Regulation of gene silencing by an imprinted non-coding RNA

印迹非编码RNA对基因沉默的调控

基本信息

批准号：
8913206
负责人：
NORA I ENGEL
金额：
$ 29.07万
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：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8913206
关键词：
11p15.5 Ablation Address Alleles Beckwith-Wiedemann Syndrome Binding Sites Biochemical Bioinformatics Boundary Elements Childhood Chromatin Chromosomes Chromosomes, Human, Pair 7 Code Complex Cyclin-Dependent Kinase Inhibitor Data Defect Development Disease Down-Regulation Embryo Embryonic Development Enhancers Environment Epigenetic Process Eukaryota Event Gene Activation Gene Expression Regulation Gene Silencing Genes Genetic Genetic Transcription Genome Genomic Imprinting Goals Growth Health Human Human Chromosomes In Vitro Link Location Maintenance Malignant Neoplasms Modeling Modification Molecular Molecular Genetics Mus Mutation Neoplasms Organism Pattern Potassium Channel Predisposition Process Proteins RNA Interference Regulation Regulatory Element Repression Role Signal Transduction Staging Syndrome System Technology Testing Time Tissues Transgenic Mice Transgenic Organisms Untranslated RNA comparative genomics embryonic stem cell fetal gene repression human disease imprint in vivo insight prenatal response stem cell differentiation tool

项目摘要

DESCRIPTION (provided by applicant): Gene regulation is a complex process that orchestrates the precise timing and location of both gene activation and gene silencing. Genomic imprinting is a specialized mechanism whereby a gene displays silencing of one parental allele. The imprinted region on human chromosome 11p15.5 and its homologous domain in the mouse consists of a cluster of genes that are silenced on the paternal chromosome by an antisense non-coding RNA, Kcnq1ot1. Very little is known of the molecular mechanisms involved in allele-specific silencing and the role of the non-coding RNAs in modulating this process. This proposal will first exploit transgenic RNA interference technology to test the role of Kcnq1ot1 in establishing imprinting at this locus. In the second and third aims, we will study the epigenetic processes that allow some genes to escape silencing, applying a combination of bioinformatic, biochemical and in vivo approaches to identify regulatory elements in this domain that interact physically and create transcriptionally active domains interspersed with the silenced regions. Identifying the molecular mechanisms underlying the establishment and maintenance of imprinting will advance our understanding of human growth defects and disease.

描述（由申请人提供）：基因调节是一个复杂的过程，它策划了基因激活和基因沉默的精确时机和位置。基因组印记是一种专门的机制，基因显示一个父母等位基因的沉默。人类染色体11p15.5的印迹区域及其在小鼠中的同源结构域由一组基因组成，这些基因通过反义的非编码RNA KCNQ1OT1在父亲染色体上沉默。对于参与等位基因特异性沉默涉及的分子机制以及非编码RNA在调节此过程中的作用，知之甚少。该提案将首先利用转基因RNA干扰技术来测试KCNQ1OT1在该基因座建立烙印中的作用。在第二和第三目的中，我们将研究表观遗传过程，这些过程使某些基因可以逃避沉默，并采用生物信息学，生化和体内方法的组合，以鉴定该域中的调节元素，这些调节元素在物理上相互作用并与沉默的区域散布了转录域。确定建立和维持印迹的分子机制将提高我们对人类生长缺陷和疾病的理解。