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.

Public Health Relevance

Epigenetic processes; instigated by non-coding RNAs; regulate many facets of biology and underlie the etiology of human disease. We are using genetic approaches to investigate how non-coding RNA directs epigenetic inheritance in the model system C. elegans. We believe that insights from our research will prove to be globally applicable to our understanding of epigenetic inheritance in all animals; and might make it possible to influence epigenetic inheritance in humans with the goal of mitigating disease.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular Genetics B Study Section (MGB)
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Carter, Anthony D
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Harvard Medical School
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United States
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Spracklin, George; Fields, Brandon; Wan, Gang et al. (2017) The RNAi Inheritance Machinery of Caenorhabditis elegans. Genetics 206:1403-1416
Juang, Bi-Tzen; Gu, Chen; Starnes, Linda et al. (2013) Endogenous nuclear RNAi mediates behavioral adaptation to odor. Cell 154:1010-1022
Buckley, Bethany A; Burkhart, Kirk B; Gu, Sam Guoping et al. (2012) A nuclear Argonaute promotes multigenerational epigenetic inheritance and germline immortality. Nature 489:447-51