Jump to main content
Jump to site search

Issue 7, 2016
Previous Article Next Article

Pathway-based network modeling finds hidden genes in shRNA screen for regulators of acute lymphoblastic leukemia

Author affiliations

Abstract

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.

Graphical abstract: Pathway-based network modeling finds hidden genes in shRNA screen for regulators of acute lymphoblastic leukemia

Back to tab navigation
Please wait while Download options loads

Supplementary files

Publication details

The article was received on 18 Mar 2016, accepted on 31 May 2016 and first published on 02 Jun 2016


Article type: Paper
DOI: 10.1039/C6IB00040A
Citation: Integr. Biol., 2016,8, 761-774
  • Open access: Creative Commons BY-NC license
  •   Request permissions

    Pathway-based network modeling finds hidden genes in shRNA screen for regulators of acute lymphoblastic leukemia

    J. L. Wilson, S. Dalin, S. Gosline, M. Hemann, E. Fraenkel and D. A. Lauffenburger, Integr. Biol., 2016, 8, 761
    DOI: 10.1039/C6IB00040A

Search articles by author