少弱畸形精子症是导致男性不育症的最常见病因，但致病机制大都未明。我们在小鼠生殖细胞特异敲除精氨酸甲基转移酶Carm1，发现小鼠呈现典型的少弱畸形精子症和雄性不育/低生育。初步研究发现缺失Carm1的小鼠精子细胞后期组蛋白不能被鱼精蛋白替换，推测组蛋白-鱼精蛋白替换存在不依赖于传统的组蛋白超乙酰化修饰（H4K5/K8/K16ac）途径，而可能通过CARM1依赖的转换蛋白TP和鱼精蛋白的甲基化。因此，本项目中，我们将在前期工作基础上，利用质谱结合细胞分子生物学等方法进一步深入探讨Carm1在单倍体精子细胞的蛋白质修饰底物及其调控作用。以期揭示不同CARM1底物及其介导的信号通路在配子发生中的作用，解析甲基化调控在OAT的发病机制，为临床上少弱畸形精子症诊治提供新的思路。

Oligoasthenoteratozoospermia (OAT) is one of the most common causes of male infertility in the clinics, but the mechanisms underlying this disease are largely unknown. We show that germline-specific knockout of Carm1, a member of protein arginine methyltransferase (PRMT) family, resulted in the typical OAT phenotype leading to male infertility/subfertility in mice. Histones failed to be replaced by protamines in the Carm1-null spermatids. We hypothesize that histone-to-protamine transition may be not dependent on the canonical histone marker, i.e., hyper-acetylation of histone 4 (H4K5/K8/K16ac), but likely relies on the arginine methylation of TPs and protamines. Thus, in this study, we will further identify the substrates of CARM1 and explore their regulatory roles in haploid spermatids through cellular and molecular methods. Together, this study potentially uncovers a novel histone-to-protamine transition pathway that is dependent on arginine methylation, thus providing new therapeutic approaches for diagnosis and cure of OAT patients in the clinics.