PIWIL2 suppresses pluripotency in the male mouse germline

Germ cells can give rise to teratomas and express pluripotency-associated genes, yet they remain intrinsically resistant to reprogramming by Yamanaka factors. The mechanisms governing this resistance are poorly understood. Here we identify PIWIL2 as a key suppressor of pluripotency in the male germline. While spermatogonial stem cells (SSCs) normally lack SOX2 expression, Piwil2 - but not Piwil4 -deficient SSCs aberrantly express SOX2 and readily acquire pluripotency upon concurrent loss of Dmrt1 and Trp53 . piRNAs associated with the Sox2 locus are detected in embryonic gonocytes but not in SSCs. Piwil2 deficiency reduces DNA methylation at the Sox2 promoter and increases DMRT1 and the RNA-binding protein DAZL, which jointly restrict Sox2 expression. These findings reveal a previously unrecognized role of PIWIL2 in repressing germline pluripotency and underscore the importance of coordinated transcriptional and translational regulation in maintaining germ cell identity.