MOUSE X-CHROMOSOME INACTIVATION

描述(改编自《调查者摘要》)：这项研究旨在 确定小鼠和人以及人类的性染色体的进化途径 了解与特定基因调控相关的机制 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染色体的退化，一旦有性行为 由Y染色体上的一个基因决定，重组被抑制。 X和Y基因表达的复杂调控进化为适应戏剧性 性染色体之间基因含量的差异。X失活，它 很可能构成了一系列控制机制，在女性身上进化 以恢复男性和女性之间的平等表达。与X一起 单个活性X染色体上基因的失活和上调 以恢复与二体常染色体基因的表达平衡。X/Y基因对 有功能的Y基因和逃脱X失活的X基因有 持久的，但在物种之间不同，提供了进化的证据 性染色体上的基因途径。 调查人员计划：(目标1)通过以下方式系统地比较薪酬 X/Y基因对的Y配对在男性中的表达及逃避X 雌性的失活。这种补偿很重要，因为拥有 单个X染色体患有特纳综合征，可能是因为 X/Y基因单倍性缺失。Y基因和失活X基因的表达 基因可能在物种、组织或细胞类型之间有所不同，从而改变 单倍体功能不全。因此，研究人员将测量X/Y的表达 小鼠和人类单个细胞和组织以及小鼠体内的基因 发展；(目标2)跟踪和操纵与以下方面有关的表观遗传变化 X/Y基因表达和逃逸X失活。这样的随机损失 开发期间的控件可能会导致重新激活，如 调查人员之前的研究。他们将遵循DNA甲基化和 雌性和雄性小鼠X/Y基因组蛋白乙酰化的关系 发展。DNA甲基化和组蛋白乙酰化将在细胞内被修饰 调查表达式控件层次结构的行；(目标3)执行 CLC4基因的大规模基因组测序及活性比较 两种小鼠物种中的启动子，它们要么具有X-连锁的 基因或常染色体复制体。CLC4在单活性细胞上的表达倍增 他们之前发现的X染色体，可能是适应性的结果 保持常染色体基因剂量平衡的进化变化 代表Active X上调的过程。通过将CLC4插入到 在转基因小鼠中进入常染色体和X染色体，它们将概括 进化中的染色体重排。

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.