Histone proteins are responsible for efficient packaging of DNA and, more importantly, the modulation of almost every chromatin-templated activity. The histone ?code? hypothesis states that the combination of a set of PTMs in histone may elicit a specific transcriptional program. In these three aims, we will develop, validate and apply a comprehensive approach, based on two flavors of mass spectrometry, to the analysis of histone modifications in several disease and model systems.
Specific Aim 1. To Develop and Validate a Quantitative Triple Quadrupole (QqQ) Method to Monitor 100 Histone Modifications from 1,000 Cells using a Bottom-Up Approach.
Specific Aim 2. To Develop and Validate a Quantitative Top-Down Mass Spectrometry Method to Monitor 1000 Histone Proteoforms from 10,000 Cells.
Specific Aim 3. To Integrate Quantitative Measurements of Histone Modifications with Genetic Information. ? Development and Validation of a Robust Pipeline for Clinical Specimens. Using technology developed in Specific Aims 1 and 2, Specific Aim 3 integrates those mass spectrometry approaches with genetic data to provide insight into clinical samples coming from cancer patients carrying targeted mutations in epigenetic modifiers. In many cases, these mutations are thought to be the ?drivers? behind tumorigenesis. While TR&Ds 1, 2 and 3 focus on specific technical hurdles in proteomics analyses, TR&D 4 seeks to harmonize multiple, dense, diverse datasets. This TR&D project will advance the burgeoning field we refer to as ?epiproteomics? by standardizing methods and maximizing the quality and quantity of information acquired from limited and heterogeneous clinical specimens to gain insight into complex diseases.
| Skinner, Owen S; Haverland, Nicole A; Fornelli, Luca et al. (2018) Top-down characterization of endogenous protein complexes with native proteomics. Nat Chem Biol 14:36-41 |
| Ting, See-Yeun; Bosch, Dustin E; Mangiameli, Sarah M et al. (2018) Bifunctional Immunity Proteins Protect Bacteria against FtsZ-Targeting ADP-Ribosylating Toxins. Cell 175:1380-1392.e14 |
| Ntai, Ioanna; Fornelli, Luca; DeHart, Caroline J et al. (2018) Precise characterization of KRAS4b proteoforms in human colorectal cells and tumors reveals mutation/modification cross-talk. Proc Natl Acad Sci U S A 115:4140-4145 |
| Killinger, Bryan A; Madaj, Zachary; Sikora, Jacek W et al. (2018) The vermiform appendix impacts the risk of developing Parkinson's disease. Sci Transl Med 10: |
| Martin, Rey W; Des Soye, Benjamin J; Kwon, Yong-Chan et al. (2018) Cell-free protein synthesis from genomically recoded bacteria enables multisite incorporation of noncanonical amino acids. Nat Commun 9:1203 |
| Kenney, Grace E; Dassama, Laura M K; Pandelia, Maria-Eirini et al. (2018) The biosynthesis of methanobactin. Science 359:1411-1416 |
| Swaroop, Alok; Oyer, Jon A; Will, Christine M et al. (2018) An activating mutation of the NSD2 histone methyltransferase drives oncogenic reprogramming in acute lymphocytic leukemia. Oncogene : |
| Davis, Roderick G; Park, Hae-Min; Kim, Kyunggon et al. (2018) Top-Down Proteomics Enables Comparative Analysis of Brain Proteoforms Between Mouse Strains. Anal Chem 90:3802-3810 |
| LeDuc, Richard D; Schwämmle, Veit; Shortreed, Michael R et al. (2018) ProForma: A Standard Proteoform Notation. J Proteome Res 17:1321-1325 |
| Aebersold, Ruedi; Agar, Jeffrey N; Amster, I Jonathan et al. (2018) How many human proteoforms are there? Nat Chem Biol 14:206-214 |
Showing the most recent 10 out of 53 publications
