MicroRNAs are versatile regulators of gene expression and as such, they are essential parts of the gene regulatory networks controlling development and physiology of animals and plants. In particular, a number of miRNAs have been implicated in cell-type differentiation. Adding miRNAs to existing networks in particular subsets of cells can increase the complexity of developmental programs, and thus contribute to the vast diversity of cell types found in complex multicellular organisms.
In order to achieve this function, miRNAs have very diverse and highly specific spatio-temporal patterns of expression. Understanding, when and where miRNAs are expressed and how their expression is regulated is essential to place them in the correct cellular context and grasp their contribution to normal development and disease.
miRNA expression can be regulated at the transcriptional and post-transcriptional levels. While transcriptional regulation is known to generate distinct patterns of miRNA production, the contribution of post-transcriptional regulation of miRNA biogenesis and function to their spatio-temporal specificity is virtually unexplored. A few RNA binding proteins have been shown to affect miRNA biogenesis mostly in cell culture yet with one exception, none have been studied in the context of a whole developing organism where their roles in providing specificity to miRNA function could be assessed. Furthermore, only a handful of miRNAs are known to be post-transcriptionally regulated in tissue or stage-specific manners, mostly in organisms not amenable to genetic analysis, thus making it difficult to identify the underlying mechanisms.
I propose to use the genetic model system C. elegans to bridge these two stunted approaches. We will identify post-transcriptional regulators of miRNA biogenesis and activity and dissect their contribution to generating specific spatio-temporal domains of miRNA function and in doing so, increasing cell-type diversity.
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Funding SchemeERC-SG - ERC Starting Grant