Deciphering mechanisms governing functional partitioning of the C. elegans genome

三维基因组组织，其中线性DNA序列被分割成 功能不同的区域，对于在每个细胞中精确地部署遗传信息是必不可少的 打字。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，然而其机制基础仍然鲜为人知， 尤其是在活体内。尤其是结合因子和序列元件的活性如何被翻译成 表观遗传状态和控制基因表达残基的三维基因组结构域 很神秘。线虫提供了一种实验上有利的活体模型来解剖 管理基因组结构域正确建立的机制。手头的数据指向一部小说 序列特异性因子(SNAP190)与RNA组分作用的机制 聚合酶III复合体，以定义一个大的基因组结构域，表现出组织特异性的、协调的 对数千个非编码小RNA的调控。在这项提议中，强大的基因和基因组 线虫的工具将被用来研究SNAP190，RNA聚合酶III，粘附素，和 其他候选因子，与染色质状态(目标1)、染色体环(目标2)和顺式作用- 元素(目标3)定义这个独特的基因组的边界，并调节其中的基因表达 域。拟议中的实验的成功完成将照亮那些还鲜为人知的 推动体内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.