SPOCD1是piRNA指導DNA從頭甲基化的重要執行者
作者：
小柯機器人發布時間：2020/7/18 8:07:34
英國愛丁堡大學Dónal O』Carroll研究團隊發現，SPOCD1是piRNA指導DNA從頭甲基化的重要執行者。這一研究成果於2020年7月16日在線發表在國際學術期刊《自然》上。
研究人員表示，在哺乳動物中，從體細胞中獲取生殖系細胞具有一項重要的挑戰，即消除和重置基因組甲基化。在雄性生殖系中，RNA指導DNA甲基化使年輕活躍的轉座因子（TE）沉默。PIWI蛋白MIWI2（PIWIL4）及其相關的PIWI相互作用RNA（piRNA）指導TE DNA甲基化。有研究提出piRNA可束縛MIWI2到新生的TE轉錄本。但是，人們對MIWI2指導從頭進行TE甲基化的機制了解甚少，但對於生殖系的永生性至關重要。
研究人員定義了從頭進行基因組甲基化的胎兒生殖細胞MIWI2相互作用組，並鑑定了一個新的MIWI2相關因子SPOCD1，這對於年輕TE甲基化和沉默至關重要。小鼠中Spocd1的缺失導致雄性不育，但既不影響piRNA生成，也不影響MIWI2在細胞核中的定位。SPOCD1是一種核蛋白，其表達僅限於從頭基因組甲基化的時期。
研究人員發現SPOCD1與DNMT3L和DNMT3A（即頭甲基化機器的組成部分以及NURD和BAF染色質重塑複合物的成分）能夠從體內共純化出來。研究人員提出了一個模型：MIWI2被束縛到新生的TE轉錄本上，通過SPOCD1募集了抑制性染色質重塑活性以及從頭甲基化機器。總而言之，研究人員確定了哺乳動物piRNA指導DNA甲基化的一種新穎且必不可少的執行者。
附：英文原文
Title: SPOCD1 is an essential executor of piRNA-directed de novo DNA methylation
Author: Ansgar Zoch, Tania Auchynnikava, Rebecca V. Berrens, Yuka Kabayama, Theresa Schpp, Madeleine Heep, Lina Vasiliauskait, Yuvia A. Prez-Rico, Atlanta G. Cook, Alena Shkumatava, Juri Rappsilber, Robin C. Allshire, Dnal OCarroll
Issue&Volume: 2020-07-16
Abstract: In mammals, the acquisition of the germline from the soma provides the germline with an essential challenge, the necessity to erase and reset genomic methylation1. In the male germline, RNA-directed DNA methylation silences young active transposable elements (TEs)2–4. The PIWI protein MIWI2 (PIWIL4) and its associated PIWI-interacting RNAs (piRNAs) instruct TE DNA methylation3,5. piRNAs are proposed to tether MIWI2 to nascent TE transcripts; however, the mechanism by which MIWI2 directs de novo TE methylation is poorly understood but central to the immortality of the germline. Here we define the interactome of MIWI2 in foetal gonocytes that are undergoing de novo genome methylation and identify a novel MIWI2-associated factor, SPOCD1, that is essential for young TE methylation and silencing. The loss of Spocd1 in mice results in male-specific infertility but impacts neither piRNA biogenesis nor localization of MIWI2 to the nucleus. SPOCD1 is a nuclear protein and its expression is restricted to the period of de novo genome methylation. We found SPOCD1 co-purified in vivo with DNMT3L and DNMT3A, components of the de novo methylation machinery as well as constituents of the NURD and BAF chromatin remodelling complexes. We propose a model whereby tethering of MIWI2 to a nascent TE transcript recruits repressive chromatin remodelling activities and the de novo methylation apparatus through SPOCD1. In summary, we have identified a novel and essential executor of mammalian piRNA-directed DNA methylation.
DOI: 10.1038/s41586-020-2557-5
Source: https://www.nature.com/articles/s41586-020-2557-5