Mechanisms of heterochromatin targeting and epigenetic genome regulation

异染色质靶向和表观遗传基因组调控机制

• 批准号: 10337814
• 负责人: Aaron M. Johnson
• 金额: $ 42.22万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-20 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10337814
• 关键词: Address; Base Pairing; Biochemical; Biological; Cell Nucleus; Cells; Chromatin; Development; Disease; Epigenetic Process; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genome; Genome Stability; Genomic approach; Goals; Heritability; Heterochromatin; Histones; Human; Human Genome; Intervention; Junk DNA; Lead; Link; Malignant Neoplasms; Mediating; Messenger RNA; Modeling; Molecular; Molecular Mechanisms of Action; Nuclear; Pathway interactions; Pharmacology; Public Health; RNA; RNA-Binding Proteins; Reader; Regulation; Research; Study models; System; Transcript; Untranslated RNA; Work; gene repression; human disease; insight; piRNA; programs

PROJECT SUMMARY Epigenetic gene repression by heterochromatin is necessary for multi-cellular organismal development and genome stability. Mis-regulation of heterochromatin is a cause of multiple diseases through perturbed gene expression patterns. The long-term goals of our research program are to determine at a molecular level how noncoding RNAs (ncRNAs) participate in heterochromatin formation and function. Many ncRNAs act in the nucleus to regulate gene expression through association with chromatin regulatory machinery. We and others have shown that certain RNA-mediated heterochromatin pathways require intermolecular RNA-RNA interactions between ncRNAs and nascent RNA that serve as the trigger to form heterochromatin. However, many systems where RNA is implicated have unexplored molecular mechanisms of action. We will address three high-level major outstanding questions in the field: 1) Which heterochromatin systems are controlled through RNA-RNA interactions? 2) How is heterochromatin built around nascent RNA? 3) How are RNA binding proteins re- purposed from mRNA processing functions to contribute to RNA-mediated heterochromatin formation? Our research program focuses on multiple heterochromatin systems that incorporate different species of noncoding RNAs. We study long noncoding RNAs (lncRNAs), such as HOTAIR and pericentromeric transcripts, which can inhibit heterochromatic histone modifiers to control their activity. In addition, we have developed the first biochemical system to study the human nuclear piRNA pathway, which uses base-pairing of the small piRNA to target nascent transcripts of repeats that then are suppressed via heterochromatin. Finally, we address how RBPs such as the N6-methyladenosine reader YTHDC1 can work with ncRNAs to promote gene repression. We use biochemical, structural, cell biological, and genomic approaches to study these models of RNA-regulated heterochromatin. Mechanistic insight into these pathways will provide a fuller understanding of how they work normally and in disease, which will prove useful in targeting for pharmacological intervention. Relevance to public health Noncoding RNAs are produced from regions of the human genome originally thought to be "junk" DNA. Many ncRNAs participate in epigenetic mechanisms of gene regulation and mis-regulation can lead to diseases such as cancer. ncRNAs are therefore clear candidates to provide a missing link to understanding the molecular mechanisms of many human diseases for which there is a "hidden heritability" factor that has not yet been identified.

项目摘要 异染色质表观遗传基因抑制对于多细胞生物发育是必不可少的 和基因组稳定性。异染色质的错误调节是通过扰动基因引起多种疾病的原因 表达模式。我们研究计划的长期目标是在分子层面确定如何 非编码RNA（NCRNA）参与异染色质形成和功能。许多NCRNA在 细胞核通过与染色质调节机制结合来调节基因表达。我们和其他人 已经表明某些RNA介导的异染色质途径需要分子间RNA-RNA相互作用 在NCRNA和新生的RNA之间，它们是形成异染色质的触发因素。但是，许多系统 与RNA有关的地方具有未开发的作用分子机制。我们将解决三个高级 该领域的主要杰出问题：1）通过RNA-RNA控制哪种异染色质系统 互动？ 2）如何在新生的RNA周围建立异染色质？ 3）RNA结合蛋白如何重复 从mRNA加工功能中目的是有助于RNA介导的异染色质形成？我们的 研究计划的重点是多种异染色质系统，这些系统结合了不同种类的非编码 RNA。我们研究长的非编码RNA（LNCRNA），例如Hotair和cortentromeric转录本，可以 抑制异型组蛋白修饰剂以控制其活性。此外，我们开发了第一个 研究人类核piRNA途径的生化系统，该途径使用小培养学的碱基对 重复的目标新生转录本，然后通过异染色质抑制。最后，我们解决了如何 诸如N6-甲基读剂读取器YTHDC1之类的RBP可以与NCRNA一起使用以促进基因抑制。 我们使用生化，结构，细胞生物学和基因组方法来研究这些RNA调节的模型 异染色质。对这些途径的机械洞察力将为他们的工作方式提供更深入的了解 通常，在疾病中，这将被证明可用于靶向药理干预措施。 与公共卫生有关 非编码RNA是由最初被认为是“垃圾” DNA的人类基因组地区产生的。许多 NCRNA参与基因调节和错误调节的表观遗传机制可能导致这种疾病 作为癌症。因此，NCRNA是明确的候选者，可以提供理解分子的缺失链接 许多人类疾病的机制尚未存在“隐藏的遗传力”因素 确定。