RNA and Genomic Junk in Fundamental Chromosome Architecture and Regulation

基本染色体结构和调控中的 RNA 和基因组垃圾

• 批准号: 10552441
• 负责人: JEANNE Bentley LAWRENCE
• 金额: $ 62.84万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10552441
• 关键词: Architecture; Biology; Chromatin; Chromosome Structures; Chromosomes; Code; DNA; Development; Disease; Euchromatin; Genes; Genome; Genomics; Goals; Grant; Heterochromatin; Histones; Human Genome; Introns; Modeling; Nuclear; Proteins; RNA; Recommendation; Regulation; Repression; Sex Chromatin; Structure; Text; Untranslated RNA; Vision; Work; X Chromosome; X Inactivation; insight; mRNA Precursor; novel; scaffold

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.

在此输入文本，它是应用程序的新摘要信息。此部分不得超过30行文本。 这个项目有可能照亮人类基因组中一个非常大但知之甚少的组成部分，因为我们试图在非编码，重复序列丰富的序列中找到有意义的信息，我们的大部分基因组。新出现的证据表明，大部分非编码基因组都有表达，但通常水平较低。已知一些功能明确的长链非编码RNA（lncRNA），但仍不清楚其他数千种低水平（主要是核）lncRNA是否具有功能相关性。基于当前周期的许多进展，我们准备进一步推进一个广泛的、有影响力的假设，即“垃圾RNA”如何共同促进基因组调控。我们最近的工作表明，许多长重复丰富（Cot-1）RNA（包括lncRNA和内含子/前mRNA），不只是“产品”，但基本上作为开放的常染色质结构的动态组件。目前的MIRA资助代表了两个以前独立的项目的融合，一个专注于将活性X染色体转化为浓缩异染色质巴尔体的长非编码XIST RNA，另一个专注于活性基因的核组织。然而，我们的见解越来越多地表明，两者之间存在明显的二分法，统一的假设是XIST RNA不是影响染色体结构的RNA的特殊例子，而是阐明了基因组/染色体生物学的更广泛方面。我们的研究结果支持XIST RNA还可以直接修饰影响异染色质与常染色质状态的“RNP支架”的组分，而不是简单地将XIST RNA拴在染色质上以修饰组蛋白。其他最近的证据表明，RNP-支架可能在某些疾病状态下被破坏。当我们在序列水平上研究RNA参与染色体结构时，我们将寻求将其与染色体如何在更大规模上组织并通过发育协调调节的整体愿景联系起来。这些雄心勃勃的目标将得到一个强大的合作团队的支持，该团队由翁志平博士和Daryl Bosco博士组成。