Non-Coding RNAs in Gene Regulation, Genome Defense, and Epigenetic Inheritance

基因调控、基因组防御和表观遗传中的非编码 RNA

• 批准号: 10551436
• 负责人: Scott G Kennedy
• 金额: $ 66.8万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551436
• 关键词: Address; Animals; Biological Process; Caenorhabditis elegans; Chromatin; DNA Transposable Elements; Development; Disease; Ensure; Epigenetic Process; Etiology; Eukaryota; Gene Expression; Gene Expression Regulation; Generations; Genetic Screening; Genome; Goals; Heritability; Heterochromatin; Insecta; Link; Mammals; Mediating; Membrane; Modification; Nuclear; Nucleic Acids; Organelles; Paramecium; Parasites; Pathway interactions; Persons; Plants; Proteins; RNA; RNA Interference Pathway; Regulation; Reproduction; Research; Small Interfering RNA; System; Totipotency; Untranslated RNA; Viral; Work; X Inactivation; Yeasts; human disease; imprint; insight; model organism; novel; programs; theories; transgenerational epigenetic inheritance; transmission process; vector

PROJECT SUMMARY / ABSTRACT Epigenetic systems regulate gene expression during reproduction and development and the misregulation of these pathways leads to disease. Non-coding RNAs are major regulators and orchestrators of epigenetic processes in all eukaryotes. For instance, non-coding RNA directs paramutation in plants, heterochromatin formation in yeast, genome rearrangement in paramecium, and X-chromosome inactivation and imprinting in mammals. Additionally, while most epigenetic information is erased each and every generation to ensure totipotency of the germline, in some cases, epigenetic information escapes reprogramming and passes across generations (termed transgenerational epigenetic inheritance or TEI). Current evidence suggests that non- coding RNAs are major informational vectors for TEI in plants, worms, insects, and, possibly, mammals. The long-term goal of my research program is to understand how non-coding RNA regulates and sculpts gene expression programs and how this regulation is, in some cases, passed across generations. We are using the metazoan model organism C. elegans to address these questions. To date our work has identified a nuclear branch of the RNA interference (RNAi) pathway, which uses small interfering (si)RNAs to regulate chromatin states and inhibit RNAP II elongation. We have also identified pathways and systems required for transmission of epigenetic information across generations. Our recent studies have identified a new type of membraneless organelle that houses proteins needed for TEI, identified two pathways that act as natural breaks on TEI, and defined an underlying mechanism for TEI mediated by a new form of RNA modification that we helped discover. And because we find that transposable elements are a major target of the C. elegans epigenetic inheritance pathways, we theorize that one function of non-coding RNAs and TEI systems is to help inoculate progeny against the expression of nucleic acid parasites. Deregulation of epigenetic pathways contributes to the etiology of a number of human diseases. The extensive links existing between non-coding RNA and epigenetic processes in all eukaryotes suggests that the work we are doing in C. elegans will lead to insights that will be applicable to all animals and, therefore may help us understand and treat disease in people.

项目总结/摘要 表观遗传系统调节生殖和发育过程中的基因表达， 这些途径导致疾病。非编码RNA是表观遗传调控的主要调控因子和指挥者， 在所有的真核生物中。例如，非编码RNA指导植物的副突变，异染色质 酵母中的X染色体形成，草履虫中的基因组重排， 哺乳动物此外，虽然大多数表观遗传信息在每一代都被删除，以确保 在某些情况下，表观遗传信息逃脱了重新编程， 跨代表观遗传（transgenerational epigenetic inheritance，TEI）。目前的证据表明，非 编码RNA是植物、蠕虫、昆虫以及可能的哺乳动物中TEI的主要信息载体。的 我的研究计划的长期目标是了解非编码RNA如何调控和塑造基因 表达程序以及这种调节在某些情况下是如何代代相传的。 我们使用的是后生动物模式生物C。elegans来解决这些问题。来确定我们工作的日期 已经确定了RNA干扰（RNAi）途径的核分支，该途径使用小干扰（si）RNA 调节染色质状态并抑制RNAP II延伸。我们还发现了一些途径和系统 这是表观遗传信息跨代传递所必需的。我们最近的研究发现了一种新的 一种无膜细胞器，容纳TEI所需的蛋白质，确定了两种途径， 断裂，并定义了一种新形式的RNA修饰介导的TEI的潜在机制， 我们帮助发现的。由于我们发现转座因子是C. elegans 表观遗传途径，我们的理论，非编码RNA和TEI系统的功能之一是帮助 抗寄生虫核酸的表达。 表观遗传途径的失调导致许多人类疾病的病因。的 所有真核生物中非编码RNA和表观遗传过程之间存在的广泛联系表明， 我们在C中做的工作elegans将导致的见解，将适用于所有动物，因此可能有助于 我们了解并治疗人类的疾病。