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 异染色质对表观遗传基因的抑制是多细胞生物发育所必需的 和基因组稳定性。异染色质的错误调控是通过基因干扰引起多种疾病的原因之一 表达模式我们研究计划的长期目标是在分子水平上确定 非编码RNA（ncRNA）参与异染色质的形成和功能。许多ncRNA在 细胞核通过与染色质调节机制的关联来调节基因表达。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RNA之间，它们是形成异染色质的触发器。然而，许多系统 其中涉及RNA具有未探索的分子作用机制。我们将讨论三个高级别 该领域的主要突出问题：1）哪些异染色质系统是通过RNA-RNA控制的 互动？2)异染色质是如何围绕新生RNA构建的？3)RNA结合蛋白是如何被... 目的是从mRNA加工功能，以促进RNA介导的异染色质形成？我们 研究计划的重点是多异染色质系统，包括不同种类的非编码 RNA。我们研究长链非编码RNA（lncRNA），如HOTAIR和近着丝粒转录本，它们可以 抑制异染色质组蛋白修饰剂以控制其活性。此外，我们还开发了第一个 这是一个生物化学系统来研究人类核皮尔纳途径，它使用小皮尔纳的碱基配对， 靶向重复的新生转录物，然后通过异染色质抑制。最后，我们讨论如何 RBP如N6-甲基腺苷读取器YTHDC 1可以与ncRNA一起工作以促进基因抑制。 我们使用生物化学、结构、细胞生物学和基因组学方法来研究这些RNA调节的模型。 异染色质对这些途径的机制性洞察将提供对它们如何工作的更全面的理解 在正常情况下和疾病中，这将证明在靶向药物干预方面是有用的。 与公共卫生的相关性 非编码RNA是由人类基因组中最初被认为是“垃圾”DNA的区域产生的。许多 ncRNA参与基因调控的表观遗传机制，而错误调控可导致疾病， 癌症因此，ncRNA是明确的候选者，以提供理解分子生物学的缺失环节。 许多人类疾病的机制，其中有一个“隐藏的遗传性”因素，尚未被发现。 鉴定