Decoding mechanism of action and sensitivity to drug candidates from integrated transcriptome and chromatin state
| Autor: | Caterina Carraro, Lorenzo Bonaguro, Jonas Schulte-Schrepping, Arik Horne, Marie Oestreich, Stefanie Warnat-Herresthal, Tim Helbing, Michele De Franco, Kristian Haendler, Sach Mukherjee, Thomas Ulas, Valentina Gandin, Richard Goettlich, Anna C Aschenbrenner, Joachim L Schultze, Barbara Gatto |
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| Přispěvatelé: | Carraro, Caterina [0000-0002-3039-4675], Bonaguro, Lorenzo [0000-0001-9675-7208], Helbing, Tim [0000-0002-1284-3254], Aschenbrenner, Anna C [0000-0002-9429-5457], Gatto, Barbara [0000-0001-9465-6913], Apollo - University of Cambridge Repository |
| Rok vydání: | 2022 |
| Předmět: |
General Immunology and Microbiology
General Neuroscience metabolism [Transposases] Transposases systems biology General Medicine multi-omics sensitivity ML prediction drug candidate Chromatin General Biochemistry Genetics and Molecular Biology computational biology chromatin accessibility RNA human mechanism of action transcriptome Precision Medicine Transcriptome ddc:600 Research Article Computational and Systems Biology |
| Zdroj: | eLife 11, e78012 (2022). doi:10.7554/eLife.78012 eLife |
| ISSN: | 2050-084X |
| DOI: | 10.7554/elife.78012 |
| Popis: | Omics-based technologies are driving major advances in precision medicine, but efforts are still required to consolidate their use in drug discovery. In this work, we exemplify the use of multi-omics to support the development of 3-chloropiperidines, a new class of candidate anticancer agents. Combined analyses of transcriptome and chromatin accessibility elucidated the mechanisms underlying sensitivity to test agents. Furthermore, we implemented a new versatile strategy for the integration of RNA- and ATAC-seq (Assay for Transposase-Accessible Chromatin) data, able to accelerate and extend the standalone analyses of distinct omic layers. This platform guided the construction of a perturbation-informed basal signature predicting cancer cell lines’ sensitivity and to further direct compound development against specific tumor types. Overall, this approach offers a scalable pipeline to support the early phases of drug discovery, understanding of mechanisms, and potentially inform the positioning of therapeutics in the clinic. |
| Databáze: | OpenAIRE |
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