Sylvia Fischer

Genome maintenance and genome defense ensure that intact and unchanged genetic material is delivered to offspring, and that genes are properly expressed without mutations. One threat to the genome comes from transposable elements (TEs) and retroviruses, DNA elements that can potentially wreak havoc in the genome by inserting into genes, and by mediating homologous recombination. Half of the human genome is derived from transposon sequences, underscoring the need to control these elements. In addition to mutagenic properties, mis-expression of repeat elements and retroviruses can disrupt cellular homeostasis and elicit stress responses and antiviral responses. Such mis-expression has been linked to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), and also to geographic atrophy (GA), an advanced form of age-related macular degeneration.

One method of defense against transposable elements employs RNA interference (RNAi), a deeply conserved genome defense mechanism that acts in organisms ranging from protist to human to recognize and suppress transposons. In non-mammalian species, RNAi also acts as an important anti-viral defense mechanism, whereas in human, viral RNA triggers the anti-viral type I interferon response.

Not all host-transposon interactions are deleterious to the host. Transposons are a major contributor to genomic plasticity; in particular, transposon activation under stress conditions can facilitate adaptation of the host in new environmental conditions by altering gene expression or gene function through transposon insertion. An extreme example of a beneficial host-transposon interaction is the repurposing of (retro)transposon proteins, e.g. the RAG1 protein that mediates V(D)J recombination and is derived from a transposase protein, and the Arc protein that mediates intercellular RNA transfer and is derived from a retrotransposon Gag protein.

Our research program focuses on the genetic and biochemical analysis of the interactions between a host and its transposable elements and viruses using the simple host organism Caenorhabditis elegans. We are interested in understanding how transposons are (mis)regulated under stress conditions, how transposable elements and viruses are silenced, and which stress responses are triggered by mis-expression of transposons, and how these responses are triggered.