On October 17, Professor Yuan Shuiqiao's research group of Institute of reproductive health published online in nature communications, entitled "uhrf1 suppresses retrotransposons and cooperates with Prmt5 and piwi proteins in male germ" This paper found that uhrf1 protein in male mammalian germ cells can be used as a molecular link between DNA methylation, histone modification and piRNA pathway to inhibit the activity of reverse transcriptional transposons (TES), so as to maintain normal spermatogenesis and male fertility.
On the basis of previous work, Professor Yuan Shuiqiao's team used conditional gene knockout strategy to specifically knock out uhrf1 gene in mouse germ cells. It was found that the knockout mice were completely infertile, with significantly smaller testis and no sperm in epididymis. Further phenotypic analysis showed that the spermatogenic cell development of knockout mice was arrested in the pachytene stage of prophase I, indicating that uhrf1 regulates the meiotic process of spermatocytes. Interestingly, our team found that the retrotransposon (line 1) in the knockout spermatocytes was abnormally activated, and the DNA in the genome of the knockout mice showed hypomethylation. Meanwhile, we found that the inhibitory histone (h3k9me3) decreased significantly in the knockout spermatocytes, while the activating histone (h3k4me2) increased significantly. Further high-throughput sequencing showed that the components of pachytene piRNA in the testis of knockout mice (p15) were significantly reduced, suggesting that the piRNA generation pathway in the germ cells of knockout mice was abnormal. Meanwhile, the expression and localization of key proteins (MiWi, mili, MVH, tdrkh, etc.) involved in piRNA generation were abnormal. Immunoprecipitation assay confirmed that uhrf1 and tdrkh were closely related Piwi family proteins interact with each other. This study revealed the molecular mechanism of retrotransposon silencing during meiosis in spermatocytes, and innovatively proposed uhrf1 as a molecular link to inhibit the abnormal activation of retrotransposon in spermatocytes by regulating DNA methylation, histone modification and piRNA pathway (Fig. 1).
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