RNA and Genomic Junk in Fundamental Chromosome Architecture and Regulation

在此输入文本，它是您的应用程序的新摘要信息。此部分不得超过30行文本。 这个项目有可能阐明人类基因组中一个非常大但知之甚少的组成部分，因为我们正在寻求在非编码、富含重复的序列中寻找有意义的信息，这些序列是我们基因组的主体。新出现的证据表明，许多非编码基因组都得到了表达，但通常水平较低。已知一些功能明确的长非编码RNA(LncRNAs)，但尚不清楚数千个其他低水平的、主要是核的LncRNAs是否与功能相关。基于当前周期中的许多进展，我们准备进一步提出一个广泛、有影响力的假说，说明“垃圾RNA”如何共同对基因组调控做出贡献。我们最近的工作表明，许多富含长重复序列(Cot-1)的RNA(包括lncRNAs和内含子/前mRNAs)不仅是“产物”，而且本质上是开放常染色质结构的动态成分。目前的Mira拨款代表了之前两个独立项目的融合，一个专注于将活跃的X染色体转化为浓缩的异染色质Barr小体的长的非编码XIST RNA，另一个专注于活跃基因的核组织。然而，我们的洞察力越来越多地表明，两者之间存在明显的二分法，统一于这样一个假设，即XIST RNA不是影响染色体结构的RNA的特例，而是体现了基因组/染色体生物学的更广泛的方面。我们的发现支持XIST RNA也能直接修饰“RNP-支架”的成分，从而影响异染色质与等染色质状态，而不是简单地与染色质捆绑在一起来修饰组蛋白。最近的其他证据表明，在某些疾病状态下，RNP-支架可能会被破坏。当我们在序列水平上研究RNA对染色体结构的参与时，我们将寻求将其与染色体如何在更大的规模上组织并通过发育协调调节的总体愿景联系起来。这些雄心勃勃的目标将得到由翁志平博士和达里尔·博斯科博士组成的强大合作团队的支持。

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. This project has potential to illuminate a very large but poorly understood component of the human genome, as we seek to find meaningful information in non-coding, repeat-rich sequence, the bulk of our genomes. Emerging evidence shows that much of the non-coding genome is expressed, but often at low levels. A few clearly functional long non-coding RNAs (lncRNAs) are known, yet it remains unclear whether thousands of other low-level, mostly nuclear, lncRNAs are functionally relevant. Based on much progress in the current cycle, we are primed to further advance a broad, impactful hypothesis for how “junk RNAs” may collectively contribute to genome regulation. Our recent work suggests that many long repeat rich (Cot-1) RNAs (including lncRNAs and introns/pre-mRNAs), are not just “products”, but serve essentially as dynamic components of open euchromatin structure. This current MIRA grant represents the convergence of two previously separate projects, one which focused on the long non-coding XIST RNA which transforms an active X-chromosome to a condense heterochromatic Barr Body, and the other focused on nuclear organization of active genes. However, our insights increasingly indicated there was a telling dichotomy between the two, unified by the hypothesis that XIST RNA is not a special example of RNA that impacts chromosome architecture, but exemplifies a much broader aspect of genome/chromosome biology. Rather than XIST RNA simply tethered to chromatin to modify histones, our findings support that XIST RNA also functions to directly modify components of an “RNP-scaffold” that influences the heterochromatin versus euchromatic state. Other recent evidence suggests the RNP-scaffold may be disrupted in certain disease states. As we investigate RNA involvement in chromosome structure at the sequence level, we will seek to connect that to an overall vision of how chromosomes are organized at a much larger scale, and coordinately regulated through development. These ambitious goals will be bolstered by a strong collaborative team, with Dr. Zhiping Weng and Dr. Daryl Bosco.