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。

• 批准号: 8710279
• 负责人: JOANNE ENGEBRECHT
• 金额: $ 28.48万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 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/8710279
• 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' 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' 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

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类型的细胞分裂，产生单倍体配子进行有性生殖。在减数分裂过程中，染色体配对、突触和交叉依赖于父本和母本同源染色体之间的同源性，以确保正确的分离和形成具有正确染色体数的配子。交叉是由同源重组诱导双链断裂（DSBs）的形成和修复引起的。染色体配对缺陷破坏DSB修复并导致检查点激活，导致细胞凋亡或形成非整倍体配子。在男性中，性染色体大部分是半合子的（即缺乏同源染色体），这对修复dsb和逃避检查点激活提出了特殊的挑战。我们的初步结果表明，DSB修复和检查点抑制发生在仅在雄性X染色体上发现的特殊染色质结构的背景下。我们的总体假设是，性染色体的表观遗传景观和男性减数分裂的其他方面改变了与DSB修复和检查点机制的相互作用，以确保男性基因组通过减数分裂准确传播。为了验证这一假设，我们建议使用后生动物模型秀丽隐杆线虫来阐明雄性减数分裂过程中染色体行为的保守机制，这特别适合于遗传学，细胞生物学和分子方法。在目标1中，我们将通过分析野生型和修复缺陷突变体中减数分裂和工程DSB的细胞学、分子和功能修复来定义介导性染色体半合子区域DSB修复的途径。在Aim 2中，我们将通过分析DSB加工因子和检查点蛋白在染色质改变的种系中对DSB的募集来阐明特定组蛋白修饰在DSB修复和检查点沉默中的作用。在这里，我们还将探讨染色质，染色质修饰剂，DNA修复和检查点蛋白之间的物理相互作用。在目标3中，我们将定义DSB处理在男性和女性生殖系中的整体差异。总之，在这个遗传上可处理的系统中对这些过程的理解将为如何修改减数分裂程序以促进成功的雄性减数分裂提供新颖而重要的见解。这些研究与理解与人类减数分裂相关的性染色体非整倍体增加的频率直接相关，导致发育障碍，包括特纳综合征和克兰费尔特综合征。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，它们在监测和维持所有细胞的基因组完整性中起着关键作用。