蛋白質組裝介導Xist定位和基因沉默
作者：
小柯機器人發布時間：2020/9/12 21:48:11
美國加州大學洛杉磯分校Kathrin Plath、Douglas. L. Black等研究人員合作發現，蛋白質組裝介導Xist定位和基因沉默。相關論文於2020年9月9日在線發表在《自然》雜誌上。
據研究人員介紹，核區室在調節基因表達中具有多種作用，但仍不清楚驅動區室形成的分子力和成分。長非編碼RNA Xist通過以高濃度定位在空間上靠近其轉錄基因座的區域中，並結合各種蛋白質來實現X染色體失活（XCI），從而建立染色體內區室。因此，XCI過程成為理解RNA介導的各種蛋白質如何誘導功能區室的範例。失活X（Xi）區室的特性會隨時間變化，因為在早期的Xist擴散和轉錄關閉後，即使Xist已關閉，基因沉默的穩定狀態也已經實現。
研究人員發現，Xist RNA結合蛋白PTBP1、MATR3、TDP-43和CELF1組裝在Xist7的多價E重複元件上，並且通過自身聚集和異型蛋白-蛋白相互作用，在Xi中形成了濃縮物。該濃縮物是基因沉默和將Xist錨定到Xi區域所需的，可在沒有Xist的情況下維持。值得注意的是，這些與E-重複結合的蛋白質對於過渡到Xist不依賴的XCI相是必不可少的，這表明E-重複介導的濃縮物是從Xist依賴性轉變為Xist不依賴性的基礎。
因此，這些數據表明Xist通過促進RNA結合蛋白組成的異聚濃縮物來形成Xi區室，從而揭示了遺傳基因沉默的新機制。
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