Multi-Generational Epigenetic Inheritance and Germline Immortality

多代表观遗传和种系永生

• 批准号: 8607973
• 负责人: Scott G Kennedy
• 金额: $ 16.45万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-24 至 2014-08-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8607973
• 关键词: Alleles; Animals; Atrophic; Biological Models; Biological Process; Biology; Caenorhabditis elegans; Cell Lineage; Cell Nucleus; Chromatin; DNA Sequence; Data; Disease; Double-Stranded RNA; Employee Strikes; Ensure; Epigenetic Process; Etiology; Event; Failure; Functional RNA; Future Generations; Gene Expression; Gene Silencing; Generations; Genes; Genetic; Genetic Screening; Genomics; Germ Cells; Goals; Growth; Histones; Human; Inherited; Knowledge; Life Cycle Stages; Lysine; Mammals; Mediating; Memory; Methylation; Modeling; Molecular; Nuclear RNA; Nucleic Acids; Organism; Parents; Pathway interactions; Phenotype; Play; Process; RNA Interference; RNA Interference Pathway; Regulation; Reproduction; Research; Research Design; Research Proposals; Role; Signal Transduction; Small RNA; Sterility; System; Testing; X Inactivation; chromatin modification; design; human disease; imprint; insight; mutant; novel; offspring; public health relevance; research study

DESCRIPTION (provided by applicant): Epigenetics is the study of changes in gene expression or phenotype that occur without associated changes in DNA sequence. Epigenetic processes drive and/or regulate a wide-variety of biological processes such as imprinting, X-chromosome inactivation, and paramutation. Epigenetic information can be inherited across generational boundaries. A particularly striking example of epigenetic inheritance is dsRNA mediated gene silencing (RNAi). In C. elegans gene the effects of RNAi can persist for more than ten generations; a process termed RNAi inheritance. The following questions concerning RNAi inheritance have not been answered. What is the molecular agent that drives RNAi inheritance? How are non-coding RNA- directed epigenetic "memories" maintained across generations? Are genes normally subjected to heritable epigenetic regulation during reproduction? If so, why? Our long-term goal is to answer these questions. Towards this goal, we have conducted a genetic screen in C. elegans designed to identify cellular factors specifically required for inheritance of dsRNA-mediated silencing signals. This screen identified at least four genes including the gene failure to inherit RNAi (finn)-1. finn-1 encodes an Argonaute (Ago) that associates with siRNAs, and promotes RNAi inheritance, in germ cells of the progeny of animals exposed to dsRNA. Under normal growth conditions, FINN-1 associates with endogenously expressed small RNAs, which direct chromatin modifications in germ cells. In animals lacking FINN-1, these chromatin marks are lost over generations, and, concomitantly, these animals become sterile due to multi-generational atrophy of the germline. These results establish that small RNAs, acting in conjunction with FINN-1, are required for RNAi inheritance and germline immortality. In this proposal, we seek to identify additional components of the RNAi inheritance machinery and explore in more detail how FINN-1 and small regulatory RNAs direct RNAi inheritance and germline immortality. Our experiments are revealing how and why non-coding RNAs drive epigenetic inheritance. Non-coding RNAs are associated with a diverse array of epigenetic phenomena. Therefore, we believe that insights from our research will prove to be globally applicable to our understanding of epigenetic inheritance in animals. In addition, mis-regulation of epigenetic pathways in humans contributes to disease. Thus, the knowledge we provide might make it possible to influence epigenetic processes with the goal of mitigating human disease.

描述（由申请人提供）：表观遗传学是研究基因表达或表型的变化，这些变化在没有DNA序列的没有相关变化的情况下发生。表观遗传过程驱动和/或调节广泛的生物学过程，例如印刷，X染色体灭活和参数。表观遗传信息可以在世代界面上遗传。表观遗传遗传的一个特别引人注目的例子是DSRNA介导的基因沉默（RNAi）。在秀丽隐杆线虫基因中，RNAi的作用可以持续十多个世代。一个称为RNAi继承的过程。有关RNAi继承的以下问题尚未得到回答。驱动RNAi遗传的分子剂是什么？如何维持非编码RNA的表观遗传“记忆”？基因通常在繁殖过程中受到可遗传的表观遗传调节吗？如果是这样，为什么？我们的长期目标是回答这些问题。 为了实现这一目标，我们在秀丽隐杆线虫中进行了一个遗传筛选，旨在识别DSRNA介导的沉默信号所需的细胞因子。该屏幕鉴定了至少四个基因，包括遗传RNAi（FINN）-1的基因失败。 Finn-1编码了与siRNA相关的Argona（AGO），并促进RNAi遗传，该遗传在暴露于DSRNA的动物后代的生殖细胞中。在正常生长条件下，FINN-1与内源表达的小RNA相关联，该RNA导致生殖细胞中的染色质修饰。在缺乏FINN-1的动物中，这些染色质标记在几代人中丧失了，同时，由于种系的多代萎缩，这些动物变得无菌。这些结果表明，RNAi遗传和种系永生所必需的小RNA与Finn-1结合起来。在此提案中，我们试图确定RNAi遗传机制的其他组成部分，并更详细地探索Finn-1和小监管RNA如何直接RNAi遗传和种系不朽。 我们的实验揭示了非编码RNA如何以及为什么驱动表观遗传遗传的原因。非编码RNA与各种表观遗传现象有关。因此，我们认为，我们研究的见解将被证明适用于我们对动物表观遗传遗传的理解。另外，人类表观遗传途径的错误调节会导致疾病。因此，我们提供的知识可能使影响表观遗传过程以减轻人类疾病的目的而成为可能。