Epigenetic Dysregulation Induces Translocation of Histone H3 into Cytoplasm.
Epigenetic Dysregulation Induces Translocation of Histone H3 into Cytoplasm.
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表观遗传失调诱导组蛋白 H3 易位到细胞质中。
DOI：
10.1002/advs.202100779
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发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Wu M
中科院分区：
文献类型：
--
作者：
Wang Z;Chen J;Gao C;Xiao Q;Wang XW;Tang SB;Li QL;Zhong B;Song ZY;Shu HB;Li LY;Wu M
在真核生物细胞中，染色质的核心成分，如组蛋白和DNA，被包装在细胞核中。核物质渗漏到胞质中会引起病理效应。然而，其潜在机制仍然难以捉摸。在这里，细胞质定位的核物质诱导的染色质失调（CLIC）在哺乳动物细胞中的报告。通过小分子化学物质、HP 1 α敲低或敲除H3K9甲基化酶SETDB 1抑制H3K9me3，诱导形成含有组蛋白H3.1、H4和胞质DNA的细胞质斑点，这反过来激活炎症基因和自噬降解。自噬缺陷拯救H3降解，并增强炎症基因的激活。MRE 11是MRN复合体的一个亚基，在异染色质失调后进入细胞质。MRE 11或NBS1的缺乏，而不是RAD 50的缺乏，抑制胞质溶胶中的CLIC斑点。MRE 11缺失可抑制HP 1 α缺乏引起的肿瘤生长，提示CLIC与肿瘤发生之间存在联系。这项研究揭示了一个新的途径，异染色质失调诱导核物质易位到细胞质中，这是重要的炎症性疾病和癌症。目前的研究揭示了一种新的途径，导致细胞质定位的核物质诱导的染色质失调（CLIC）。HP 1 α基因敲除、SETDB 1基因敲除或H3K9me3基因药物抑制可诱导含有组蛋白H3.1、H4和DNA的细胞质斑点形成，其受MRE 11和NBS1的调节。CLIC激活炎症基因表达、γH2AX形成和自噬，与炎症和肿瘤发生有关。
In eukaryote cells, core components of chromatin, such as histones and DNA, are packaged in nucleus. Leakage of nuclear materials into cytosol will induce pathological effects. However, the underlying mechanisms remain elusive. Here, cytoplasmic localization of nuclear materials induced by chromatin dysregulation (CLIC) in mammalian cells is reported. H3K9me3 inhibition by small chemicals, HP1α knockdown, or knockout of H3K9 methylase SETDB1, induces formation of cytoplasmic puncta containing histones H3.1, H4 and cytosolic DNA, which in turn activates inflammatory genes and autophagic degradation. Autophagy deficiency rescues H3 degradation, and enhances the activation of inflammatory genes. MRE11, a subunit of MRN complex, enters cytoplasm after heterochromatin dysregulation. Deficiency of MRE11 or NBS1, but not RAD50, inhibits CLIC puncta in cytosol. MRE11 depletion represses tumor growth enhanced by HP1α deficiency, suggesting a connection between CLIC and tumorigenesis. This study reveals a novel pathway that heterochromatin dysregulation induces translocation of nuclear materials into cytoplasm, which is important for inflammatory diseases and cancer. The current study reveals a novel pathway leading to cytoplasmic localization of nuclear material induced by chromatin dysregulation (CLIC). HP1α knockdown, SETDB1 knockout or H3K9me3 inhibition by drugs, induces cytoplasmic puncta containing histones H3.1, H4 and DNA, which is regulated by MRE11 and NBS1. CLIC activates inflammatory gene expression, γH2AX formation, and autophagy, and is related with inflammation and tumorigenesis.
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影响因子：
64.8
作者：
Bakhoum SF;Ngo B;Laughney AM;Cavallo JA;Murphy CJ;Ly P;Shah P;Sriram RK;Watkins TBK;Taunk NK;Duran M;Pauli C;Shaw C;Chadalavada K;Rajasekhar VK;Genovese G;Venkatesan S;Birkbak NJ;McGranahan N;Lundquist M;LaPlant Q;Healey JH;Elemento O;Chung CH;Lee NY;Imielenski M;Nanjangud G;Pe'er D;Cleveland DW;Powell SN;Lammerding J;Swanton C;Cantley LC
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影响因子：
10.5
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通讯作者：
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影响因子：
4.6
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影响因子：
16
作者：
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通讯作者：
Jenuwein, Thomas