CHROMATINMODWEB · Functional and regulatory protein networks of chromatin modifying enzymes

Proper and controlled expression of genes is essential for normal cell growth. Chromatin modifying enzymes play afundamental role in the control of gene expression and their deregulation is often linked to cancer. In recent years chromatinmodifiers have been considered key targets for cancer therapy and this demands a full understanding of their biologicalfunctions. Previous biochemical and structural studies have focused on the identification of chromatin modifying enzymesand characterization of their substrate specificities and catalytic mechanisms. However, a comprehensive view of thebiological processes, signaling pathways and regulatory circuits in which these enzymes participate is missing. Proteinarginine methyltransferases (PRMTs), which methylate histones and are evolutionarily conserved from yeast to human,constitute an example of chromatin modifying enzymes whose functional and regulatory networks remain unexplored. Ipropose to use complementary state-of-the-art genomic and proteomic approaches in order to identify the protein networksand cellular pathways that are linked to PRMTs. In parallel, I will identify novel regulatory circuits and define the molecularmechanisms that control methylation of specific histone arginine residues. I will utilize the yeast S. cerevisiae as a modelorganism because it allows genetic, biochemical and genomic approaches to be combined. Most importantly, many of thepathways and mechanisms in yeast are highly conserved and therefore, the findings from this study will be pertinent tohuman and other eukaryotic organisms. Establishing a global cellular wiring diagram of PRMTs will serve as a paradigm forother chromatin modifiers and is imperative for assessing the efficacy of these enzymes as therapeutic targets.