The role of ZCWPW1 in meiosis

摘要：虽然精子和卵子通过减数分裂产生是精确协调和严格调控的， 染色体分离非常容易出错。在人类中，据估计~5%的精子和~30%的精子 卵母细胞有错误的染色体组成--称为非整倍体。因此，减数分裂中的错误 染色体分离是导致精神残疾、流产和不孕的主要原因。在哺乳动物身上， 确保可靠的染色体分离的关键步骤包括产生程序化的DNA双倍体. PRDM9热点处富含双组蛋白H3赖氨酸4和赖氨酸36的链状断裂(DSB) 三甲基化(K4/H3K36me3)，双亲染色体配对(同源)，同源共对 纵向上，以及通过交叉连接同源基因--染色体臂之间的交换 同系物。尽管知识如此丰富，但在这一过程中，知识的一个关键缺口是如何依赖PRDM9 双重H3K4/H3K36me3修饰影响同源配对和重组。我们和其他人已经展示了 ZCWPW1，一个双组蛋白甲基化阅读器，在PRDM9靶点富含，对数量没有影响 或DSB的位置，但对于DSB修复可能很重要。更具体地说，我们的初步数据表明 ZCWPW1可能是有效的同源配对所必需的，当受损时最终形成染色体 缠结、DSB修复缺陷，最终导致染色体错误分离和不孕。因此，我们 提出使用遗传、基因组、分子和生化的全面和综合分析 分析ZCWPW1在同源配对和重组中的作用的方法。总体而言，这些研究将 提供关于减数分裂染色体动力学的基本知识，并从机理上理解 ZCWPW1在哺乳动物减数分裂中的作用

Abstract: While generation of sperm and eggs through meiosis is exquisitely coordinated and tightly regulated, chromosome segregation is remarkably error prone. In humans it is estimated that ~5% of sperm and ~30% of oocytes have the wrong chromosome complement - known as aneuploidy. As such, errors in meiotic chromosome segregation are a leading cause of mental disability, miscarriage, and infertility. In mammals, critical steps that ensure faithful chromosome segregation include generation of programmed DNA double- stranded breaks (DSBs) at PRDM9 hotspots that are enriched for dual Histone H3 lysine 4 and lysine 36 trimethylation (K4/H3K36me3), the pairing of parental chromosomes (homologs), the co-alignment of homologs lengthwise, and the tethering of homologs by crossing over – the exchange of chromosome arms between homologs. Despite this wealth in knowledge, a key gap in knowledge in this process is how PRDM9-dependent dual H3K4/H3K36me3 modifications influence homolog pairing and recombination. We and others have shown that ZCWPW1, a dual histone methylation reader, is enriched at PRDM9 target sites, has no effect on the number or location of DSBs, but may be important for DSB repair. More specifically, our preliminary data suggest that ZCWPW1 may be required for efficient homolog pairing which when compromised culminates in chromosome entanglements, DSB repair defects, and ultimately chromosome mis-segregation and infertility. Therefore, we propose a comprehensive and integrative analysis using genetic, genomic, molecular, and biochemical approaches to dissect the role of ZCWPW1 in homolog pairing and recombination. Overall, these studies will provide fundamental knowledge about meiotic chromosome dynamics and a mechanistic understanding of the role of ZCWPW1 in mammalian meiosis.