Multi-Generational Epigenetic Inheritance and Germline Immortality

点击翻译按钮获取中文摘要

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.