RESEARCH ARTICLE STEM CELLS AND REGENERATION DNMT3L promotes quiescence in postnatal spermatogonial

The ability of adult stem cells to reside in a quiescent state is crucial for preventing premature exhaustion of the stem cell pool. However, the intrinsic epigenetic factors that regulate spermatogonial stem cell quiescenceare largelyunknown.Here,we investigate inmicehowDNA methyltransferase 3-like (DNMT3L), an epigenetic regulator important for interpreting chromatin context and facilitating de novo DNA methylation, sustains the long-term male germ cell pool. We demonstrated that stem cell-enriched THY1+ spermatogonial stem/ progenitor cells (SPCs) constituted a DNMT3L-expressing population in postnatal testes. DNMT3L influenced the stability of promyelocytic leukemia zinc finger (PLZF), potentially by downregulatingCdk2/CDK2 expression, which sequestered CDK2-mediated PLZF degradation. Reduced PLZF inDnmt3l KOTHY1+ cells released its antagonist, Sal-like protein 4A (SALL4A), which is associated with overactivated ERK and AKT signaling cascades. Furthermore, DNMT3L was required to suppress thecell proliferation-promoting factorSALL4B inTHY1+SPCs and to prevent premature stem cell exhaustion. Our results indicate that DNMT3L is required todelicatelybalance the cyclingandquiescenceof SPCs. These findings reveal a novel role for DNMT3L in modulating postnatal SPC cell fate decisions