减数分裂染色体结构对交叉重组的调节及其机制

不孕不育严重影响国民生殖健康。减数分裂交叉重组异常导致的配子发生障碍或质量低下是造成不孕不育的重要原因。交叉重组的数目和分布主要受减数分裂染色体轴长调控，但其机制尚不明晰。本项目将以减数分裂染色体轴长分别增加和降低的Hr6b和Smc1β小鼠突变体为材料，通过RNA-seq和定量蛋白质组学，筛选影响减数分裂染色体结构的关键因子；综合利用细胞学、遗传学方法结合ATAC-seq、超高分辨显微等先进技术和定量的理论模拟，明确关键调控因子在减数分裂染色体上的动态及染色体开放性的变化，阐明重组过程中各种标记蛋白的数目和位置的变化。最终，解析HR6B和SMC1β调控减数分裂染色体轴长及交叉重组的分子机制。本项目的完成，将有助于人们深入认识减数分裂染色体结构及其在交叉重组调控中的重要地位，有利于全面解析交叉重组调控的分子机制，为减数分裂重组异常导致的不孕不育、出生缺陷的精准诊疗提供新思路和新靶点。

Infertility has seriously affected human reproductive health. Gametogenesis disorder and low gamete quality are the leading causes of infertility. Meiosis is the essential cellular program for gametogenesis. The formation of DNA crossovers（COs）between maternal and paternal chromosome is a critical event in meiosis. COs play important roles in ensuring proper chromosome segregation and increasing genetic diversity of species. Abnormally placed COs or absence of COs will lead to chromosome mis-segregation and thus aneuploidy. Therefore, the number and distribution of COs are tightly controlled. Studies from us and others have shown that the number and distribution of CO are mainly regulated by the length of meiotic chromosome axis. SMC1β is a meiosis-specific component of cohesion. Smc1β deficient mice have decreased axis lengths of meiotic chromosome and crossover numbers. HR6B is one of the ubiquitin ligases. Hr6b deleted mice have increased axis lengths of chromosome and crossover numbers. In this project, we will study how meiotic chromosome axis is modulated and how chromosome structure regulates meiotic crossovers in Smc1β and Hr6b knockout mice. To elucidate the roles of SMC1β and HR6B in regulation of meiotic chromosome structure and recombination, we will screen the critical factors using meiotic cells in different stages by RNA-seq and proteomics analysis. The dynamics of key proteins on chromosomes during meiotic progression and high-order meiotic chromosome structures in the mutants will be compared between wild type and knockout mice. The simulation of meiotic recombination process based on Beam-Film model will help us analyze the effects of different factors on meiotic recombination. Finally, we will discover the mechanisms of the regulation of SMC1β and HR6B on meiotic chromosome axis and recombination. We anticipate that the completion of this project will provide theoretical guidance and new targets for precise diagnosis and treatment for infertility.