State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
Department of Neurobiology, School of Basic Medical Science, Nanjing Medical University, Nanjing 211166, China.
Science. 2024 Oct 25;386(6720):eadj8172. doi: 10.1126/science.adj8172.
Despite continuous expansion of the RNA binding protein (RBP) world, there is a lack of systematic understanding of RBPs in the mammalian testis, which harbors one of the most complex tissue transcriptomes. We adapted RNA interactome capture to mouse male germ cells, building an RBP atlas characterized by multiple layers of dynamics along spermatogenesis. Trapping of RNA-cross-linked peptides showed that the glutamic acid-arginine (ER) patch, a residue-coevolved polyampholytic element present in coiled coils, enhances RNA binding of its host RBPs. Deletion of this element in NONO (non-POU domain-containing octamer-binding protein) led to a defective mitosis-to-meiosis transition due to compromised NONO-RNA interactions. Whole-exome sequencing of over 1000 infertile men revealed a prominent role of RBPs in the human genetic architecture of male infertility and identified risk ER patch variants.
尽管 RNA 结合蛋白 (RBP) 的研究不断扩展，但人们对睾丸这一拥有最复杂组织转录组的哺乳动物组织中的 RBP 仍缺乏系统的了解。我们采用 RNA 相互作用组捕获技术对雄性小鼠生殖细胞进行研究，构建了一个 RBP 图谱，图谱特征是沿着精子发生过程具有多层次的动态变化。RNA 交联肽的捕获表明，卷曲螺旋中存在的一个残基共进化的多两性电解质元件谷氨酸-精氨酸 (ER) 补丁，增强了其宿主 RBP 的 RNA 结合。NONO（非 POUS 域包含八聚体结合蛋白）中该元件的缺失会导致有丝分裂到减数分裂的转变出现缺陷，因为 NONO-RNA 相互作用受损。对 1000 多名不育男性的全外显子组测序揭示了 RBPs 在男性不育的人类遗传结构中的重要作用，并确定了风险 ER 补丁变体。
