Analysis of Imprinting Control of the Beckwith Wiedeman Domain

Beckwith Wiedeman 域的印记控制分析

基本信息

批准号：
8115775
负责人：
NORA I ENGEL
金额：
$ 16.84万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8115775
关键词：
Address Alleles Antisense RNA Beckwith-Wiedemann Syndrome Binding Binding Sites Biochemical Bioinformatics Biological Assay CDK6-associated protein p18 Characteristics Chromosomes Chromosomes, Human, Pair 11 Chromosomes, Human, Pair 7 Code Collaborations Complex Cyclin-Dependent Kinase Inhibitor Development Disease Distal Down-Regulation Elements Embryo Enhancers Environment Epigenetic Process Event Exons Functional RNA Gene Expression Gene Silencing Genes Genetic Genetic Polymorphism Genetic Transcription Genome Genomic Imprinting Goals Growth Growth Factor Growth and Development function H19 gene Hepatoblastoma Human Human Chromosomes Hybrids In Vitro Insulin-Like Growth Factor II Laboratories Lead Loss of Heterozygosity Maintenance Malignant Childhood Neoplasm Malignant Neoplasms Methylation Mitotic Recombination Molecular Molecular Conformation Mus Mutation Nephroblastoma Nucleic Acid Regulatory Sequences Pattern Play Potassium Channel Promoter Regions Proteins RNA RNA Interference Regulatory Element Repression Request for Applications Research Research Personnel Role Staging Technology Testing Tissues Transcriptional Regulation Transgenic Organisms Wild Type Mouse career career development comparative genomics fetal human disease imprint improved in vivo promoter tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): This application requests support for Dr. Nora Engel, a junior investigator starting up her laboratory as an independent investigator. The study of epigenetic mechanisms will lead to an understanding of how the genome functions as a developmental blueprint and how perturbations of gene expression patterns can lead to cancer. The goal of this proposal is to elucidate epigenetic mechanisms leading to allele-specific gene silencing in a cluster of imprinted genes. Imprinted genes have parental-specific monoallelic expression. This proposal focuses on the Kcnq1 domain, in which a non-coding, antisense RNA is expressed from the paternal chromosome and silences its neighboring genes. We will first exploit transgenic RNA interference technology to test whether transcription of Kcnq1ot, an imprinted antisense non-coding RNA produced from exon 11 of Kcnq1, is required to maintain the imprinting at this locus. Second, we will study the physical interactions between regulatory elements at the Kcnq1 domain through chromosome conformation capture technology, testing the hypothesis that there are allele-specific interactions. Mice with a targeted mutation in the region will be compared to the wild-type mice. A third aim is to apply a combination of bioinformatic, biochemical and in vivo approaches to identify regulatory elements in the Kcnq1 domain. This proposal will open avenues for research that will improve our understanding of imprinting dysregulation in cancer. It will also serve the immediate career goal of the applicant of establishing herself as an independent investigator in an emerging field. With the help of the excellent career development environment available, and through the expertise and collaborations she will develop, the applicant will pursue the long term goal of becoming an academic leader in cancer epigenetics.

描述（由申请人提供）：本申请请求对 Nora Engel 博士的支持，她是一名初级研究员，作为独立研究员创办了自己的实验室。表观遗传机制的研究将有助于了解基因组如何作为发育蓝图发挥作用，以及基因表达模式的扰动如何导致癌症。该提案的目标是阐明导致印记基因簇中等位基因特异性基因沉默的表观遗传机制。印记基因具有亲本特异性的单等位基因表达。该提案重点关注 Kcnq1 结构域，其中非编码反义 RNA 从父本染色体表达并沉默其邻近基因。我们将首先利用转基因RNA干扰技术来测试Kcnq1ot（一种由Kcnq1外显子11产生的印迹反义非编码RNA）的转录是否需要维持该位点的印迹。其次，我们将通过染色体构象捕获技术研究Kcnq1域调控元件之间的物理相互作用，检验存在等位基因特异性相互作用的假设。该区域具有靶向突变的小鼠将与野生型小鼠进行比较。第三个目标是应用生物信息学、生物化学和体内方法相结合来识别 Kcnq1 结构域中的调控元件。该提案将为研究开辟途径，提高我们对癌症印记失调的理解。它还将服务于申请人在新兴领域成为独立研究者的近期职业目标。借助现有的优秀职业发展环境，并通过她将发展的专业知识和合作，申请人将追求成为癌症表观遗传学学术领导者的长期目标。