H3K18 lactylation-mediated Ythdf2 activation restrains mouse female germline stem cell proliferation via promoting Ets1 mRNA degradation

Germline stem cells are critical for sustaining fertility by balancing self-renewal and differentiation, and are regulated by genetic and epigenetic programs. Although extensively investigated, the rare female germline stem cells (FGSCs) in mammalian ovaries hinder their application in regenerative medicine. The N6-methyladenosine (m6A) reader YTHDF2 is required for female germ cell competence. However, the mechanistic underpinnings of how YTHDF2 regulates FGSC proliferation remain elusive. Here, we show that knockout of Ythdf2 enhances FGSC proliferation in vitro. YTHDF2 binds m6A-modified Ets1 mRNA and facilitates its degradation in an m6A-dependent manner. ETS1 functions as a key downstream effector of YTHDF2, as suppression of ETS1 expression partially reverses the Ythdf2-KO-induced phenotype. Additionally, we demonstrate that YTHDF2/ETS1 axis participates in regulating FGSC proliferation by modulation of proliferation-related gene expression. Moreover, histone lactylation modification H3K18la activates the expression of YTHDF2 in FGSCs. Overall, our study reveals that YTHDF2 intrinsically restrains mouse FGSC proliferation and provides a potential strategy to increase FGSC abundance for its potential clinical application.