Role of histone PTMs in epigenetic control of metazoan transcription and RNA processing

Abstract/Summary The research in our laboratory centers on foundational mechanisms that regulate eukaryotic gene expression. In particular, we are interested in roles played by histone residues and their 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 expression control. Crucially, these models allow direct interrogation of specific amino acid residues present within conserved genes and multi-gene families. For example, we can now directly study the biological function of histone PTMs by changing the acceptor residue to one that cannot be appropriately modified and then replacing all wild-type copies of that histone gene with mutant ones. Due to differences in the genomic organization of histone gene families, this approach is not currently 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 residue contributes to cell fate and organismal development. We employ genome-wide techniques together with molecular genetics and biochemistry to identify cellular pathways and binding partners that are dysregulated by missense mutations in histone tail residues. We compare and contrast them with mutations in chromatin modifying enzymes (i.e. readers, writers, erasers) to gain a clearer picture of the factors governing metazoan gene expression and organismal development. Because histone tail residues are nearly 100% conserved between humans and flies, our work is expected to provide fundamental knowledge, elucidating epigenetic mechanisms important in human cancers and other disorders. Using this powerful genetic platform, we also expect to identify factors and mechanisms that enable a specific chromatin mark or enzyme complex to modulate the expression of an individual transcript, scattered groups of genes or even an entire chromosome.