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mirspecificity Report Summary

Project ID: 337161
Funded under: FP7-IDEAS-ERC
Country: Austria

Mid-Term Report Summary - MIRSPECIFICITY (Spatio-temporal specificity of miRNA function)

Multicellular organisms are composed of many different cell types, each of which is defined by a precise combination of gene expression patterns. The set of genes each cell expresses is defined first at the transcriptional level, but this can be modfied by post-transcriptional regulation. An interesting class of such post-transcriptional regulators encompasses short RNA molecules, called microRNAs (miRNAs) that can direct a so-called silencing complex to specific mRNA transcripts and prevent their expression. While miRNAs have been known for over a decade, we only know what a relatively small fraction of individual miRNAs actually regulate and therefore what they contribute to generating and maintaining different cell types.

Using an animal model system like the nematode Caenorhabditis elegans, where the number of cells is defined (959 cells in an adult worm) and the number of miRNAs is relatively limited (~150), we can have a bird's eye view that encompasses every cell, every miRNA, and at the same time we can zoom in with extreme precision to understand what happens in a particular cell with a specific miRNA. This has allowed us to realize that within this animal, only a fraction of miRNAs is broadly and abundantly expressed, while the majority are expressed with high cellular specificity. This means that to understand what a large fraction of miRNAs contribute to complex organisms we have to know precisely when and where miRNAs are expressed and how their production is controlled.

Our work so far has revealed the precise cellular expression pattern for almost one third of all C. elegans miRNAs. Thanks to this knowledge, we have uncovered a function of a new miRNA that it is expressed exclusively in 6 neurons of C. elegans that sense carbon dioxide and we are investigating a number of other miRNAs, which are conserved from worms to humans, in order to dissect their molecular functions.

The production of miRNAs themselves, in such a cell-type specific manner, can also be regulated at the level of transcription of a precursor RNA or the processing of that precursor into a mature miRNA is produced. During this period we have established reliable methods to monitor transcription of the precursor RNAs as well as production of the mature miRNA with high cellular specificity. These methods combined with the possibility to perform pretty much any desirable genetic manipulation in this microscopic worm, allow us to probe how production of miRNAs is regulated and what impact this has eventually on the biology of a complex multicellular organism.

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