Epigenetic control of sex chromosome behavior in meiosis.

减数分裂中性染色体行为的表观遗传控制。

基本信息

批准号：
8577755
负责人：
JOANNE ENGEBRECHT
金额：
$ 28.54万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-05 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8577755
关键词：
Aneuploidy Animal Model Apoptosis Architecture BRCA1 gene BRCA2 gene Behavior Binding Biological Caenorhabditis elegans Cell division Cells Chromatin Chromatin Structure Chromosome Pairing Chromosome abnormality Chromosomes Co-Immunoprecipitations Constitution DNA Repair DNA Sequence Data Defect Disease Double Strand Break Repair Employee Strikes Engineering Ensure Epigenetic Process Evolution Female Fluorescent Antibody Technique Frequencies Genetic Genetic Crossing Over Genetic Recombination Genetic Variation Genome Germ Cells Germ Lines Haploidy Health Histones Homologous Gene Human Infertility Klinefelter&apos s Syndrome Link Maintenance Malignant Neoplasms Measures Mediating Meiosis Meiotic Recombination Modeling Modification Molecular Monitor Nonhomologous DNA End Joining Orthologous Gene Pathway interactions Phenotype Play Process Proteins Regulation Repair Complex Reproduction Role SET Domain Sex Chromosomes Signal Transduction Sister Chromatid Site Structure System Testing Time Tumor Suppressor Proteins Turner&apos s Syndrome Work X Chromosome autosome chromatin modification chromatin protein developmental disease egg histone methyltransferase histone modification homologous recombination insight male mutant novel prevent programs public health relevance repaired restoration segregation sex sexual dimorphism sperm cell tool transmission process

项目摘要

DESCRIPTION (provided by applicant): Meiosis is a special type of cell division that produces haploid gametes for sexual reproduction. During meiosis, chromosome pairing, synapsis and crossing over rely on homology between the paternal and maternal homologous chromosomes to ensure proper segregation and formation of gametes with the correct number of chromosomes. Crossovers are initiated by the formation and repair of induced double-strand breaks (DSBs) by homologous recombination. Defects in chromosome pairing disrupt DSB repair and result in checkpoint activation, leading to either apoptosis or the formation of aneuploid gametes. In males, sex chromosomes are largely hemizygous (i.e., lack a homologous chromosome), which presents a special challenge to repair DSBs and, moreover, to evade checkpoint activation. Our preliminary results show that DSB repair and checkpoint suppression occur in the context of a specialized chromatin structure found only on the X chromosome of males. Our overall hypothesis is that the epigenetic landscape of sex chromosomes and other aspects of male meiosis alter interactions with DSB repair and checkpoint machinery to ensure accurate transmission of the male genome through meiosis. To test this hypothesis we propose to elucidate the conserved mechanisms underlying chromosome behavior during male meiosis using the metazoan animal model Caenorhabditis elegans, which is particularly amenable to genetic, cell biological and molecular approaches. In Aim 1 we will define the pathways that mediate DSB repair on hemizygous regions of sex chromosomes by analyzing repair of both meiotic and engineered DSBs cytologically, molecularly and functionally in wild type and repair-defective mutants. In Aim 2 we will elucidate the role of specific histone modifications on DSB repair and checkpoint silencing by analyzing the recruitment of DSB processing factors and checkpoint proteins to DSBs in germ lines with altered chromatin. Here we will also probe the physical interactions between chromatin, chromatin modifiers, DNA repair and checkpoint proteins. In Aim 3 we will define global differences in DSB processing in the male versus female germ line. Together, an understanding of these processes in this genetically tractable system will provide novel and important insights into how the meiotic program is modified to promote successful male meiosis. These studies have direct relevance to understanding the increased frequency of sex chromosome aneuploidy associated with human meiosis resulting in developmental disorders including Turner and Klinefelter's Syndromes. Importantly, these studies will also elucidate general mechanisms of DNA repair and checkpoint signaling, which play critical roles in monitoring and maintaining genome integrity in all cells.

描述（由申请人提供）：减数分裂是一种特殊的细胞分裂类型，可产生单倍型配子进行有性繁殖。在减数分裂，染色体配对，突触和越过的过程中，依赖父亲和母体同源染色体之间的同源性，以确保与正确数量的染色体数量的适当分离和形成配子。通过同源重组的形成和修复诱导的双链断裂（DSB）来启动交叉。染色体配对的缺陷破坏DSB修复并导致检查点激活，导致凋亡或非整倍型配子的形成。在男性中，性染色体在很大程度上是半合子（即缺乏同源染色体），这给修复DSB和逃避检查点激活带来了特殊的挑战。我们的初步结果表明，DSB修复和检查点抑制作用发生在仅在男性X染色体上发现的专门染色质结构。我们的总体假设是，性染色体的表观遗传景观以及男性减数分裂的其他方面改变了与DSB修复和检查点机械的相互作用，以确保通过减数分裂的男性基因组准确地传播。为了检验这一假设，我们建议使用后唑动物模型Caenorhabditis秀丽隐杆线虫在男性减数分裂过程中阐明染色体行为的保守机制，这特别适合遗传，细胞生物学和分子方法。在AIM 1中，我们将通过分析减数分裂和工程性DSB的修复在细胞学上，分子和功能上在野生型和维修缺陷性突变体中分析性染色体的修复，从而定义在性别染色体上介导DSB修复的途径。在AIM 2中，我们将通过分析DSB加工因子的募集和检查点蛋白在具有改变染色质的细菌系中的DSB中募集到DSB修复和检查点沉默对DSB修复和检查点沉默的作用。在这里，我们还将探测染色质，染色质修饰剂，DNA修复和检查点蛋白之间的物理相互作用。在AIM 3中，我们将定义男性与女性系中DSB处理的全球差异。总之，对这种遗传处理系统中这些过程的理解将提供新颖而重要的见解，以了解如何修改减数分裂程序以促进成功的男性减数分裂。这些研究与了解与人类减数分裂相关的性染色体非整倍性的增加频率直接相关，从而导致了包括Turner和Klinefelter综合征在内的发育障碍。重要的是，这些研究还将阐明DNA修复和检查点信号的一般机制，这些机制在监测和维持所有细胞中的基因组完整性方面起着关键作用。