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

• 批准号: 8896814
• 负责人: Satoshi Namekawa
• 金额: $ 28.92万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8896814
• 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' s Anemia; Feedback; Genes; Genetic; Genetic Recombination; Genetic Variation; Genomics; Germ Cells; Goals; Haploidy; Histone H3; Histones; Immunofluorescence Immunologic; Infertility; Klinefelter' s Syndrome; Lead; Link; Lysine; Maintenance; Male Infertility; Meiosis; Meiotic Recombination; 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' s Syndrome; Variant; Work; X Chromosome; Y Chromosome; autosome; base; design; histone methylation; male; mouse model; mutant; next generation; novel; programs; reproductive; response; sex; sperm cell

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）：该项目的目标是阐明生殖细胞中表观遗传编程的机制，特别关注DNA损伤反应途径在性染色体失活中的作用。生殖细胞能够进行有性生殖所需的独特表观遗传编程。更好地了解生殖细胞的表观遗传程序将阐明导致不孕和出生缺陷的各种生殖问题。当生殖细胞经历雄性减数分裂产生单倍体精子时，X 和 Y 染色体经历与常染色体不同的独特表观遗传程序。在减数分裂的粗线期，X 和 Y 上的基因在称为减数分裂性染色体失活 (MSCI) 的过程中表观遗传沉默。整个 X 和 Y 染色体形成一个染色质结构域，称为 XY 体，与常染色体区域不同。 XY 体以各种染色体范围的表观遗传修饰为标志，这可能维持 MSCI。我的博士后研究表明，即使在减数分裂后，性染色体失活仍然存在，并暗示精子发生和下一代胚胎发育中的表观遗传。在本提案中，我们的目标是剖析性染色体表观遗传沉默的分子基础。性染色体的表观遗传沉默与 DNA 损伤反应 (DDR) 途径中涉及的成分之间存在着有趣的联系。细胞学证据表明，参与 DDR 途径的各种成分在 MSCI 开始时在 X 和 Y 上积累。基于我们使用 DDR 通路缺陷的小鼠模型进行的初步研究，我们假设 DDR 通路适合启动和维持生殖细胞中性染色体的染色体范围沉默。我们将通过以下方式研究 DDR 通路在 MSCI 中的作用：（目标 1）确定染色体范围内的沉默是如何启动的； （目标 2）剖析协调潜在下游途径的遗传途径； （目标 3）确定如何建立性染色体上的表观遗传修饰以维持失活。拟议的生殖细胞研究将有可能揭示 DDR 通路和表观遗传编程之间的联系，这种联系可以推广到体细胞。