Sex chromosome control of chromatin in the gametes

配子中染色质的性染色体控制

• 批准号: 8655456
• 负责人: Bluma J Lesch
• 金额: $ 5.58万
• 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/8655456
• 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索马的性染色体相匹配，以使生殖细胞成功完成精子或卵子的发育。然而，令人惊讶的是，性染色体编码的因子在生殖细胞中起作用，以确保与索马的相容性仍然未知。这个建议将测试的假设，即两对同源脱甲基酶基因编码的X和Y染色体协调男性和女性特定的染色质状态在发展中的生殖细胞，使他们能够适当地响应性别特异性信号从周围的索马。这两对X-Y组蛋白去甲基化酶同源物靶向H3 K4 me 3和H3 K27 me 3，这两种染色质标记在调节多能性和分化之间的平衡中起核心作用。通过在XX和XY生殖细胞中的重要启动子处建立不同的染色质状态，X/Y编码的脱甲基酶可能使这些细胞倾向于对来自XX或XY体细胞组织的线索作出不同的反应，从而使适当的雄性或雌性配子分化成为可能。 这一假说有两个含义：男性和女性生殖细胞的染色质状态甚至在它们的外观和行为分化之前就不同了，并且X和Y染色体上编码的组蛋白去甲基化酶至少部分地负责这种染色质状态的差异。该提案将分别解决这些问题，通过（1）确定组蛋白甲基化状态是否在男性和女性的发育程序分化之前存在差异，以及（2）评估X和Y染色体编码的去甲基化酶基因在建立性别特异性染色质状态中的作用。这些目标的实现将增强我们目前对性别特异性配子发育的理解，并改善生育障碍和早期胚胎发育的临床方法。