Abnormal H3K27me3 underlies degenerative spermatogonial stem cells in cryptorchid testis

Cryptorchidism is the most frequent congenital defect in newborn males characterized by the absence of the testis from the scrotum. Approximately 90% of individuals with untreated bilateral cryptorchidism exhibit azoospermia due to defective spermatogenesis in the affected testis. Although abnormal spermatogonial stem cell maintenance or differentiation is suggested to cause germ cell degeneration in the cryptorchid testis, the underlying molecular mechanisms remain unclear. Here, we profiled spermatogonial epigenetic landscapes using surgically induced cryptorchid testis in the mouse. We show that cryptorchidism leads to alterations in local, but not global, H3K27me3 and H3K9me3 in undifferentiated spermatogonia. Of these, the loss of H3K27me3 was correlated with activation of developmental and proapoptotic pathway genes that are repressed by the polycomb machinery in germ cells. Cryptorchid spermatogonia exhibit an increase of the H3K27me3 demethylases KDM6A and KMD6B. Furthermore, we reveal that an increased temperature leads to Kdm6a/b upregulation in germline stem cells cultured in vitro. Thus, our study suggests that temperature-dependent histone demethylation may induce mRNA dysregulation due to the partial loss of H3K27me3 in spermatogonia.