PNAS, 10 Apr 2018，DOI: 10.1073/pnas.1800505115
Roles of the CSE1L-mediated nuclear import pathway in epigenetic silencing
Qiang Dong, Xiang Li, Cheng-Zhi Wang, Shaohua Xu, Gang Yuan, Wei Shao, Baodong Liu, Yong Zheng, Hailin Wang, Xiaoguang Lei, Zhuqiang Zhang and Bing Zhu
Regulators essential for facilitating gene silencing are interesting targets of epigenetic studies. Our work describes a regulator, CSE1L, that is essential for the silencing of many endogenous methylated genes. Depletion of CSE1L reactivates these genes without causing DNA demethylation. Interestingly, such reactivation is not due to a direct chromatin role of CSE1L. Instead, it depends on the role of CSE1L in importin-mediated protein nuclear transportation, which is confirmed by similar effects observed in cells depleted of other players in the same protein transportation pathway. Intriguingly, importin-mediated protein nuclear transportation preferentially facilitates gene silencing with specificity for a subset of genes, suggesting that the cargo specificity of protein nuclear import systems may impact the selectivity of gene regulation.
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.