatment with histone deacetylase inhibitors (HDACi). Gene silencing defects observed upon CSE1L depletion were linked to its nuclear import function for certain protein cargos because depletion of other factors involved in the same nuclear import pathway, including KPNAs and KPNB1 proteins, displayed similar derepression profiles at the genome-wide level. Therefore, CSE1L appears to be critical for the nuclear import of certain key repressive proteins. Indeed, NOVA1, HDAC1, HDAC2, and HDAC8, genes known as silencing factors, became delocalized into cytosol upon CSE1L depletion. This study suggests that the cargo specificity of the protein nuclear import system may impact the selectivity of gene silencing.