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The role of ZCWPW1 in meiosis

ZCWPW1 在减数分裂中的作用

基本信息

批准号：
10680189
负责人：
Francesca Cole
金额：
$ 63.4万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10680189
关键词：
Address Affect Aneuploidy Binding Biochemical Bypass Cell Cycle Characteristics Chromosome Arm Chromosome Pairing Chromosome Segregation Chromosome abnormality Chromosomes Compensation Constitution Constitutional Cytology DNA Double Strand Break DNA Repair Data Defect Diploidy Double Strand Break Repair Down Syndrome Ensure Etiology Event Failure Female Frequencies Functional disorder Generations Genetic Genetic Crossing Over Genetic Recombination Genome Genomic Segment Genomics Genotype Germ Cells Haploidy Histone H3 Histones Homologous Gene Human Hybrids Immunoprecipitation In Vitro Infertility Knowledge Lead Location Lysine Male Infertility Mammals Mass Spectrum Analysis Mediating Meiosis Meiotic Prophase I Meiotic Recombination Methylation Methyltransferase Modeling Modification Molecular Monitor Mus Nuclear Envelope Nuclear Inner Membrane Oocytes Play Ploidies Process Production Prophase Proteins Psyche structure Reader Role SPO11 gene Site Speed Spermatocytes Spontaneous abortion System Testing Time biophysical properties chromosome missegregation chromosome movement disability egg experimental study genetic approach genetic information high resolution imaging histone methylation in vivo insight male mutant sex sperm cell telomere

项目摘要

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.

摘要：虽然通过减数分裂产生精子和卵子是经过精心协调和严格调控的，染色体分离非常容易出错。据估计，在人类中，约 5% 的精子和约 30% 的精子卵母细胞具有错误的染色体互补体——称为非整倍体。因此，减数分裂中的错误染色体分离是精神残疾、流产和不孕的主要原因。在哺乳动物中，确保忠实染色体分离的关键步骤包括生成编程 DNA 双 PRDM9 热点处的搁浅断裂 (DSB) 富含双组蛋白 H3 赖氨酸 4 和赖氨酸 36 三甲基化 (K4/H3K36me3)、亲本染色体配对（同源染色体）、同源染色体的共同比对纵向，以及通过交叉来束缚同源物——染色体臂的交换同系物。尽管知识丰富，但在此过程中知识的一个关键差距是如何依赖 PRDM9 H3K4/H3K36me3 双重修饰影响同源配对和重组。我们和其他人已经表明 ZCWPW1，一种双组蛋白甲基化阅读器，在 PRDM9 靶位点富集，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 可能是有效同源配对所必需的，当受损时，该同源配对在染色体中达到顶峰缠结、DSB 修复缺陷，最终导致染色体错误分离和不育。因此，我们提出使用遗传、基因组、分子和生物化学进行全面综合分析剖析 ZCWPW1 在同源配对和重组中的作用的方法。总体而言，这些研究将提供有关减数分裂染色体动力学的基础知识以及对减数分裂染色体动力学的机械理解 ZCWPW1 在哺乳动物减数分裂中的作用。