Transgenerational Epigenetic Inheritance and Innate Immunity

Dr Alyson Ashe
Herchel-Smith Postdoctoral Fellow, Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge
8 November 2012 - 12:00pm
Rountree Room 356, Biological Sciences Building D26

It is now well established that small RNAs can affect gene expression by translational inhibition, mRNA degradation, and repression of transcription. Since the discovery of RNAi in C. elegans in 1998, our knowledge of the complexity of small RNA pathways in this organism has grown rapidly. Much of this knowledge has come about through advances in sequencing technology that allow us to see in great detail the numerous small RNAs present in cells. Despite this abundance of data, there are still many aspects of small RNA biology that remain unclear. From the first reports of gene silencing induced by exogenous dsRNA, it has been observed that the silencing can be heritable. For RNAi of most genes, silencing of the target gene is limited to the F1 generation, with subsequent generations reverting back to normal levels of gene expression. However, there are a small number of reported cases where silencing of a specific gene can be transmitted across multiple generations. We have developed a transgenic system to study this phenomenon. We show that silencing of a single-copy GFP transgene can be inherited for multiple generations, and that this silencing correlates with the presence of small RNAs targeted to the transgene. Through chemical mutagenesis and a candidate gene approach we identify three mutants that fail to inherit transgene silencing in this assay. These mutants suggest that both small RNAs and chromatin modifications are necessary for effective silencing.

Another important aspect of small RNA biology is their vital role in viral defence in both plants and insects. We have identified the first natural virus in C. elegans and show that animals produce small RNAs (viRNAs) which target the viral RNA in response to infection. The production of these viRNAs appears critical to resistance to viral infection. We show that the gene drh-1 is required for recognition and correct dicer processing of replicating double stranded viral RNA. DRH-1 is a homolog of RIG-I, the protein responsible in mammals for recognising viral dsRNA and signalling to the downstream innate immunity pathway. No small RNA response to viral infection has been found in mammals so far, but these results suggest that there may be many common innate immunity genes and pathways between mammals and C. elegans.