Abstract
Spermatogonia are the source of spermatogenic waves. Abnormal spermatogonia can cause ab-normal spermatogenic waves, which manifest as spermatogenic disorders such as oligospermia, hypospermia, and azoospermia. Among them, the self-renewal of spermatogonia serves as the basis for maintaining the process of spermatogenesis, and the closely regulated balance between self-renewal and differentiation of spermatogonia can maintain the continuous production of spermatozoa. Tet methylcytosine dioxygenase 1(TET1) is an important epitope modifying enzyme that catalyzes the conversion of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC), thereby causing the methylation of specific genes site hydroxylation, enabling the DNA de-methylation process, and regulating gene expression. However, the hydroxymethylation sites at which TET1 acts specifically and the mechanisms of interaction affecting key differential genes are not clear. In the present study, we provide evidence that the expression of PLZF, a marker gene for spermatogonia self-renewal, was significantly elevated in the TET1 overexpression group, while the expression of PCNA, a proliferation-related marker gene, was also elevated at the mRNA level. Significant differential expression of SP1 was found by sequencing. SP1 expression was increased at both mRNA level and protein level after TET1 overexpression, while differential gene DAXX expression was downregulated at protein level, while the expression of its reciprocal protein P53 was upregulated. In conclusion, our results suggest that TET1 overexpression causes changes in the expression of SP1, DAXX and other genes, and that there is a certain antagonistic effect between SP1 and DAXX, which eventually reaches a dynamic balance to maintain the self-renewal state of spermatogonia for sustained sperm production. These findings may contribute to the understanding of male reproductive system disorders.
Highlights
According to research estimates, approximately 8–12% of couples worldwide are deeply affected by infertility, with approximately 50% of infertility being due to problems with the male partner (Minhas et al, 2021)
QRT-PCR results showed that the mRNA expression level of TET1 was significantly increased in TET1 overexpression cells (Figure 1A), and PLZF, which is related to spermatogonia self-renewal, had its mRNA level expression increased significantly (Figure 1B) and its protein level expression increased to some extent (Figures 1F,G), the changes of mRNA expression level and protein level of GFRα1 were not obvious (Figures 1C,H,I), and the mRNA expression level of MAGE4 and PRDM1 decreased (Figures 1D,E), the above results indicate that TET1 has maintained the function of spermatogonia self-renewal
The mRNA expression levels of VASA, DAZL, and C-KIT, which are associated with spermatogonial differentiation, were all increased to some extent (Figures 3A–C), indicating that TET1 can promote spermatogonial differentiation
Summary
Approximately 8–12% of couples worldwide are deeply affected by infertility, with approximately 50% of infertility being due to problems with the male partner (Minhas et al, 2021). Epigenetic Regulation of TET1 at this time can influence the level of reproductive health of the offspring through the inheritance of epigenetic modifications (Craig et al, 2017). In order to form terminally differentiated spermatozoa and promote the totipotency of fertilized eggs, these epigenetic modifications must be precisely regulated. Male infertility or early embryonic dysplasia may be associated with reproductive disorders resulting from epigenetic alterations associated with the male reproductive process (Liu et al, 2019). Epigenetic modifications can be involved in the spermatogenesis process and affect the fate of spermatogonia by regulating reproduction-specific genes. Self-renewal is fundamental to maintaining the spermatogenesis process, and abnormal selfrenewal of spermato-gonia leads to reduced stability, causing decreased fertility, which eventually manifests as testicular atrophy or even infertility (Zheng et al, 2016)
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