Deciphering mechanisms governing functional partitioning of the C. elegans genome

三维基因组组织，其中线性DNA序列被划分为 功能上不同的区域，对于每个细胞中遗传信息的精确部署至关重要 类型.最近，越来越多的破坏性疾病和疾病被归因于 基因组组织的破坏，但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被翻译成 控制基因表达的表观遗传状态和三维基因组结构域 神秘C. elegans提供了一种实验上有利的体内模型来解剖 控制基因组域正确建立的机制。手中的数据指向一部小说 序列特异性因子（SNAP 190）与RNA组分作用的机制 聚合酶III复合物，以限定表现出组织特异性、协调的 调节成千上万的非编码小RNA。在这项提案中，强大的遗传和基因组 C的工具。线虫将被用来研究SNAP 190，RNA聚合酶III，cohesin， 其他候选因子，与染色质状态（Aim 1），染色体成环（Aim 2）和顺式- 元件（目的3），以确定边界，并调节基因表达，这一独特的基因组 域拟议实验的成功完成将阐明人们尚不了解的 在体内驱动大规模基因组组织的至关重要的机制。

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.