NRF1 coordinates with DNA methylation to regulate spermatogenesis

Abstract

Spermatogenesis is a highly coordinated process that requires tightly regulated gene expression programmed by transcription factors and epigenetic modifiers. In this study, we found that nuclear respiratory factor (NRF)-1, a key transcription factor for mitochondrial biogenesis, cooperated with DNA methylation to directly regulate the expression of multiple germ cell-specific genes, including In addition, conditional ablation of NRF1 in gonocytes dramatically down-regulated these germline genes, blocked germ cell proliferation, and subsequently led to male infertility in mice. Our data highlight a precise crosstalk between transcriptional regulation by NRF1 and epigenetic modulation during germ cell development and unequivocally demonstrate a novel role of NRF1 in spermatogenesis.-Wang, J., Tang, C., Wang, Q., Su, J., Ni, T., Yang, W., Wang, Y., Chen, W., Liu, X., Wang, S., Zhang, J., Song, H., Zhu, J., Wang, Y. NRF1 coordinates with DNA methylation to regulate spermatogenesis.

Prenatal Bisphenol A Exposure is Linked to Epigenetic Changes in Glutamate Receptor Subunit Gene Grin2b in Female Rats and Humans

“…These findings and the observed inverse correlation between Grin2b mRNA expression and methylation at rCpG1-3 is a strong indication that methylation at this region is important for transcriptional regulation and responsive to early life BPA exposures in females. Notably, rCpGs 1-3 are part of a predicted binding site for Nrf1, which has been shown to regulate Grin2b expression 27 and to be sensitive to DNA methylation 28 , 35 , 36 . Thus it is possible that the correlation between methylation at these CpGs and Grin2b mRNA expression in females is due to diminished Nrf1 binding.…”

A bioenergetic shift is required for spermatogonial differentiation

“…Images were processed with the Image-J software. For histology studies, testes were fixed in Bouin's fixative at 4°C overnight for staining with hematoxylin and eosin, as previously described 56 . For immunohistofluorescence (IHF), testes were fixed with 4% paraformaldehyde in PBS at 4°C overnight and embedded in paraffin.…”

Diverse roles for CDK‐associated activity during spermatogenesis

“…Together, these findings led us to hypothesize that the expression of CDK2 might be important to modulate NRF1 transcriptional activity during meiotic prophase, which affects the transcription of many meiotic genes including Ehmt1 , Msh4 , Asz1 , Syce1 , and Tex19.1 . This hypothesis might be best tested in future studies via the conditional deletion of Nrf1 in spermatocytes, utilizing a previously described Nrf1 flox/flox model . This work further underlines that CDK2 has multiple functions in germ cell development in addition to the established function of tethering telomeres to the nuclear envelope.…”

“…Remarkably, through ChIPseq and ChIP-reChIP approaches, we detected interactions of CDK2 with chromatin-bound NRF1 at its target gene promoters. Despite the fact that this transcription factor is canonically associated with the regulation of mitochondrial respiration, many of the genes regulated by NRF1 in male germ cells were found to function within meiotic processes, a finding also noted by a prior study [232,233]. Although a thorough analysis of this relationship in meiotic cells was precluded by the early arrest stage of Cdk2 À/À spermatocytes and the lethality associated with Nrf1 deletion [234], we were able to observe that CDK2 was a negative regulator of NRF1 transcriptional activity.…”