Regulation of chromatin metabolism by subcellular proteome dynamics

Subcellular localization is essential for protein function. Proteins localize to different compartments, membrane-less organelles or other subcellular structures and their biological functions can vary depending on these different environments. Up to half the human proteome resides in multiple compartments and protein localizations are dynamically controlled during cell state changes or in response to perturbations. Of particular importance is the control of localization for metabolic activities in the cell’s nucleus, which involve classical chromatin modifiers and additional enzymes from more central metabolic pathways. For these proteins, import into the nucleus, recruitment to certain sites in the genome, and metabolic activity can all be regulated to control chromatin structure, gene expression and cell identity. We use a combination of proteomics, metabolomics and fluorescent reporter approaches to comprehensively understand these metabolic activities, with a particular focus on nucleotide and one-carbon metabolism. We further apply these reporter systems in chemical and genetic screens for factors that alter chromatin accessibility, protein localization and protein abundance. Through this approach, we aim to identify therapeutic targets and small-molecule modulators of cell fate decisions in diabetes and cancer.