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.

项目总结 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 和基因组的稳定性。异染色质的错误调节是通过干扰基因引起多种疾病的原因 表情模式。我们研究计划的长期目标是在分子水平上确定 非编码RNA(NcRNAs)参与异染色质的形成和功能。许多ncRNA作用于 细胞核通过与染色质调节机制相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的rna-rna相互作用。 在核糖核酸和新生核糖核酸之间，它们是形成异染色质的触发物。然而，许多系统 与RNA有牵连的地方有未知的分子作用机制。我们将讨论三个高级别 该领域的主要悬而未决的问题：1)通过rna-rna控制哪些异染色质系统 相互作用？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 目的是为了促进RNA介导的异染色质的形成？我们的 研究计划侧重于多种异染色质系统，这些系统融合了不同种类的非编码基因 RNA。我们研究长非编码RNA(LncRNAs)，如HOTAIR和着丝粒周围转录本，它们可以 抑制异染色组蛋白修饰物以控制其活性。此外，我们还开发了第一个 生物化学系统来研究人类核的piRNA途径，它使用小的piRNA的碱基配对来 靶向重复序列的新转录，然后通过异染色质抑制这些重复序列。最后，我们将讨论如何 限制性商业惯例，如N6-甲基腺苷阅读器YTHDC1，可以与ncRNAs一起促进基因抑制。 我们使用生化、结构、细胞生物学和基因组学方法来研究这些rna调控的模型。 异染色质。对这些途径的机械性洞察将提供对它们如何工作的更全面的理解 在正常情况下和在疾病中，这将被证明是药物干预的靶向有用的。 与公共卫生的相关性 非编码RNA是从人类基因组中最初被认为是“垃圾”DNA的区域产生的。许多 NcRNAs参与了基因调控的表观遗传机制，错误的调控可导致此类疾病 就像癌症一样。因此，ncRNAs显然可以为理解分子提供缺失的一环。 许多人类疾病的机制，对于这些疾病来说，存在着尚未被发现的“隐性遗传”因素 确认身份。