Local enrichment of HP1alpha at telomeres alters their structure and regulation of telomere protection.
Local enrichment of HP1alpha at telomeres alters their structure and regulation of telomere protection.
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DOI：
10.1038/s41467-018-05840-y
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发表时间：
2018-09-04
影响因子：
16.6
通讯作者：
Blackburn EH
中科院分区：
文献类型：
--
作者：
Chow TT;Shi X;Wei JH;Guan J;Stadler G;Huang B;Blackburn EH
恶性癌症中端粒维持的增强是明显的。虽然端粒被认为本质上是异色的，但在人类癌症中，表观遗传修饰如何影响端粒保护和结构的详细机制在很大程度上是未知的。在这里，我们开发了一种分子束缚方法，通过实验富集端粒上的异染色质蛋白 HP1α。这导致癌细胞端粒上 H3K9me3 的沉积增加。端粒酶引起的端粒延伸减弱，端粒处损伤诱导的病灶减少，表明端粒稳定性增强。超分辨率风暴成像显示端粒结构的不规则性意外增加。 HP1α 的端粒束缚染色体阴影结构域 (CSD) 突变体 I165A 消除了端粒延伸的抑制和端粒结构的不规则性，表明至少一种 HP1α 配体参与介导这些效应。这项工作提出了一种专门操纵端粒局部表观遗传状态的方法，以揭示端粒结构动力学背后的分子机制。染色质动力学被认为在端粒的维持中发挥着重要作用，但人们对其如何发挥作用仍知之甚少。在这里，作者局部富集了人类端粒的异染色质蛋白 1α (HP1α)，以深入了解端粒的表观遗传调控和结构动力学之间的串扰。
Enhanced telomere maintenance is evident in malignant cancers. While telomeres are thought to be inherently heterochromatic, detailed mechanisms of how epigenetic modifications impact telomere protection and structures are largely unknown in human cancers. Here we develop a molecular tethering approach to experimentally enrich heterochromatin protein HP1α specifically at telomeres. This results in increased deposition of H3K9me3 at cancer cell telomeres. Telomere extension by telomerase is attenuated, and damage-induced foci at telomeres are reduced, indicating augmentation of telomere stability. Super-resolution STORM imaging shows an unexpected increase in irregularity of telomeric structure. Telomere-tethered chromo shadow domain (CSD) mutant I165A of HP1α abrogates both the inhibition of telomere extension and the irregularity of telomeric structure, suggesting the involvement of at least one HP1α-ligand in mediating these effects. This work presents an approach to specifically manipulate the epigenetic status locally at telomeres to uncover insights into molecular mechanisms underlying telomere structural dynamics. Chromatin dynamics is thought to play an important role in the maintenance of telomeres, yet how has remained poorly understood. Here the authors locally enrich heterochromatin protein 1α (HP1α) at human telomeres to provide insights into the crosstalk between epigenetic regulations and structural dynamics at the telomeres.
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影响因子：
19
作者：
Canzio, Daniele;Larson, Adam;Narlikar, Geeta J.
通讯作者：
Narlikar, Geeta J.
影响因子：
56.9
作者：
Azzalin, Claus M.;Reichenbach, Patrick;Lingner, Joachim
通讯作者：
Lingner, Joachim
影响因子：
--
作者：
Herbert, Brittney-Shea;Shay, Jerry W;Wright, Woodring E
通讯作者：
Wright, Woodring E
影响因子：
64.5
作者：
Bandaria JN;Qin P;Berk V;Chu S;Yildiz A
通讯作者：
Yildiz A
影响因子：
21.3
作者：
Gonzalo, S;Jaco, I;Blasco, MA
通讯作者：
Blasco, MA