RNA and Genomic Junk in Fundamental Chromosome Architecture and Regulation

摘要 推动我们研究的核心奥秘是，在人类基因组发育过程中， 开发以提供定义特定细胞类型的协调表达程序。我们假设 这涉及建立异染色质和常染色质的稳定模式，这些模式部分受到控制， 染色体结构域和核组织水平。对于这个MIRA应用程序，我们一直致力于 在概念上整合研究项目，解决我们整体愿景的互补方面，重点 关于非编码RNA在染色质调节中的作用的主题。我们将继续为 XIST RNA的迷人生物学，它控制女性细胞中一条X染色体的失活。然而，在这方面， 几年来的发现促使我们越来越重视基因组中富含重复序列的“垃圾”的作用， 染色体的主要成分。在我们看来，我们基因组的这一部分被严重地研究不足， 相对于其对生物学和染色体调节的潜在贡献。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结构中的DNA水平上起作用， 在RNA水平上调节这种结构。而不是RNA作为染色质的偶然修饰剂， 我们的研究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，我们会的 研究普遍存在的RNA是否对维持染色质的去凝聚和凝聚至关重要 核中的结构我们的初步RNAseq分析支持长寿的“垃圾”RNA在结构上是 嵌入在核结构中。事实上，我们的工作很可能表明， 目前认为，许多结构蛋白和调节蛋白实际上是由支架蛋白介导的。 被RNA束缚。这项工作得到了一个合作者团队的支持，他们是不同方面的领导者， RNA，染色质和计算生物学，他们热衷于与我们一起研究这些引人注目的， 潜在的范式转变的想法。虽然这项工作在很大程度上是一项基本性质的工作，但我们的工作的各个方面， 研究直接相关的翻译这方面的知识的共同问题，染色体 三体性

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.