Research in our laboratory is focused on elucidating the function and evolutionary conservation of mechanisms that govern genome organization and gene expression in eukaryotes. We pay special attention to biogenesis, processing, and activity of non-protein-coding RNAs (ncRNAs) and their potential impact on chromatin.
Our general strategy is to take advantage of the power of fission yeast (S. pombe) genetics to address fundamental mechanistic questions. Importantly, S. pombe has a functional RNA interference pathway and its chromatin shares many post-translational modifications and protein components with mammalian systems. This makes fission yeast particularly well suited for studying the link between ncRNAs and epigenetic genome regulation. Building on the findings from yeast, we investigate similar mechanisms and potential conservation in more complex model systems such as mouse embryonic stem cells, transgenic mouse models, and Drosophila melanogaster.
Our main interests lie in:
- RNA interference
- Epigenetic genome regulation
- RNA modification
- Control of endogenous retroviruses
- Trans-generational epigenetic inheritance
- Heterochromatin silencing
- (Epi)Genome engineering
To investigate the aforementioned topics, we combine several complementary approaches, including forward and reverse genetics, next generation sequencing, bioinformatics, light and electron microscopy, protein crystallography and mass spectrometry. We have direct access to cutting edge technology platforms at the FMI, the Novartis Institutes of Biomedical Research, and the NCCR RNA&Disease.
RESEARCH ACHIEVEMENTS AND ONGOING PROJECTS
Our past research has established guiding paradigms for studying ncRNA-mediated genome regulation. Asking how commonly ncRNAs are involved in regulatory circuits and by which mechanisms they might function did not only reinforce the notion that ncRNAs serve as guide molecules, but also revealed that they can function to either recruit or evict proteins to or from chromatin. This offers possible novel functions for the many non-coding RNAs that are just being discovered.
Focusing mainly on small ncRNA function in S. pombe initially, we contributed to dissecting the mechanistic details of RNA interference-mediated heterochromatin assembly and discovered that transient expression of a short interfering RNA (siRNA) can under certain conditions be sufficient to trigger sequence-specific gene silencing that is maintained across generations. The mechanism, evolutionary conservation, and potential biomedical application of ncRNA-directed epigenetic gene regulation has become a major focus of the lab. We have also provided novel insights into the subcellular organization of the RNAi pathway and regulation thereof in response to environmental cues, and discovered a novel genome-regulatory pathway that we refer to as co-transcriptional gene silencing (CTGS). Similarly, our efforts on elucidating the function of HP1 proteins in establishing and silencing of heterochromatin uncovered exciting and unexpected findings.
Here few selected past and current projects. Just click on the individual topics to read more.
- RNA-induced epigenetic gene silencing
- RNA binding to heterochromatin protein 1 (HP1)
- Co-transcriptional gene silencing
- Cellular responses to environmental cues