COMPARATIVE GENOMIC AND FUNCTIONAL ANALYSIS OF INACTIVE X EXPRESSION

非活性 X 表达的比较基因组和功能分析

• 批准号: 8099224
• 负责人: Laura Carrel
• 金额: $ 9.62万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-12 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8099224
• 关键词: Accounting; Address; Affect; Aneuploidy; Binding; Binding Sites; Boundary Elements; CCCTC-binding factor; Chromatin; Chromosome Structures; Chromosomes; Clinical; Congenital Abnormality; DNA Sequence Rearrangement; Data; Development; Disease; Distal; Elements; Embryonic Development; Environment; Epigenetic Process; Evolution; Female; Gene Cluster; Gene Dosage; Gene Expression; Gene Expression Regulation; Gene Frequency; Gene Silencing; Genes; Genetic; Genetic Counseling; Genome; Genomics; Human; Individual; Link; Live Birth; Location; Malignant Neoplasms; Mammals; Medical Genetics; Modification; Molecular Genetics; Mus; Nature; Oncogenes; Pattern; Phenotype; Play; Process; Recommendation; Regulation; Research Personnel; Rest; Role; Scanning; Series; Site; System; Testing; Transcript; Transgenes; Turner' s Syndrome; X Chromosome; X Inactivation; arm; chromatin modification; comparative; comparative genomics; embryonic stem cell; gene therapy; improved; insight; male; programs; research study; tool; transgene expression

DESCRIPTION (provided by applicant): X chromosome inactivation is an extraordinary example of long-range gene regulation, extending ~150 megabases and silencing genes on one X in females as a means of equalizing gene dosage between XX females and XY males. Nonetheless, not all genes on the X are silenced. Mechanistically, how inactivation spreads along the X and why some regions "escape" X inactivation are not well understood but are important questions. Indeed, few examples of gene regulation are so intimately tied to chromosome organization, evolution and disease. Current data support a role for underlying genomic sequence and insulation by boundary elements. Human escape genes are not rare but largely cluster, suggesting that they are organized in coordinately controlled domains. We will use comparative genomics and molecular genetics tools to address the following hypotheses: (1) Underlying genomic sequences and boundary elements regulate X inactivation and are evolutionarily conserved. This will be tested by determining X inactivation patterns in ten mammals and developing a computational and statistical platform to identify candidate regulatory sequences, (2) Insulators are a conserved mechanism to regulate escape genes. This will be tested by characterizing epigenetic features of a human insulator that lies in an escape transition and determining whether insulator function correlates with escape domains in other mammals, (3) Genomic landscape functionally influences escape gene expression, and (4) Escape gene mechanisms are functionally conserved. To address these last two hypotheses, we will introduce mouse and human escape genes to different locations on the mouse X and and determine whether this affects their expression on the inactive X. The proposed experiments have direct relevance for medical genetics. The inheritance of an abnormal number of X chromosomes is quite common, accounting for 1 in 650 live births. One specific case, Turner syndrome, is the most common genetic birth defect in females. Many problems in these individuals are due to the specific subset of genes that will be studied in this application. We need to better understand these genes to explain clinical features and to improve genetic counseling recommendations. Further, these studies will also give insight into why genes are silenced when they are placed into new chromosomal environments, such as chromosome rearrangements that commonly occur in cancers and gene insertions for gene therapy.

描述（由申请人提供）：X染色体失活是远程基因调节的一个非凡例子，在女性中延伸了一个X X型兆邦和沉默的基因，作为使XX女性和XY男性之间基因剂量均衡的一种手段。但是，并非X上的所有基因都沉默。从机械上讲，失活是如何沿X传播的，以及为什么某些地区“逃脱” X X灭活尚不很好，而是重要的问题。确实，很少有基因调节的例子与染色体组织，进化和疾病密切相关。当前数据支持基本序列和边界元素绝缘的作用。人类逃生基因并不罕见，而是很大程度上簇，这表明它们是在协同控制的域中组织的。我们将使用比较基因组学和分子遗传学工具来解决以下假设： （1）基因组序列和边界元件调节X失活并在进化上保守。这将通过确定十种哺乳动物中的X灭活模式并开发一个计算和统计平台来测试这一点，以识别候选调节序列，即 （2）绝缘子是调节逃生基因的保守机制。这将通过表征人类绝缘子的表观遗传特征来测试，该特征位于逃生过渡和确定 绝缘体功能是否与其他哺乳动物中的逃生域相关， （3）基因组景观在功能上影响逃生基因表达，而 （4）逃生基因机制在功能上是保守的。为了解决最后两个假设，我们将将小鼠和人逃生基因引入小鼠X上的不同位置，并确定这是否影响它们在无效X上的表达。 提出的实验与医学遗传学具有直接相关性。异常的遗传 X染色体的数量很常见，占650个活产的1分之一。一种特定的情况，特纳综合征，是女性最常见的遗传性先天缺陷。这些个体中的许多问题是由于本应用程序中将研究的基因的特定子集。我们需要更好地理解这些基因，以解释临床特征并改善遗传咨询建议。此外，这些研究还将深入了解为什么将基因放入新的染色体环境中，例如通常发生在癌症中通常发生的染色体重排和基因插入基因治疗的基因。