Deciphering mechanisms governing functional partitioning of the C. elegans genome

破译控制线虫基因组功能分区的机制

基本信息

批准号：
9207005
负责人：
VALERIE J REINKE
金额：
$ 31.64万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9207005
关键词：
Address Affect Architecture Automobile Driving Binding Binding Sites Bruck-de Lange syndrome C. elegans genome CCCTC-binding factor Caenorhabditis elegans Cell Nucleus Cells Chromatin Chromatin Loop Chromosomes Code Complex DNA Polymerase III DNA Sequence DNA-Directed RNA Polymerase Data Development Dimensions Disease Electron Transport Complex III Elements Environment Enzymes Epigenetic Process Event Exhibits Gene Expression Genes Genetic Genome Genomics Germ Cells Germ Lines Hand Histones Individual Intestines Location Maps Methods Mutate Organism Pattern Property RNA Polymerase II Regulation Roberts-SC phocomelia syndrome Signal Transduction Site Small RNA Specificity Techniques Tissue-Specific Gene Expression Tissues Translating Triad Acrylic Resin Untranslated RNA Work base cell type chromatin immunoprecipitation chromatin modification chromosome conformation capture cohesin deep sequencing developmental disease experimental study genetic information genome-wide genomic tools histone modification in vivo in vivo Model innovation novel permissiveness piRNA public health relevance segregation transcription factor transcription factor TFIIIC

项目摘要

DESCRIPTION (provided by applicant): Three-dimensional genome organization, in which the linear DNA sequence is partitioned into functionally distinct domains, is essential for the precise deployment of genetic information in every cell type. An increasing number of devastating disorders and diseases have recently been attributed to disruption of genome organization, yet the mechanistic underpinnings remain poorly understood, especially in vivo. In particular, how the activity of binding factors and sequence elements is translated to epigenetic states and three-dimensional genomic domains to govern gene expression remains mysterious. C. elegans provides an experimentally advantageous in vivo model to dissect the mechanisms governing proper establishment of genomic domains. Data in hand points to a novel mechanism in which a sequence-specific factor (SNAP190) acts with components of the RNA polymerase III complex to define a large genomic domain exhibiting tissue-specific, coordinated regulation of thousands of noncoding small RNAs. In this proposal, the powerful genetic and genomic tools of C. elegans will be employed to investigate how SNAP190, RNA polymerase III, cohesin, and other candidate factors, interact with chromatin states (Aim 1), chromosomal looping (Aim 2), and cis- elements (Aim 3) to define the boundaries of, and regulate gene expression within, this unique genomic domain. The successful completion of the proposed experiments will illuminate the poorly understood yet vitally important mechanisms driving large-scale genome organization in vivo.

描述（由申请人提供）：三维基因组组织（其中线性 DNA 序列被划分为功能不同的域）对于在每种细胞类型中精确部署遗传信息至关重要。最近，越来越多的破坏性病症和疾病被归因于基因组组织的破坏，但其机制基础仍然知之甚少，尤其是在体内。特别是，结合因子和序列元件的活性如何转化为表观遗传状态和三维基因组结构域以控制基因表达仍然是个谜。线虫提供了一种实验上有利的体内模型来剖析控制基因组结构域正确建立的机制。现有数据指出了一种新机制，其中序列特异性因子 (SNAP190) 与 RNA 聚合酶 III 复合物的成分相互作用，定义了一个大型基因组结构域，该结构域表现出对数千个非编码小 RNA 的组织特异性、协调调节。在本提案中，将利用线虫强大的遗传和基因组工具来研究 SNAP190、RNA 聚合酶 III、粘连蛋白和其他候选因子如何与染色质状态（目标 1）、染色体环（目标 2）和顺式元件（目标 3）来定义这个独特的基因组结构域的边界并调节该结构域内的基因表达。所提出的实验的成功完成将阐明驱动体内大规模基因组组织的知之甚少但至关重要的机制。