Sex chromosome control of chromatin in the gametes

描述(申请人提供)：哺乳动物生殖细胞的性染色体必须与周围体细胞的性染色体匹配，才能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，在生殖细胞中起作用以确保与胞体相容的性染色体编码因子仍然未知。这项提议将检验这样一种假设，即由X和Y染色体编码的两对同源去甲基酶基因协调发育中的生殖细胞中男性和女性特有的染色质状态，使它们能够适当地对来自周围体细胞的性别特异信号做出反应。这两对X-Y组蛋白去甲基酶同源物针对H3K4me3和H3K27me3，这两个染色质标记在调节多能性和分化之间的平衡方面发挥着核心作用。通过在XX和XY生殖细胞的重要启动子上设置不同的染色质状态，X/Y编码的去甲基酶可能使这些细胞对来自XX或XY体细胞组织的信号做出不同的反应，从而使适当的雄配子或雌配子分化。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已经不同，并且编码在X和Y染色体上的组蛋白去甲基酶至少部分地导致了染色质状态的这种差异。这项建议将通过(1)确定组蛋白甲基化状态在男性和女性发育程序分化之前是否存在差异，以及(2)评估X和Y染色体编码的去甲基酶基因在建立性别特异性染色质状态中的作用，分别讨论这些影响。这些目标的实现将增强我们目前对特定性别配子发育的理解，并改进生育和早期胚胎发育障碍的临床方法。

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.