NRF1 Coordinates With DNA Methylation To Regulate Spermatogenesis

All sexually reproducing organisms arise from gametes,by which the genetic information is passed across generations.In male,the formation and quality of sperm are very important as it contains the genetic information.Spermatogenesis is a highly coordinated process requiring a tightly regulated gene expression program by numerous regulators,such as transcription factors and epigenetic modifiers.Nuclear Respiratory Factor 1(NRF1)has a classic role in mitochondrial biogenesis and energy production as a nuclear DNA coded transcription factor.DNA methylation is a key epigenetic modification that regulates genes expression.The competition between DNA methylation and transcription factors determines binding affinity of transcription factors to their target gnens.In our study,we found that NRF1 cooperated with DNA methylation to directly regulate the expression of multiple germ cell specific genes,such as ASZ1.NRF1 is mainly expressed in spermatogonial stem cells and spermatocytes in male mice.In addition,conditional ablation of NRF1 in gonocytes blocked germ cell proliferation and led to the decreased expression of multiple germ cell specific genes.In NRF1 deficient mouse testes,the differentiation of germ cells were blocked and no functional sperms were found,which finally led to male infertility.Further NRF1-ablated germ cells showed no significant up-regulation of DNA methylation at the promoters of its target genes.These data thus confirm that NRF1 deletion,but not increased DNA methylation,is responsible for reduced expression of germline genes.In other words,NRF1 deficiency itself is not sufficient for the increasing DNA methylation.Taken together,our data thus highlight a precise crosstalk between transcriptional regulation by NRF1 and DNA methylation during germ cell development,and unequivocally demonstrate a novel role of NRF1 in spermatogenesis.