DNA Damage Response Pathways in Meiotic Sex Chromosome Inactivation

减数分裂性染色体失活中的 DNA 损伤反应途径

基本信息

批准号：
8516535
负责人：
Satoshi Namekawa
金额：
$ 27.9万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8516535
关键词：
Affect Aneuploidy BRCA1 gene Binding Cell Culture System ChIP-seq Chromatin Chromosome Pairing Chromosomes Complex Congenital Abnormality DNA Damage Defect Embryonic Development Epigenetic Process Event Exhibits Failure Fanconi Anemia-BRCA Pathway Fanconi&apos s Anemia Feedback Genes Genetic Genetic Recombination Genetic Variation Genomics Germ Cells Goals Haploidy Histone H3 Histones Immunofluorescence Immunologic Infertility Klinefelter&apos s Syndrome Lead Link Lysine Maintenance Male Infertility Meiosis Meiotic Recombination Methylation Modeling Modification Molecular Mutant Strains Mice Organism Outcomes Research Pachytene Stage Pathway interactions Phosphorylation Phosphotransferases Process RNA Reproduction Reproductive History Research Role SPO11 gene Sex Chromosomes Site Somatic Cell Spermiogenesis TOPBP1 Gene TREX1 gene Turner&apos s Syndrome Variant Work X Chromosome Y Chromosome autosome base design male mouse model mutant next generation novel programs reproductive response sex sperm cell

项目摘要

DESCRIPTION (provided by applicant): The goal of this project is to elucidate the mechanism of epigenetic programming in germ cells, especially focusing on the roles of DNA damage response pathways in sex chromosome inactivation. Germ cells are capable of unique epigenetic programming which is required for sexual reproduction. A better understanding of the epigenetic program in germ cells will illuminate various reproductive issues underlying infertility and birth defects. When germ cells undergo male meiosis to generate haploid sperm, X and Y chromosomes go through a distinct epigenetic program different from autosomes. At the pachytene stage of meiosis, the genes on the X and Y are epigenetically silenced in a process called meiotic sex chromosome inactivation (MSCI). The entire X and Y chromosomes form a chromatin domain, known as the XY body, which is distinct from autosome regions. The XY body is marked by various chromosome-wide epigenetic modifications, which presumably maintain MSCI. My postdoctoral work revealed that sex chromosome inactivation is maintained even after meiosis, and implicated epigenetic inheritance in spermiogenesis and the embryonic development of the next generation. In this proposal, we aim to dissect the molecular basis of epigenetic silencing of sex chromosomes. An intriguing link between epigenetic silencing of sex chromosomes and components involved in DNA damage response (DDR) pathways has been suggested. Cytological evidence shows that various components involved in DDR pathways accumulate on the X and Y at the onset of MSCI. Based on our preliminary studies using mouse models defective for DDR pathways, we hypothesize that DDR pathways are adapted to initiate and maintain chromosome-wide silencing of sex chromosomes in germ cells. We will investigate the role of DDR pathways in MSCI by: (Aim 1) determining how chromosome-wide silencing is initiated; (Aim 2) dissecting the genetic pathways that coordinate potential downstream pathways; and (Aim 3) determining how epigenetic modifications on sex chromosomes are established to maintain inactivation. The proposed study in germ cells will potentially reveal a link between DDR pathways and epigenetic programming that can be generalized to somatic cells.

描述（由申请人提供）：该项目的目的是阐明生殖细胞中表观遗传编程的机理，尤其是专注于DNA损伤反应途径在性染色体灭活中的作用。生殖细胞能够进行独特的表观遗传编程，这是性繁殖所必需的。对生殖细胞中表观遗传程序的更好理解将阐明不育症和先天缺陷的各种生殖问题。当生殖细胞发生男性减数分裂以产生单倍体精子时，X和Y染色体会通过与常染色体不同的不同表观遗传学程序。在减数分裂的Pachytene阶段，X和Y上的基因在称为减数分裂性染色体失活的过程中表观遗传沉默（MSCI）。整个X和Y染色体形成一个染色质结构域，称为XY体，与自染色体区域不同。 XY体以各种染色体的表观遗传学修饰为特征，大概可以维持MSCI。我的博士后工作表明，即使在减数分裂后，性别染色体灭活也能够维持，并暗示了精子发生和下一代的胚胎发育中的表观遗传遗传。在此提案中，我们旨在剖析性染色体表观遗传沉默的分子基础。已经提出了性别染色体的表观遗传沉默与参与DNA损伤反应（DDR）途径的成分之间的有趣联系。细胞学证据表明，在MSCI发作时，与DDR途径相关的各种组成部分积聚在X和Y上。基于我们使用小鼠模型缺陷DDR途径的初步研究，我们假设DDR途径适应生殖细胞中性别染色体的启动和维持全染色体的沉默。我们将通过以下方式研究DDR途径在MSCI中的作用：（ AIM 1）确定如何启动染色体的沉默；（AIM 2）解剖协调下游途径电势的遗传途径；（目标3）确定如何建立对性染色体的表观遗传修饰以保持失活。提出的在生殖细胞中的研究将有可能揭示DDR途径与表观遗传编程之间的联系，可以推广到体细胞。