RNA结合蛋白PIWIL4在雄性生殖细胞中的功能机制研究

精子发生是一个高度复杂的发育过程，其中任何阶段出现问题均会导致精子形成的异常，进而引起男性不育。非梗阻性无精子症（Non-Obstructive Azoospermia, NOA）是最严重的精子发生障碍，但目前人们对其致病机理了解甚少。在本课题组前期测得的934例NOA患者全基因组测序数据中，我们发现了一系列Piwil4基因相关突变。PIWIL4属于PIWI家族蛋白，PIWI/piRNA“机器”通过沉默转座元件和调控mRNA等方式在动物生殖系细胞发育分化过程中发挥重要作用。在小鼠睾丸中，与之结合的piRNA将PIWIL4带到高度互补的转座元件转录本上，招募DNA甲基化机器，指导从头甲基化，然而该过程具体的机制还并不清楚。对这些突变的作用机制研究将拓宽我们对PIWIL4蛋白功能的理解，从分子层面进一步揭示男性不育症的致病机理，为相关男性不育症的诊断和治疗提供理论基础。

Spermatogenesis is a highly complex process and any defects occurring in this process may lead to abnormal sperm production, finally resulting in male infertility. Non-obstructive azoospermia (NOA) is the most severe form of male infertility. However, the knowledge of the causes of NOA is very limited. We have finished the whole-genome sequencing of 934 NOA patients and found some mutations in Piwil4 gene. PIWIL4 belongs to the PIWI family proteins. PIWI/piRNA machinery silence transposable elements and regulate the expression of mRNAs during the spermatogenesis. It is proposed that the associated piRNAs guide the nuclear PIWIL4 to transposable elements where it recruits the DNA methylation apparatus and instruct de novo DNA methylation. However, the mechanisms underlying have remained largely unexplored. The obtained results by investigating these mutations will bring new insights into the function of PIWIL4 protein, and also may provide new molecular targets for the diagnosis and therapeutic of male infertility.