Final 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 modified 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 contributes to complex organisms we have to know precisely when and where miRNAs are expressed and how their production is controlled.
Over the course of this project, we developed new methods to explore when and where miRNAs are expressed and what are the mechanisms that control this specificity. We have discovered the function of two specific miRNAs, which has led to a new concept in how these small RNAs contribute to the production of a multicellular animal. One of these miRNAs is deeply conserved across all animals studied, and may have an impact for understanding a special type of myopathy in humans. Finally, we uncovered a novel mechanism for transcriptional regulation of miRNA production, which impacts our understanding of how specialized cells develop in vivo and in vitro.
Overall, our work in this system, combined with state-of-the-art methodology has enabled us to discover new concepts in miRNA biology with important implications for understanding animal development and disease, and for the production of specialized cells in vitro.
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 contributes to complex organisms we have to know precisely when and where miRNAs are expressed and how their production is controlled.
Over the course of this project, we developed new methods to explore when and where miRNAs are expressed and what are the mechanisms that control this specificity. We have discovered the function of two specific miRNAs, which has led to a new concept in how these small RNAs contribute to the production of a multicellular animal. One of these miRNAs is deeply conserved across all animals studied, and may have an impact for understanding a special type of myopathy in humans. Finally, we uncovered a novel mechanism for transcriptional regulation of miRNA production, which impacts our understanding of how specialized cells develop in vivo and in vitro.
Overall, our work in this system, combined with state-of-the-art methodology has enabled us to discover new concepts in miRNA biology with important implications for understanding animal development and disease, and for the production of specialized cells in vitro.