Multi-Generational Epigenetic Inheritance and Germline Immortality

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，而DNA序列无相关变化。表观遗传过程驱动和/或调节各种各样的生物过程，如印记、X染色体失活和副突变。表观遗传信息可以跨代遗传。表观遗传的一个特别突出的例子是dsRNA介导的基因沉默（RNAi）。In C. RNA干扰的影响可以持续十多代;这个过程被称为RNA干扰遗传。以下关于RNAi遗传的问题尚未得到解答。驱动RNAi遗传的分子因子是什么？非编码RNA指导的表观遗传“记忆”是如何跨代维持的？基因在生殖过程中是否受到可遗传的表观遗传调控？如果是，为什么？我们的长期目标是回答这些问题。 为此，我们在C. elegans设计用于鉴定dsRNA介导的沉默信号遗传所需的细胞因子。该筛选确定了至少四个基因，包括不能遗传RNAi（finn）-1的基因。finn-1编码Argonaute（Ago），其在暴露于dsRNA的动物的后代的生殖细胞中与siRNA缔合并促进RNAi遗传。在正常生长条件下，FINN-1与内源性表达的小RNA结合，其指导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中丢失，并且伴随着这些动物由于生殖系的多代萎缩而变得不育。这些结果表明，与FINN-1一起作用的小RNA是RNAi遗传和种系永生所必需的。在这项提案中，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和小调控RNA如何指导RNAi遗传和种系永生。 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。非编码RNA与多种表观遗传现象有关。因此，我们相信，我们的研究成果将在全球范围内适用于我们对动物表观遗传的理解。此外，人类表观遗传途径的错误调节也会导致疾病。因此，我们提供的知识可能会影响表观遗传过程，以减轻人类疾病。

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.