A Library of Phosphoproteomic and Chromatin Signatures for Characterizing Cellular Responses to Drug Perturbations
| Autor: | Desiree Davison, Zihan Liu, Courtney Toder, Lev Litichevskiy, Alison E. Mungenast, Daniel D. Lam, Andrew A. Tubelli, Jarrett D. Egertson, Ryan Peckner, John F. Davis, Li-Huei Tsai, Todd R. Golub, Nicholas J. Lyons, Jacob D. Jaffe, Steven A. Carr, Malvina Papanastasiou, Shawn Egri, Michael J. MacCoss, Joshua Gould, Amanda L. Creech, Vagisha Sharma, Ted Natoli, Xiaodong Lu, Jinal Patel, Caitlin M. Dunning, Aravind Subramanian, Jacob K. Asiedu, Sarah A. Johnson, David L. Lahr, Brendan MacLean, Jennifer G. Abelin, Jennie Z. Young, Adam Officer, Tak Ko |
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| Přispěvatelé: | Broad Institute of MIT and Harvard, Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory |
| Rok vydání: | 2018 |
| Předmět: |
Proteomics
0301 basic medicine Cell type Histology Lineage (genetic) Databases Factual Systems biology Datasets as Topic Computational biology Bioinformatics Mass Spectrometry Cell Line Pathology and Forensic Medicine 03 medical and health sciences 0302 clinical medicine Gene expression Humans Pharmacological and Toxicological Phenomena Epigenetics 030304 developmental biology 0303 health sciences biology Drug discovery Cell Biology Phosphoproteins 3. Good health Chromatin Histone Code Gene expression profiling 030104 developmental biology Histone Gene Expression Regulation Drug development 030220 oncology & carcinogenesis biology.protein Algorithms Software Chromatography Liquid Signal Transduction |
| Zdroj: | Elsevier |
| ISSN: | 2405-4712 |
| DOI: | 10.1016/j.cels.2018.03.012 |
| Popis: | Although the value of proteomics has been demonstrated, cost and scale are typically prohibitive, and gene expression profiling remains dominant for characterizing cellular responses to perturbations. However, high-throughput sentinel assays provide an opportunity for proteomics to contribute at a meaningful scale. We present a systematic library resource (90 drugs × 6 cell lines) of proteomic signatures that measure changes in the reduced-representation phosphoproteome (P100) and changes in epigenetic marks on histones (GCP). A majority of these drugs elicited reproducible signatures, but notable cell line- and assay-specific differences were observed. Using the “connectivity” framework, we compared signatures across cell types and integrated data across assays, including a transcriptional assay (L1000). Consistent connectivity among cell types revealed cellular responses that transcended lineage, and consistent connectivity among assays revealed unexpected associations between drugs. We further leveraged the resource against public data to formulate hypotheses for treatment of multiple myeloma and acute lymphocytic leukemia. This resource is publicly available at https://clue.io/proteomics. A large compendium of cellular responses to drugs as profiled through proteomic assays of phosphosignaling and histone modifications reveals cellular responses that transcend lineage, discovers unexpected associations between drugs, and recognizes therapeutic hypotheses for treatment of multiple myeloma and acute lymphocytic leukemia. Keywords: mass spectrometry; proteomics; drug discovery; signaling; epigenetics; mechanism of action; LINCS project; GCP; P100; L1000 NIH Common Fund's Library of Integrated Network-based Cellular Signatures (LINCS) program (Grant U54HG008097) NIH Common Fund's Library of Integrated Network-based Cellular Signatures (LINCS) program (Grant U54HG008699) |
| Databáze: | OpenAIRE |
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