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We are interested in all aspects of gene regulation by regulatory RNA. Current research themes include: miRNA biology and pathology, miRNA mechanism, piRNA biology and the germline, endo-siRNAs in epigenetic inheritance and evironmental conditioning, small RNA evolution and the role of RNAi in host pathogen interaction.

miRNA biology and pathologyMicroRNAs (miRNAs), a large class of short non-coding RNAs found in many plants and animals, often act to inhibit gene expression post-transcriptionally. Approximately 3% of all known human genes encode miRNAs. Important functions for miRNAs in animal development and physiology are emerging. A number of miRNAs have been directly implicated in human disease. We have generated loss-of-function mutations in almost all of the 112 known miRNA genes in the nematode Caenorhabditis elegans. This collection provides the only comprehensive resource for the genetic analysis of individual miRNAs to date. Our main goal is to understand the genetic networks underlying miRNA-dependent control. One particular focus is on miRNAs and pathways relating to human cancer.Javier & Alejandra, Ethan

miRNA mechanismTo date the analysis of miRNA-dependent gene regulation has been focussed on a static model (fold reduction of protein or mRNA levels at steady-state), whereas miRNAs likely play important roles during temporal or spatial transition. Indeed, modes of action that have been proposed for miRNAs include fine-tuning, thresholding or dampening of gene expression noise. We are measuring the effects of miRNA-dependent regulation of gene expression in vivo with single-animal resolution in large populations of C. elegans. We previously demonstrated this using a miRNA sensor strain for a target of the let-7 miRNA.

piRNA biology and the germline
In 2008 we identified the piRNAs of C. elegans. We have demonstrated that Piwi proteins and piRNAs are important for gemline development and fertility. Now we are investigating how piRNAs are generated in the germline and how they act to silence their targets. We are also working to understand how the piRNA pathway regulated germline development and how this pathway is regulated.

RNAi in host pathogen interactionsTogether with our collaborators Marie-Anne Felix and Dave Wang we recently discovered the first virus to naturally infect C. elegans. We are using this virus to study virus host interactions in the laboratory and in natural isolates of C. elegans.

endo-siRNAs
Specifically inheritance and environment. It is commonly thought that the only information passed from parent to offspring is genetic. Epigenetic marks that regulate gene expression, such as DNA methylation and histone modifications, are erased during the development of gametes and early embryonic development. In most cases there seems to be no transfer of epigenetic information between generations. Imprinted genes, which are silenced or activated depending on their parent-of-origin, are a notable exception. In this case the epigenetic mark is established in the gametes of each new generation, dependent on the sex of the organism. Some other well characterised exceptions are paramutable alleles and metastable epialleles in plants and mammals. In these cases the epigenetic state can survive reprogramming both in the gametes and also in the early embryo, so that the epigenetic state in the parent is reflected to some extent in the offspring. This phenomenon is termed transgenerational epigenetic inheritance. We are investigating the biology and mechanism of this phenomenon in C. elegans.

small RNA evolution
Many miRNAs are highly conserved from worm to man, yet miRNA target space can evolve very rapidly. We are investigating the role of miRNAs in evolutionary change using the cichlid fishes of the African Rift Lakes as a model. We are working on this project with the laboratory of Tom Kocher. Learn more about these amazing fish here.

Why C.elegans?
C. elegans is the simplest laboratory organism that expresses miRNAs, endo-siRNAs an piRNAs. Both miRNAs and RNAi were discovered in C. elegans. This makes the “worm” the animal of choice to study these pathways. Learn more about this fantastic animal from these online resources: WormBook, WormAtlas and WormBase.