Simone Sidoli, Pau Pascual Garcia, Katarzyna Kulej, Maya Capelson and Benjamin A Garcia
University of Pennsylvania, USA
Posters & Accepted Abstracts: J Proteomics Bioinform
Integrating omics strategies is becoming a new frontier in systems biology, since disciplines like genomics and proteomics are now established. However, the traditional view of how these disciplines interplay, i.e., genomics�transcriptomics�proteomics�metabolomics, is too static to exhaustively represent a biological system. Events like early response to stimulus (protein phosphorylation) and structural gene regulation (epigenetic mechanisms) must enter in the equation. We investigated the development of larvae from Drosophila melanogaster upon treatment with kinase inhibitors. By integrating proteomics, phosphoproteomics, histone modification analysis and chromatin immunoprecipitation coupled with DNA sequencing (ChIP-seq) we reconstructed links between drug treatment and phenotypic abnormalities during development. Larvae from wild type (OregonR) hatched and grew from eggs laid on food w/o inhibitors for the kinases EGFR and c-Met. Considering the phosphoproteome as indicative of early response to stimulus we characterized pathways of proteins with regulated phosphorylations connecting the inhibitor target with nuclear receptors and histone modifier enzymes. Specifically, we found down-regulated phosphosites in both inhibitor treatments on the ecdysone nuclear receptor and the interacting trithorax complex, which last catalyzes methylation on histone H3 lysine 4 (H3K4me). This modification, enriched in actively transcribed genes, globally decreased upon inhibitor treatment. ChIP-seq analysis mapped H3K4me on genes coding for proteins involved in translational initiation in wild type, which we found expressed in lower abundance in treated larvae. Collectively, our preliminary data indicate how drug treatment might be related to developmental abnormalities (slower growth), using epigenomics to link early response to proteome regulation.
Email: simone.sidoli@gmail.com
