Abnormal H3K27me3 underlies degenerative spermatogonial stem cells in cryptorchid testis [ChIP-Seq]

Cryptorchidism is the most frequent congenital defect in newborn males characterized by the absence of the testis from the scrotum. Approximately 90% of patients with untreated bilateral cryptorchidism exhibit azoospermia due to defective spermatogenesis in the affected testis. While abnormal spermatogonial stem cell maintenance or differentiation is suggested to cause germ cell degeneration in the cryptorchid testis, 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 leads to activation of developmental and apoptotic pathway genes that are repressed by the polycomb machineries in germ cells. Cryptorchid spermatogonia exhibit the increase of 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 a temperature-dependent histone demethylation induces mRNA dysregulation due to the partial loss of H3K27me3 in spermatogonia.