哺乳动物精子发生是一个高度复杂和受到精细调控的过程。日益增多的研究表明，作为表观遗传调控重要方式之一的组蛋白甲基化参与了精子发生的调控。SetD2编码蛋白质是特异性催化形成H3K36me3的酶；然而，国内外对SetD2及其介导的H3K36me3是否调控精子发生一无所知。基于申请人的预实验结果，本项目假设SetD2及其介导的H3K36me3能直接控制与精子发生相关的基因表达，从而调控精子发生。为了验证此假设，以生殖细胞特异性SetD2基因敲除小鼠为模型，本课题研究内容包括：（1）特异性失活生殖细胞SetD2基因后，精子发生是否异常？（2）特异性失活生殖细胞SetD2后，生殖细胞的组蛋白甲基化和DNA甲基化如何变化？（3）SetD2调控精子发生的分子机制是什么？完成本项目将推动对表观遗传调控精子发生的机理的全面认识，并会为以SetD2为靶标的男性不症诊治和抗生育手段的开发奠定技术和理论基础。

Mammalian spermatogenesis is a highly complex and coordinated developmental process. A growing body of evidence indicates that histone methylation, one of the most important epigenetic modification mechanisms, could play critical roles in spermatogenesis.SETD2 is the sole enzyme that trimethylates histone H3 on lysine 36 (H3K36me3) in mammalian cells. To date, little is known about whether and how SetD2 and its mediated H3K36me3 control spermatogenesis. Based on our preliminary data, we hypothesize that SetD2 and its mediated H3K36me3 control spermatogenesis by directly regulating expression of spermatogenesis-related genes. To test this hypothesis, we will use conditional (e.g. germ cell specific) SetD2 knockout mouse models to focus on (1) determining whether SetD2 controls spermatogenesis; (2) establishing how methylation of histone and/or DNA changes in germ cells; and (3) elucidating molecular mechanisms that Setd2 and its mediated H3K36me3 govern spermatogenesis. Successful completion of the proposed research will lead to a more complete understanding of epigenetic mechanisms controlling spermatogenesis and furthermore will help develop new strategies (e.g. SetD2-based) for infertility/subfertility and male contraception.