RNA and Genomic Junk in Fundamental Chromosome Architecture and Regulation

摘要 推动我们研究的中心谜团是数千个基因是如何在 提供定义特定细胞类型的精心编排的表达程序的开发。我们假设 这涉及到建立稳定的异染色质和常染色质模式，它们在一定程度上被控制在 染色体结构域和核组织的水平。对于这个Mira应用程序，我们已经努力 从概念上整合研究项目，解决我们总体愿景的互补方面，专注于 关于非编码RNA在染色质调节中的作用的主题。我们将继续致力于 XIST RNA的迷人生物学，它控制着女性细胞中一条X染色体的失活。然而， 几年来的发现促使我们越来越重视富含重复序列的基因组“垃圾”的作用， 染色体的主要组成部分。在我们看来，我们基因组的这一部分被极大地忽视了 相对于它对生物学和染色体调控的潜在贡献。基于强大的初步 结果，我们假设富含重复序列的元件在染色体构型的DNA水平上起作用，并且 在RNA水平上对该架构进行监管。而不是将RNA作为染色质的临时修饰物， 我们的结果支持具有染色体结构的RNA更多的是规则而不是例外。事实上，我们会 研究无处不在的RNA是否对维持去浓缩和浓缩染色质是必不可少的 核内的结构。我们的初步RNAseq分析支持长寿命的“垃圾”RNA在结构上 嵌入到核结构中。事实上，我们的工作很可能证明了这一点，而不是将RNA拴在 染色质由一种骨架蛋白组成，正如目前认为的那样，许多结构和调控蛋白实际上是 被RNA捆绑在一起。这项工作由一个合作者团队支持，他们是不同方面的领导者 RNA，染色质和计算生物学，他们热衷于与我们在这些引人注目的， 潜在的范式转变的想法。虽然这项工作很大程度上是根本性的，但我们的一些方面 研究与将这一知识转化为常见的染色体问题有直接关系 三体。

ABSTRACT The central mystery that drives our research is how thousands of genes are coordinately regulated during development to provide orchestrated expression programs that define specific cell-types. We hypothesize that this involves establishing stable patterns of heterochromatin and euchromatin which are, in part, controlled at the level of chromosomal domain and nuclear organization. For this MIRA application, we have worked to conceptually integrate research projects which address complementary aspects of our overall vision, focusing on a theme around the role of non-coding RNAs in chromatin regulation. We continue to contribute to the fascinating biology of XIST RNA, which controls inactivation of one X-chromosome in female cells. However, findings over several years motivate our increasing emphasis on the role of repeat-rich “junk” of the genome, the main component of chromosomes. In our view, this part of our genomes is dramatically understudied relative to its potential contribution to the biology and regulation of chromosomes. Based on strong preliminary results, we hypothesize that repeat-rich elements play a role at the DNA level in chromosome architecture, and at the RNA level in regulation of that architecture. Rather than RNA as an occasional modifier of chromatin, our results support that RNA with chromosome structure is more the rule than the exception. In fact, we will investigate whether ubiquitous RNAs are essential to maintaining decondensed and condensed chromatin structure in nuclei. Our preliminary RNAseq analysis supports that long-lived “junk” RNAs are structurally embedded in nuclear structure. In fact, our work is likely to show that, rather than RNA being tethered to chromatin by a scaffold protein, as currently believed, many architectural and regulatory proteins are actually tethered by RNA. This work is supported by a team of collaborators who are leaders in different aspects of RNA, chromatin and computational biology, and who are enthused to work with us on these compelling, potentially paradigm shifting ideas. Although this work is largely of a fundamental nature, aspects of our studies have direct relevance to the translation of this knowledge to the common problem of chromosomal trisomy.