Quantitative Translation of the Cancer Genome to Proteome

Quantitative Effects of Transcriptional and Translational Regulation on the Human Proteome

Cellular phenotype occurs at the level of the proteome. The first major component of proteome-level phenotype is governed by protein abundance. Two major ways to regulate protein abundance occur at the levels of transcriptional as well as translational regulation. In terms of translational regulation, ribosome profiling, the deep sequencing of mRNA fragments protected by activity translating ribosomes, has proven to be a powerful strategy to directly measure translational regulation. We recently described an analytical comparison of ribosome profiling to quantitative synthesis of new proteins as measured by pulsed-SILAC proteomics (Liu et al, Cell Syst (2017)). We are now focused on extending these methods across other systems and perturbations, as well as delineating biological mechanisms that govern translational regulation across different cell types.

We are also currently investigating the mechanisms by which protein architecture associated with DNA regulates the proteome via transcriptional regulation. To this end, we are developing novel chemical biology-mass spectrometry strategies to perform locus-specific epigenetic proteomics. We belive this tool, akin to a "reverse-ChiP", will prove to be a widespread method to study mechanisms of transcriptional regulation in cancer biology, developmental biology, neuroscience, and immunology. We also aim to integrate these methods with emerging fields examining chromatin architecture, mediating both short- and long-range contacts across the genome, driven by specific binding proteins.