| First Author | Chowdhury T | Year | 2026 |
| Journal | Nature | Volume | 650 |
| Issue | 8102 | Pages | 779-785 |
| PubMed ID | 41535457 | Mgi Jnum | J:387962 |
| Mgi Id | MGI:8355587 | Doi | 10.1038/s41586-025-09940-w |
| Citation | Chowdhury T, et al. (2026) A nowhere-to-hide mechanism ensures complete piRNA-directed DNA methylation. Nature 650(8102):779-785 |
| abstractText | The mouse PIWI-interacting RNA (piRNA) pathway provides sustained anti-transposon immunity to the developing male germline by directing transposon DNA methylation(1-3). The first step in this process is the recruitment of SPOCD1 to young LINE1 loci(4). Thereafter, piRNA-mediated tethering of the PIWI protein MIWI2 (also known as PIWIL4) to the nascent transposon transcript recruits the DNA methylation machinery(5,6). 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 pores(7). 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. |
