小柯机器人

美国加州大学洛杉矶分校Kathrin Plath、Douglas. L. Black等研究人员合作发现，蛋白质组装介导Xist定位和基因沉默。相关论文于2020年9月9日在线发表在《自然》杂志上。

据研究人员介绍，核区室在调节基因表达中具有多种作用，但仍不清楚驱动区室形成的分子力和成分。长非编码RNA Xist通过以高浓度定位在空间上靠近其转录基因座的区域中，并结合各种蛋白质来实现X染色体失活（XCI），从而建立染色体内区室。因此，XCI过程成为理解RNA介导的各种蛋白质如何诱导功能区室的范例。失活X（Xi）区室的特性会随时间变化，因为在早期的Xist扩散和转录关闭后，即使Xist已关闭，基因沉默的稳定状态也已经实现。

研究人员发现，Xist RNA结合蛋白PTBP1、MATR3、TDP-43和CELF1组装在Xist7的多价E重复元件上，并且通过自身聚集和异型蛋白-蛋白相互作用，在Xi中形成了浓缩物。该浓缩物是基因沉默和将Xist锚定到Xi区域所需的，可在没有Xist的情况下维持。值得注意的是，这些与E-重复结合的蛋白质对于过渡到Xist不依赖的XCI相是必不可少的，这表明E-重复介导的浓缩物是从Xist依赖性转变为Xist不依赖性的基础。

因此，这些数据表明Xist通过促进RNA结合蛋白组成的异聚浓缩物来形成Xi区室，从而揭示了遗传基因沉默的新机制。

附：英文原文

Title: A protein assembly mediates Xist localization and gene silencing

Author: Amy Pandya-Jones, Yolanda Markaki, Jacques Serizay, Tsotne Chitiashvili, Walter R. Mancia Leon, Andrey Damianov, Constantinos Chronis, Bernadett Papp, Chun-Kan Chen, Robin McKee, Xiao-Jun Wang, Anthony Chau, Shan Sabri, Heinrich Leonhardt, Sika Zheng, Mitchell Guttman, Douglas. L. Black, Kathrin Plath

Issue&Volume: 2020-09-09

Abstract: Nuclear compartments have diverse roles in regulating gene expression, yet the molecular forces and components that drive compartment formation remain largely unclear1. The long non-coding RNA Xist establishes an intra-chromosomal compartment by localizing at a high concentration in a territory spatially close to its transcription locus2 and binding diverse proteins3,4,5 to achieve X-chromosome inactivation (XCI)6,7. The XCI process therefore serves as a paradigm for understanding how RNA-mediated recruitment of various proteins induces a functional compartment. The properties of the inactive X (Xi)-compartment are known to change over time, because after initial Xist spreading and transcriptional shutoff a state is reached in which gene silencing remains stable even if Xist is turned off8. Here we show that the Xist RNA-binding proteins PTBP19, MATR310, TDP-4311 and CELF112 assemble on the multivalent E-repeat element of Xist7 and, via self-aggregation and heterotypic protein–protein interactions, form a condensate1 in the Xi. This condensate is required for gene silencing and for the anchoring of Xist to the Xi territory, and can be sustained in the absence of Xist. Notably, these E-repeat-binding proteins become essential coincident with transition to the Xist-independent XCI phase8, indicating that the condensate seeded by the E-repeat underlies the developmental switch from Xist-dependence to Xist-independence. Taken together, our data show that Xist forms the Xi compartment by seeding a heteromeric condensate that consists of ubiquitous RNA-binding proteins, revealing an unanticipated mechanism for heritable gene silencing.

DOI: 10.1038/s41586-020-2703-0

Source: https://www.nature.com/articles/s41586-020-2703-0

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