爱丁堡大学Dnal OCarroll研究团队揭示了无处隐藏的机制确保了完全的piRNA导向的DNA甲基化。该研究于2026年1月14日发表于国际一流学术期刊《自然》杂志上。

在这里，该团队发现核piRNA和新生甲基化因子都是常染色质，暴露了组成型异染色质作为piRNA途径的基因组盲点。研究人员发现了一种“无处可藏”的机制，使piRNA途径介导的LINE1对整个基因组的监视成为可能。研究人员发现SPOCD1直接与核孔组分TPR相互作用，形成核孔附近的异染色质排斥区。在发生piRNA定向DNA甲基化的胎儿性腺细胞中，TPR在核外周和整个核质中都有发现。研究小组发现SPOCD1-TPR相互作用是完成非随机piRNA导向的LINE1甲基化所必需的。SPOCD1 - TPR相互作用的缺失导致部分SPOCD1和其他染色质结合的piRNA因子重新定位到组成型异染色质，在那里它们不再被MIWI2和重新甲基化机制所接近。综上所述，piRNA通路选择了TPR来保证LINE1s能够被piRNA和从头甲基化机制所访问。

据介绍，母主题PIWI相互作用RNA （piRNA）途径通过引导转座子DNA甲基化，为发育中的雄性种系提供持续的抗转座子免疫。这个过程的第一步是将SPOCD1招募到年轻的LINE1位点。此后，piRNA介导的PIWI蛋白MIWI2（也称为PIWIL4）与新生转座子转录物的拴系会激活DNA甲基化机制。piRNA通路需要将所有活性转座子拷贝甲基化，但这是如何实现的仍然未知。

附：英文原文

Title: A nowhere-to-hide mechanism ensures complete piRNA-directed DNA methylation

Author: Chowdhury, Tamoghna, Boyle, Shelagh, Zoch, Ansgar, Xiang, Xinyu, Mirandela, Madeleine Dias, Fieler, Hanna, Spanos, Christos, Zou, Juan, Kelly, David, Bickmore, Wendy A., Cook, Atlanta G., OCarroll, Dnal

Issue&Volume: 2026-01-14

Abstract: The mouse PIWI-interacting RNA (piRNA) pathway provides sustained anti-transposon immunity to the developing male germline by directing transposon DNA methylation1,2,3. The first step in this process is the recruitment of SPOCD1 to young LINE1 loci4. Thereafter, piRNA-mediated tethering of the PIWI protein MIWI2 (also known as PIWIL4) to the nascent transposon transcript recruits the DNA methylation machinery5,6. The piRNA pathway needs to methylate all active transposon copies but how this is achieved remains unknown. Here we show that nuclear piRNA and de novo methylation factors are all euchromatic, exposing constitutive heterochromatin as a genomic blind spot for the piRNA pathway. We discover a ‘nowhere-to-hide’ mechanism that enables piRNA pathway-mediated LINE1 surveillance of the entire genome. We find that SPOCD1 directly interacts with the nuclear pore component TPR, which forms heterochromatin exclusion zones adjacent to nuclear pores7. In fetal gonocytes undergoing piRNA-directed DNA methylation, TPR is found both at the nuclear periphery and throughout the nucleoplasm. We find that the SPOCD1–TPR interaction is required for complete non-stochastic piRNA-directed LINE1 methylation. The loss of the SPOCD1–TPR interaction results in a fraction of SPOCD1 and other chromatin-bound piRNA factors relocalizing to constitutive heterochromatin where they are no longer accessible to MIWI2 and the de novo methylation machinery. In summary, the piRNA pathway has co-opted TPR to guarantee that LINE1s are accessible to the piRNA and de novo methylation machineries.

DOI: 10.1038/s41586-025-09940-w

Source: https://www.nature.com/articles/s41586-025-09940-w