An Autosomal Analog of X-Inactivation

X 失活的常染色体类似物

• 批准号: 6674436
• 负责人: Andrew J Chess
• 金额: $ 38.95万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6674436
• 关键词: DNA replication; alleles; autosome; chromatin; chromosome deletion; chromosome translocation; chromosomes; diploidy; flow cytometry; fluorescent in situ hybridization; gene expression; gene induction /repression; genetic mapping; genetic regulation; immunoprecipitation; laboratory mouse; polymerase chain reaction

DESCRIPTION (provided by applicant): In diploid eukaryotic organisms it is generally assumed that the maternally and paternally derived copies of each gene are simultaneously expressed at comparable levels and are replicated during the same portion of S phase. However there are exceptions where one of the two copies is not expressed and the two copies are asynchronously replicated. Exceptions include genes subject to X inactivation, imprinted genes and the autosomal randomly monoallelically expressed genes we have analyzed (starting with our studies of odorant receptor genes and extending to immunoglobulin, T cell receptor and interleukin genes). Asynchronous replication is established early in development and is found in various cell types irrespective of transcription. Examining four mouse autosome pairs, we have recently shown that every cell has randomly chosen either the maternal or paternal copy of each given autosome pair, such that alleles of randomly monoallelically expressed genes scattered across the chosen chromosome are earlier replicating than the alleles on the homologous chromosome. Additionally, different chromosomes are not coordinated with one another. Therefore, our data indicate that the maternal and paternal copies of each autosome pair are rendered non-equivalent in individual mouse cells, a process that contributes to cellular diversity through its link to monoallelic transcription. Our data suggest that chromosome pair non-equivalence, rather than being limited to X-inactivation, is a fundamental property of mouse chromosomes. Following on our findings, I describe a series of experiments to further define mechanisms controlling genomewide regulation of monoallelically expressed genes. We propose to: 1. Establish that the observation of an autosomal analog of X-inactivation we have made in mice extends to human cells. 2. Examine the effects of various types of aneuploidies of one or more autosomes or portions thereof on the allele specific replication timing of autosomal genes. 3. Explore other epigenetic changes that may be involved in the allele-specific replication timing of autosomal genes. These studies will explore the novel, fundamental property of autosomes that we have discovered and will set the stage for exploring the role of this level of genome-wide gene regulation on genes relevant to human disease.

描述（由申请人提供）：在二倍体真核生物中，通常假定每个基因的母体和父子衍生的副本同时在可比的水平上同时表达，并在S相同一部分复制。但是，有一个例外，其中两个副本之一未表达，并且两个副本是异步复制的。例外包括我们已经分析的基因，印迹基因和常染色体随机单相表达的基因（从我们对气味受体基因的研究开始，并扩展到免疫球蛋白，T细胞受体和白介素基因）。异步复制是在发育早期建立的，并且在各种细胞类型中发现，而与转录无关。检查了四个小鼠的常染色体对，我们最近表明，每个细胞都随机选择了每个给定的自染色体对的母体或父亲的副本，因此散布在整个染色体上的随机单相表达的基因等位基因比同源染色体上的等位基因更早地复制。此外，不同的染色体不相互协调。因此，我们的数据表明，每个自染色体对的母体和父亲拷贝在单个小鼠细胞中呈现不等，这一过程通过与单相关转录的联系有助于细胞多样性。我们的数据表明，染色体对非等效性，而不是仅限于X灭活，是小鼠染色体的基本特性。 根据我们的发现，我描述了一系列实验，以进一步定义控制全基因组调节单相表达基因的机制。我们建议： 1。确定我们在小鼠中产生的X灭活的常染色体类似物延伸到人类细胞。 2。检查一个或多个常染色体或其部分对常染色体基因的特异性复制时间的各种类型的非整倍性的影响。 3。探索常染色体基因的等位基因特异性复制时间可能涉及的其他表观遗传变化。 这些研究将探索我们发现的新型常染色体的新颖，基本特性，并为探索这种全基因组基因调节对与人类疾病相关的基因的作用奠定了基础。