Gene regulation is the fundamental process that controls genome function and it pervades most biology, from organismal development to cellular differentiation and physiological responses to external stimuli and pathogens. To this end, gene expression is controlled at multiple levels, including RNA transcription, processing, translation and stability and deviations in most of these aspects invoke detrimental consequences to organisms and represent a major cause for human disease.
We aim to study the mechanisms of RNA silencing, the least understood aspect of gene regulation. We bridge temporal resolution gaps to unravel the fundamental biological principles of RNA decay at the molecular and genomic scale. Our goal is to understand how the quality and quantity of the transcriptome is controlled at the molecular level in flies and mammals. Our studies will [1] provide insights into the emerging role of RNA modifications in the regulation of RNA fate and function, [2] determine possible causes for aberrant gene expression profiles that have been associated with human diseases, such as the Perlman Syndrome; and [3] establish technologies that unravel the molecular signatures of RNA decay, as well as the underlying gene silencing modules and their organization in pathways at the genomic scale.
In this proposal, we combine diverse scientific approaches and experimental techniques to dissect the regulation of gene expression at the molecular and genomic scale in flies and mammals. To this end, we unravel the molecular basis, physiological targets and biological functions of uridylation-triggered RNA silencing; we identify and dissect fundamental principles in global and transcript-specific RNA decay; and we establish novel tools to unravel the molecular signatures, and mechanistic components of RNA turnover at the genomic scale. Throughout, we link our results back to the established function of RNA silencing in the regulation of organismal development, physiology and disease. In summary, our work will significantly advance our understanding of post-transcriptional gene regulation, a phenomenon with enormous biological and biomedical relevance.
