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锌指蛋白300通过DNA甲基化和组蛋白乙酰化实现紧密的自我调节和功能。

ZNF300 tight self-regulation and functioning through DNA methylation and histone acetylation.

作者信息

Yan Feng-Juan, Fan Jingyi, Huang Zan, Zhang Jun-Jian

机构信息

College of Life Science, Wuhan University, Wuhan, 430072 Hubei People's Republic of China.

Department of Pediatrics, Zhongnan Hospital of Wuhan University, Wuhan, 430072 Hubei People's Republic of China.

出版信息

Cell Biosci. 2017 Jun 28;7:33. doi: 10.1186/s13578-017-0160-8. eCollection 2017.

DOI:10.1186/s13578-017-0160-8
PMID:28670441
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5490171/
Abstract

BACKGROUND

Accumulating evidence demonstrates that the KRAB-ZNFs involve in various biological processes. As a typical member of KRAB-ZNFs, dysregulation of ZNF300 contributes to multiple pathologies such as leukemia and cancer. However, mechanisms underlying ZNF300 tight regulation and its pathophysiological function remain largely unknown.

METHODS

The effect of ZNF300ZFR on gene transcriptional activity was measured by Dual luciferase reporter system. ChIP-PCR assay were performed to detect the enrichment of ZNF300 protein and H3K9Ac in the ZNF300 gene. Co-immunoprecipitation assays followed by western blot were performed to detect the interaction between ZNF300 and KAP1. The DNA methylation in the ZNF300 gene promoter was analyzed by BSP. ZNF300 function on K562 cell differentiation was analyzed by flow cytometry.

RESULTS

In this study, we found that the zinc finger domain-encoding region (ZFR) of ZNF300 functioned as a repressor possibly by mediating DNA methylation and ZNF300 bound to its ZNF300ZFR, suggesting a potential auto-inhibition mechanism. To support this, DNA methylation inhibition upregulated ZNF300 expression and ZNF300 overexpression inhibited endogenous ZNF300 expression. More importantly, DNA methylation inhibition restored megakaryocyte differentiation in K562 cells suppressed by ZNF300 downregulation, suggesting an important role of DNA methylation in ZNF300 function. Interestingly, ZNF300 knockdown restored global H3K9Ac that was reduced in K562 cells undergoing megakaryocyte differentiation.

CONCLUSIONS

Our study revealed novel features of ZNF300 that possibly mediate its regulation and function by modulating epigenetic modifications.

摘要

背景

越来越多的证据表明，KRAB锌指蛋白参与多种生物学过程。作为KRAB锌指蛋白的典型成员，ZNF300的失调会导致多种病理状况，如白血病和癌症。然而，ZNF300严格调控的机制及其病理生理功能在很大程度上仍不清楚。

方法

采用双荧光素酶报告系统检测ZNF300ZFR对基因转录活性的影响。进行染色质免疫沉淀PCR分析以检测ZNF300基因中ZNF300蛋白和H3K9Ac的富集情况。进行免疫共沉淀分析，随后进行蛋白质印迹以检测ZNF300与KAP1之间的相互作用。通过亚硫酸氢盐测序法分析ZNF300基因启动子中的DNA甲基化情况。通过流式细胞术分析ZNF300对K562细胞分化的作用。

结果

在本研究中，我们发现ZNF300的锌指结构域编码区（ZFR）可能通过介导DNA甲基化发挥阻遏作用，并且ZNF300与其ZNF300ZFR结合，提示一种潜在的自我抑制机制。为支持这一观点，DNA甲基化抑制上调了ZNF300的表达，而ZNF300的过表达抑制了内源性ZNF300的表达。更重要的是，DNA甲基化抑制恢复了因ZNF300下调而受抑制的K562细胞中的巨核细胞分化，表明DNA甲基化在ZNF300功能中起重要作用。有趣的是，ZNF300的敲低恢复了在经历巨核细胞分化的K562细胞中减少的整体H3K9Ac。

结论

我们的研究揭示了ZNF300的新特性，其可能通过调节表观遗传修饰来介导其调控和功能。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6269/5490171/1619a4152b29/13578_2017_160_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6269/5490171/03600a819f96/13578_2017_160_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6269/5490171/33e2f683ebd0/13578_2017_160_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6269/5490171/ea7c22d26263/13578_2017_160_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6269/5490171/f6a2ea9be0b8/13578_2017_160_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6269/5490171/1619a4152b29/13578_2017_160_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6269/5490171/03600a819f96/13578_2017_160_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6269/5490171/33e2f683ebd0/13578_2017_160_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6269/5490171/ea7c22d26263/13578_2017_160_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6269/5490171/f6a2ea9be0b8/13578_2017_160_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6269/5490171/1619a4152b29/13578_2017_160_Fig5_HTML.jpg

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