Chromatin of repetitive elements

重复元件的染色质

• 批准号: 10595528
• 负责人: Mario Halic
• 金额: $ 35.9万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595528
• 关键词: Address; Biochemistry; Biogenesis; Biological Process; Biology; Cell Nucleolus; Cells; Characteristics; Chromatin; Chromatin Structure; Cryoelectron Microscopy; DNA Sequence; DNA Transposable Elements; DNA-Binding Proteins; Data; Defect; Elements; Environment; Eukaryotic Cell; Event; Evolution; Fission Yeast; Genes; Genetic; Genetic Transcription; Genome; Genome Stability; Genomics; Goals; HMGN Proteins; Heterochromatin; Human; Invaded; Knowledge; Lead; Liquid substance; Malignant Neoplasms; Mediating; Molecular Biology; Mutate; Mutation; Parasites; Pathway interactions; Phase; Positioning Attribute; Proliferating; Proteins; RNA Interference; Regulation; Repetitive Sequence; Research; Ribosomal DNA; Ribosomal RNA; Ribosomes; Role; Site; Sorting; Sterility; Structure; System; Tandem Repeat Sequences; Time; Transcriptional Silencer Elements; Work; Yeasts; base; cancer cell; cancer genome; cell growth; chromatin protein; fibrillarin; fighting; genetic element; genetic information; genome integrity; genomic locus; in vivo; next generation; nucleophosmin; particle; physical separation; prevent

Summary Silencing of transposable and repetitive elements maintains genome integrity, and defects in silencing pathways lead to cancer formation. Despite the importance, little is known how transposable and repetitive elements are initially recognized and targeted for silencing and how they regulate important biological processes. To address this knowledge gap, we will combine genetics and molecular biology with biochemistry and cryo-EM. Genomes are under constant threat of invasion by transposable elements and other genomic parasites. These foreign genomic elements will use the host for their own expression and proliferation. Silencing of existing transposable and repetitive elements has been well studied, however, little is known how new transposable elements are recognized. Although most of the repetitive genome consist of transposable and other foreign elements, repeats of ribosomal DNA (rDNA) form a unique type of a repetitive genome, in which some repeats are silenced while others are highly expressed. rDNA is localized in the nucleolus, a special compartment that is considered to be phase separated by nucleophosmin and fibrillarin, and where ribosome assembly occurs. Despite the importance of the rDNA locus, it is largely unknown how chromatin structure at rDNA is regulated. The major goals of the proposed research is to determine how new transposable elements are recognized and how and why chromatin regulates sorting and separation of nascent ribosomes. Guided by the strong preliminary data, we propose to pursue two Specific Aims to understand biology of repetitive elements. We will determine what features in invasion of new transposable elements are recognized by the host and which host machineries can discover those elements (Aim 1). Moreover, we will combine cryo-EM with biochemistry and genetics to determine the role of chromatin in ribosome biogenesis (Aim 2). Together, our proposed studies will have broad impact in chromatin field by showing how chromatin regulates ribosome biogenesis and how insertions of new transposons are recognized by the host. Our long-term goals are to understand the regulation of genome expression by chromatin and discover why mutations in chromatin proteins lead to the formation of cancer cells.

总结 转座和重复元件的沉默维持基因组的完整性， 导致癌症形成的途径。尽管重要性，很少有人知道如何转座和重复 元件最初被识别并靶向沉默，以及它们如何调节重要的生物学特性。 流程.为了解决这一知识缺口，我们将联合收割机结合遗传学和分子生物学， 生物化学和冷冻电镜。 基因组不断受到转座因子和其他基因组寄生虫入侵的威胁。 这些外源基因组元件将利用宿主进行其自身的表达和增殖。沉默 现有的转座元件和重复元件已得到充分研究，然而，人们对新元件的作用知之甚少 转座因子被识别。虽然大多数重复基因组由转座和 其他外源元件，核糖体DNA（rDNA）的重复序列形成一种独特类型的重复基因组， 其中一些重复被沉默而另一些被高度表达。rDNA定位于核仁中， 被认为是由核磷蛋白和原纤蛋白相分离的特殊隔室，并且其中 核糖体组装发生。尽管rDNA基因座很重要，但很大程度上不知道染色质是如何 rDNA的结构受到调控。这项研究的主要目标是确定新的 转座因子的识别和如何以及为什么染色质调节分选和分离， 新生核糖体 在强有力的初步数据的指导下，我们建议追求两个具体目标，以了解生物学 重复的元素。我们将确定新的转座因子入侵的特征是什么 以及哪些主机机器可以发现这些元素（Aim 1）。此外，我们将联合收割机冷冻电镜与生物化学和遗传学相结合，以确定的作用， 染色质在核糖体生物发生中的作用（Aim 2）。 总之，我们提出的研究将在染色质领域产生广泛的影响，通过展示染色质如何 调节核糖体的生物发生以及宿主如何识别新转座子的插入。我们 长期目标是了解染色质对基因组表达的调控，并发现其原因 染色质蛋白的突变导致癌细胞的形成。