Ribonucleoprotein Biogenesis and Epigenetic Gene Regulation

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Abstract The research in our laboratory centers on foundational mechanisms that regulate eukaryotic gene expression. In particular, we are interested in roles played by small nuclear ribonucleoproteins (RNPs) and histone post- translational modifications (PTMs) in the transmission of genetic and epigenetic information required for proper metazoan development and genome function. We have developed innovative model systems in Drosophila melanogaster to study gene regulation and neuromuscular disease. Critically, these models allow direct interrogation of specific residues present within conserved genes and multi-gene families. For example, we can now study the biological function of a specific histone PTM by changing the acceptor residue to an amino acid that cannot be appropriately modified and then replacing all wild-type copies of a given histone gene with mutant copies. This approach is not possible in other animal models. Hence, for the first time in any multicellular eukaryote, we can now directly determine the extent to which a given histone PTM contributes to cell fate and organismal development. Similarly, we generated an allelic series of animals that express missense mutations in the Survival Motor Neuron (SMN) gene that are derived from human Spinal Muscular Atrophy (SMA) patients. This series represents the largest number of SMA-causing point mutants currently available in any model organism. Several of these alleles serve as separation-of-function mutations that uncouple the putative housekeeping and tissue-specific activities of SMN, enabling us to study these processes independently. We employ genome-wide techniques together with molecular genetics and biochemistry to identify cellular pathways and binding partners that are dysregulated in human cancer and neuromuscular disease. Using these two powerful genetic platforms, we expect to identify factors and mechanisms that enable a specific chromatin mark to modulate the expression of an individual transcript or an entire chromosome, as well as those that carry out the assembly and maturation of spliceosomal and messenger RNPs.