Sex chromosome control of chromatin in the gametes

配子中染色质的性染色体控制

• 批准号: 8525607
• 负责人: Bluma J Lesch
• 金额: $ 5.39万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8525607
• 关键词: Address; Affect; Appearance; Behavior; Cell Cycle Arrest; Cell Nucleus; Cells; Child; Child Development; Chromatin; Clinical; Cues; Defect; Development; Disease; Embryo; Embryonic Development; Ensure; Equilibrium; Exhibits; Female; Fertility Disorders; Genes; Genetic; Genome; Genotype; Germ Cells; Gonadal structure; Histones; Homologous Gene; Individual; Infertility; Location; Mammals; Meiosis; Methylation; Oocytes; Oogenesis; Parents; Pattern; Play; Recording of previous events; Recruitment Activity; Role; Sex Chromosomes; Signal Transduction; Spermatogenesis; Testing; Tissues; X Chromosome; Y Chromosome; egg; gene function; genome-wide; histone modification; improved; male; member; neuronal cell body; offspring; pluripotency; precursor cell; programs; promoter; public health relevance; sex; sex determination; sperm cell

DESCRIPTION (provided by applicant): The sex chromosomes of mammalian germ cells must match those of the surrounding soma in order for the germ cells to successfully complete development as sperm or eggs. Surprisingly, however, the sex chromosome-encoded factors acting in the germ cells to ensure compatibility with the soma remain unknown. This proposal will test the hypothesis that two pairs of homologous demethylase genes encoded by the X and Y chromosomes coordinate male- and female-specific chromatin states in the developing germ cells, enabling them to respond appropriately to sex-specific signals from the surrounding soma. These two pairs of X-Y histone demethylase homologs target H3K4me3 and H3K27me3, two chromatin marks that play a central role in regulating the balance between pluripotency and differentiation. By setting up different chromatin states at important promoters in XX and XY germ cells, the X/Y-encoded demethylases may predispose these cells to respond differently to cues from XX or XY somatic tissue, thus enabling appropriate male or female gamete differentiation. This hypothesis has two implications: that the chromatin state of male and female germ cells differs even before their appearance and behavior diverges, and that the histone demethylases encoded on the X and Y chromosomes are at least partly responsible for this difference in chromatin state. This proposal will address each of these implications separately, by (1) determining whether histone methylation states differ between males and females just before their developmental programs diverge, and (2) evaluating the role of the X- and Y-chromosome-encoded demethylase genes in setting up sex-specific chromatin states. Fulfillment of each of these aims will enhance our current understanding of sex-specific gamete development, and improve clinical approaches to disorders of fertility and early embryonic development.

描述（由申请人提供）：哺乳动物生殖细胞的性染色体必须与周围体内的性质相匹配，以使生殖细胞成功完成作为精子或卵子的发育。然而，令人惊讶的是，作用在生殖细胞中的性染色体编码的因素以确保与SOMA的兼容性仍然未知。该提议将检验以下假设：由X和Y染色体编码的两对同源脱甲基酶基因在发育中的生殖细胞中协调男性和女性特异性染色质状态，使它们能够对周围躯体的性别特异性信号做出适当反应。这两对X-Y组蛋白脱甲基酶同源物靶向H3K4ME3和H3K27ME3，这是两个染色质标记，它们在调节多能和分化之间的平衡方面起着核心作用。通过在XX和XY生殖细胞中的重要启动子上设置不同的染色质状态，X/Y编码的脱甲基酶可能会使这些细胞倾向于对XX或XY体细胞组织的提示有所不同，从而实现适当的男性或女配子分化。 该假设具有两个含义：男性生殖细胞的染色质状态甚至在其外观和行为分歧之前都有不同，并且在X和Y染色体上编码的组蛋白脱甲基酶至少部分负责染色质状态的这种差异。该提议将通过（1）确定在其发育程序发育差异之前确定组蛋白甲基化状态在男性和女性之间是否有所不同，以及（2）评估X-和Y染色体编码的脱甲基酶基因在设置性别特异性染色质态在设置X-和Y-Cromosom-染色体的作用。实现这些目标将增强我们当前对特定于性别配子发展的理解，并改善生育能力和早期胚胎发育障碍的临床方法。