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RNA silencing

Our primary research interest is the role of RNA molecules in gene regulation, in particular in vertebrate development. In the last few years it has become absolutely clear that small RNA molecules (like siRNAs, miRNAs and piRNAs) are very potent and important regulators of gene expression and have been found to have effects on virtually any step of gene expression (transcription, RNA stability and translation efficiency). Yet both the precise modes of action of these molecules and the impact thereof on development are still poorly understood. It is definitively clear that these small RNA molecules are crucial both in development as in mature organisms, given the absolute requirement of small RNAs in development, and the characteristic expression profiles of small RNAs in tumors. It is therefore of the utmost importance to completely understand the full scope of small RNA silencing effects.

That is why we study a protein family that is intimately connected with every small RNA mediated silencing pathway sofar: the argonaute family. This family of proteins consists of two characteristic protein domains: the PAZ domain and the PIWI domain. Both domains interact with the small RNA molecules, and both appear to be required for functionality. In addition, the PIWI domain of certain family members appears to harbor an RNaseH activity, which is most clearly demonstrated during RNA interference, when the targeted mRNA is cleaved by this domain. Other family members cannot induce such cleavages, and appear to silence genes through other mechanisms, such as translational repression, or the induction of chromatin changes.

To focus our research aims, we study one of the two subfamilies of the Argonautes: the PIWI proteins. We, and others, have shown that Piwi proteins are required in germcells of animals to control transposable element activity and to ensure a proper germ cell maintenance and functionality. Our studies now focus on the biogenesis of the small RNA cofactors (piRNAs) of the zebrafish PIWI proteins Ziwi and Zili, and on the identification and function of proteins acting in the PIWI pathway.

Nuclear effects
We are also interested in nuclear effects of small RNA molecules. These molecules have been shown to induce chromatin changes in various organisms, and we are interested if, how and when such effects on transcriptional activity occur during development and functioning of germline tissue. In particular, we are studying the link between RNAi and chromatin in C. elegans, and are setting up studies to investigate how RNAi pathways interact with genome-wide histone-modifcation changes during germ cell development.

A third topic of research in the group is related to the identification of biologically relevant targets for miRNAs in zebrafish development. Here we mainly focus on bone development.

Model organisms
To accomplish all these goals we are using two genetic model systems, the worm and the zebrafish. In both systems we are developing reagents and are generating mutants, and are integrating information from both systems to provide a complete and accurate picture of these silencing processes.

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H3K4 methylation (green) in somatic cells and primordial germ cells, indicated by red PGL-1 staining.

C. elegans embryo stained for H3K4 methylation (green), germ cell marker PGL-1 (red) and DAPI (blue).







zili mutant

Lack of germ cell (red) proliferation in zili mutant zebrafish embryos. Left panel: wild-type; right panel: zili mutant.