MOUSE X-CHROMOSOME INACTIVATION

描述（改编自研究者摘要）：本研究旨在 定义小鼠和人类性染色体的进化途径， 了解基因调控机制，特别是与 性染色体的进化特征哺乳动物性别的进化 染色体的特征是Y染色体的变性，一旦性被 由Y染色体上的基因决定，重组被抑制。 X和Y基因表达的复杂调节进化为适应巨大的 性染色体之间基因含量的差异。X失活， 很可能构成了一个控制机制的层次结构， 恢复男女之间的平等表达。沿着X 失活，单个活性X染色体上的基因上调进化 恢复二体常染色体基因表达的平衡。X/Y基因对 有功能的Y基因和X基因从X失活中逃脱， 持续存在，但在物种之间存在差异，提供了进化的证据。 性染色体上的基因路径。 研究人员计划：（目标1）系统地比较薪酬， 男性中X/Y基因对的Y配偶体的表达以及通过逃避X 在女性中失活。这种补偿是重要的，因为个人 一个单一的X染色体有特纳综合征，可能是因为 X/Y基因单倍型不足。来自Y基因和失活X的表达 基因可能在物种、组织或细胞类型之间存在差异， 单倍不足因此，研究者将测量X/Y的表达， 小鼠和人类个体细胞和组织中的基因，以及小鼠 发展;（目标2）跟踪和操纵表观遗传变化， X/Y基因表达和逃避X失活。这种随机损失 发展过程中的控制可能会导致重新激活，如建议， 研究人员以前的研究。它们将遵循DNA甲基化， 雌、雄小鼠X/Y基因组蛋白乙酰化的相关性研究 发展DNA甲基化和组蛋白乙酰化在细胞中将被修饰 行来研究表达式控件的层次结构;（目标3）执行 围绕CLC 4基因进行大规模基因组测序，并比较 两种小鼠物种中的启动子，其具有X-连锁拷贝的 基因或常染色体拷贝。CLC 4在单一活性细胞上的表达加倍， 他们先前发现的X染色体，可能是由于适应性 进化的变化，以维持与常染色体基因剂量的平衡，或 代表活性X的上调过程。通过将CLC 4插入 在转基因小鼠中， 进化染色体重排。

DESCRIPTION (Adapted from the Investigator's Abstract): The study is aimed at defining evolutionary pathways of the sex chromosomes in mouse and human and at understanding mechanisms of gene regulation specifically related to evolutionary features of the sex chromosomes. Evolution of the mammalian sex chromosomes is characterized by degeneration of the Y chromosome, once sex was determined by a gene on the Y chromosome and recombination was inhibited. Complex regulation of X-and Y-gene expression evolved to accommodate dramatic differences in gene content between the sex chromosomes. X inactivation, which is likely to constitute a hierarchy of control mechanisms, evolved in females to restore equal expression between males and females. Along with X inactivation, upregulation of genes on the single active X chromosome evolved to restore balance of expression with disomic autosomal genes. X/Y gene pairs with functional Y genes and X genes that escape from X inactivation have persisted but differ between species, providing evidence of the evolutionary pathways of genes on the sex chromosomes. The investigators plan: (Aim 1) to systematically compare compensation by expression of Y partners of X/Y gene pairs in males and by escape from X inactivation in females. Such compensation is important since individuals with a single X chromosome have Turner syndrome, likely because of haploinsufficiency of X/Y genes. Expression from the Y gene and the inactive X gene could vary between species, tissues or cell types, modifying the impact of haploinsufficiency. Thus, the investigators will measure expression of X/Y genes in mouse and human individual cells and tissues and during mouse development; (Aim 2) to follow and manipulate epigenetic changes in relation to X/Y gene expression and escape from X inactivation. Stochastic loss of such controls during development may result in reactivation, as suggested by the investigators' previous studies. They will follow DNA methylation and association with histone acetylation of X/Y genes during female and male mouse development. DNA methylation and histone acetylation will be modified in cell lines to investigate the hierarchy of expression controls; (Aim 3) to perform large scale genomic sequencing around the CLC4 genes and compare activity of the promoters in two mouse species which either have an X-linked copy of the gene or an autosomal copy. The doubling of CLC4 expression on the single active X chromosome that they previously discovered, may result from adaptive evolutionary changes to maintain balance with autosomal gene dosage or represent a process of active X upregulation. By inserting CLC4 into an autosome and into the X chromosome in transgenic mice, they will recapitulate the evolutionary chromosomal rearrangement.