Chromatin of repetitive elements

重复元件的染色质

• 批准号: 10185471
• 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/10185471
• 关键词: Address; Binding Proteins; 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; Heterochromatin; Human; Invaded; Knowledge; Lead; Liquid substance; Location; Malignant Neoplasms; Mediating; Molecular Biology; Mutate; Mutation; Nucleosomes; Parasites; Pathway interactions; Phase; Play; Positioning Attribute; Proteins; RNA; RNA Interference; Regulation; Repetitive Sequence; Research; Ribosomal DNA; Ribosomal RNA; Ribosomes; Role; Site; Sorting - Cell Movement; 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; 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.

概括 迁移和重复元件的沉默保持基因组完整性，并在沉默中存在缺陷 途径导致癌症形成。尽管很重要，但知之甚少 最初将元素识别和针对沉默，以及它们如何调节重要的生物学 过程。为了解决这一知识差距，我们将结合遗传学和分子生物学 生物化学和冷冻EM。 基因组受到转座元素和其他基因组寄生虫的侵袭的不断威胁。 这些外国基因组元素将使用宿主进行自身的表达和增殖。沉默 现有的转座和重复性元素已经进行了充分的研究，但是，知之甚少 识别转座元素。尽管大多数重复的基因组由可转座和 其他外国元素，核糖体DNA（rDNA）的重复序列形成了重复基因组的独特类型， 有些重复被沉默，而另一些则高度表达。 rDNA位于核仁中，a 特殊的室被认为是被核磷酸盐和纤维蛋白分离的相位的特殊室，其中 核糖体组装发生。尽管rDNA基因座的重要性，但在很大程度上尚不清楚染色质 调节rDNA的结构。拟议研究的主要目标是确定新的 识别转座元素以及如何以及为什么染色质调节分类和分离 新生核糖体。 在强大的初步数据的指导下，我们提议追求两个具体的目标，以了解 重复元素。我们将确定新迁移元素入侵的特征是 由主机认可以及哪些主机可以发现这些元素（AIM 1）。此外，我们将结合冷冻EM与生物化学和遗传学，以确定 核糖体生物发生中的染色质（AIM 2）。 一起，我们提出的研究将通过显示染色质如何在染色质领域产生广泛的影响 调节核糖体生物发生以及宿主识别新转座子的插入方式。我们的 长期目标是了解染色质对基因组表达的调节，并发现为什么 染色质蛋白的突变导致癌细胞的形成。