| Autor: |
Wilson JL; Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, 16-343, Cambridge MA 02139, USA. fraenkel@mit.edu lauffen@mit.edu., Dalin S, Gosline S, Hemann M, Fraenkel E, Lauffenburger DA |
| Jazyk: |
angličtina |
| Zdroj: |
Integrative biology : quantitative biosciences from nano to macro [Integr Biol (Camb)] 2016 Jul 11; Vol. 8 (7), pp. 761-74. Date of Electronic Publication: 2016 Jun 17. |
| DOI: |
10.1039/c6ib00040a |
| Abstrakt: |
Data integration stands to improve interpretation of RNAi screens which, as a result of off-target effects, typically yield numerous gene hits of which only a few validate. These off-target effects can result from seed matches to unintended gene targets (reagent-based) or cellular pathways, which can compensate for gene perturbations (biology-based). We focus on the biology-based effects and use network modeling tools to discover pathways de novo around RNAi hits. By looking at hits in a functional context, we can uncover novel biology not identified from any individual 'omics measurement. We leverage multiple 'omic measurements using the Simultaneous Analysis of Multiple Networks (SAMNet) computational framework to model a genome scale shRNA screen investigating Acute Lymphoblastic Leukemia (ALL) progression in vivo. Our network model is enriched for cellular processes associated with hematopoietic differentiation and homeostasis even though none of the individual 'omic sets showed this enrichment. The model identifies genes associated with the TGF-beta pathway and predicts a role in ALL progression for many genes without this functional annotation. We further experimentally validate the hidden genes - Wwp1, a ubiquitin ligase, and Hgs, a multi-vesicular body associated protein - for their role in ALL progression. Our ALL pathway model includes genes with roles in multiple types of leukemia and roles in hematological development. We identify a tumor suppressor role for Wwp1 in ALL progression. This work demonstrates that network integration approaches can compensate for off-target effects, and that these methods can uncover novel biology retroactively on existing screening data. We anticipate that this framework will be valuable to multiple functional genomic technologies - siRNA, shRNA, and CRISPR - generally, and will improve the utility of functional genomic studies. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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