The overarching goal of this project is to test the hypothesis that modulation of phosphorylation-mediated signaling events in response to perturbations can establish new cellular states by altering their epigenetic landscapes. To achieve this goal, we propose performing mass spectrometry (MS)-based proteomic assays that specifically target quantitative readouts of phosphosignaling and chromatin modifications in cells on > 15,000 perturbational conditions. These perturbations will focus on modulation of signaling cascades and epigenetic marks by small molecules and gene inactivations. We will study several different cellular model systems, including comprehensive studies neuronal lineage differentiation starting from human embryonic stem cells. We propose to establish a center in order to develop the necessary infrastructure, pipelines, data management, and analytics required to perform what would be the largest set of related experiments with MS proteomic read outs to date. We will also explore next-generation MS acquisition technologies to establish a permanently minable MS data resource that will be accessible to the public. We will contribute the resulting data and tools to the Library of Integrated Network-based Cellular Signatures (LINCS) program for the purpose of making connections among disparate perturbations through phosphoproteomic and chromatin modification signatures in concert with other data types to be contributed to LINCS by other centers. The resulting analyses will help identify novel therapeutic opportunities and synergies, as dysregulation of phosphosignaling and epigenetic systems are two of the most common molecular etiologies identified in a growing number of genetic, developmental, and environmental diseases. In this component of the project we describe the logistics of how our center will operate on a day-to-day basis and over the long term. We describe timelines and milestones that will allow evaluation of our center as we progress towards our goals, and describe methods to measure the impact of our research.

Public Health Relevance

This project is relevant because we will learn how to develop new drugs that target the common ways that diseases like cancer are caused in the cells of our bodies. We will use cutting edge scientific techniques to understand how these diseases cause normally healthy cells to become sick, and identify possible ways to block or reverse these effects.

National Institute of Health (NIH)
National Human Genome Research Institute (NHGRI)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-CB-D (50))
Program Officer
Pillai, Ajay
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Broad Institute, Inc.
United States
Zip Code
Peckner, Ryan; Myers, Samuel A; Jacome, Alvaro Sebastian Vaca et al. (2018) Specter: linear deconvolution for targeted analysis of data-independent acquisition mass spectrometry proteomics. Nat Methods 15:371-378
Horwitz, Steven M; Koch, Raphael; Porcu, Pierluigi et al. (2018) Activity of the PI3K-?,? inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma. Blood 131:888-898
Javasky, Elisheva; Shamir, Inbal; Gandhi, Shashi et al. (2018) Study of mitotic chromatin supports a model of bookmarking by histone modifications and reveals nucleosome deposition patterns. Genome Res 28:1455-1466
Gopal, Srila; Lu, Qing; Man, Joshua J et al. (2018) A phosphoproteomic signature in endothelial cells predicts vascular toxicity of tyrosine kinase inhibitors used in CML. Blood Adv 2:1680-1684
Litichevskiy, Lev; Peckner, Ryan; Abelin, Jennifer G et al. (2018) A Library of Phosphoproteomic and Chromatin Signatures for Characterizing Cellular Responses to Drug Perturbations. Cell Syst 6:424-443.e7
Keenan, Alexandra B; Jenkins, Sherry L; Jagodnik, Kathleen M et al. (2018) The Library of Integrated Network-Based Cellular Signatures NIH Program: System-Level Cataloging of Human Cells Response to Perturbations. Cell Syst 6:13-24
Sharma, Vagisha; Eckels, Josh; Schilling, Birgit et al. (2018) Panorama Public: A Public Repository for Quantitative Data Sets Processed in Skyline. Mol Cell Proteomics 17:1239-1244
Searle, Brian C; Pino, Lindsay K; Egertson, Jarrett D et al. (2018) Chromatogram libraries improve peptide detection and quantification by data independent acquisition mass spectrometry. Nat Commun 9:5128
Ting, Ying S; Egertson, Jarrett D; Bollinger, James G et al. (2017) PECAN: library-free peptide detection for data-independent acquisition tandem mass spectrometry data. Nat Methods 14:903-908
Abelin, Jennifer G; Patel, Jinal; Lu, Xiaodong et al. (2016) Reduced-representation Phosphosignatures Measured by Quantitative Targeted MS Capture Cellular States and Enable Large-scale Comparison of Drug-induced Phenotypes. Mol Cell Proteomics 15:1622-41

Showing the most recent 10 out of 12 publications