ATARiS: Computational quantification of gene suppression phenotypes from multisample RNAi screens

Shao, Diane D.; Tsherniak, Aviad; Gopal, Shuba; Weir, Barbara A.; Tamayo, Pablo; Stransky, Nicolas; Schumacher, Steven E.; Zack, Travis I.; Beroukhim, Rameen; Garraway, Levi A.; Margolin, Adam A.; Root, David E.; Hahn, William C.; Mesirov, Jill P.

doi:10.1101/gr.143586.112

Cited by 118 publications

(167 citation statements)

References 57 publications

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“…S1D). Notably, application of the ATARIS algorithm (25), which provides a statistical method for identifying shRNAs that share a common activity profile, revealed that 10 of 17 independent KRAS shRNAs displayed similar antiproliferative profiles (SI Appendix, Fig. S1E).…”

Section: Resultsmentioning

confidence: 99%

Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers

Hoffman¹,

Rahal²,

Buxton³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

352

315

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Defects in epigenetic regulation play a fundamental role in the development of cancer, and epigenetic regulators have recently emerged as promising therapeutic candidates. We therefore set out to systematically interrogate epigenetic cancer dependencies by screening an epigenome-focused deep-coverage design shRNA (DECODER) library across 58 cancer cell lines. This screen identified BRM/SMARCA2, a DNA-dependent ATPase of the mammalian SWI/ SNF (mSWI/SNF) chromatin remodeling complex, as being essential for the growth of tumor cells that harbor loss of function mutations in BRG1/SMARCA4. Depletion of BRM in BRG1-deficient cancer cells leads to a cell cycle arrest, induction of senescence, and increased levels of global H3K9me3. We further demonstrate the selective dependency of BRG1-mutant tumors on BRM in vivo. Genetic alterations of the mSWI/SNF chromatin remodeling complexes are the most frequent among chromatin regulators in cancers, with BRG1/SMARCA4 mutations occurring in ∼10-15% of lung adenocarcinomas. Our findings position BRM as an attractive therapeutic target for BRG1 mutated cancers. Because BRG1 and BRM function as mutually exclusive catalytic subunits of the mSWI/SNF complex, we propose that such synthetic lethality may be explained by paralog insufficiency, in which loss of one family member unveils critical dependence on paralogous subunits. This concept of "cancerselective paralog dependency" may provide a more general strategy for targeting other tumor suppressor lesions/complexes with paralogous subunits.

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Section: Resultsmentioning

confidence: 99%

Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers

Hoffman¹,

Rahal²,

Buxton³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

352

315

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“…(i) Gene-level shRNA scores were derived from individual shRNA scores using ATARiS. ATARiS is a computational method that enriches for related phenotypic effects caused by individual shRNAs (27). (ii) The gene mutation status for SMARCA4 in cancer cell lines was next determined using information from the Cancer Cell Line Encyclopedia (www.broadinstitute.org/ccle) and prior publications (Table 1).…”

Section: Methodsmentioning

confidence: 99%

Residual Complexes Containing SMARCA2 (BRM) Underlie the Oncogenic Drive of SMARCA4 (BRG1) Mutation

Wilson

Helming

Wang

et al. 2014

Molecular and Cellular Biology

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199

142

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f Collectively, genes encoding subunits of the SWI/SNF (BAF) chromatin remodeling complex are mutated in 20% of all human cancers, with the SMARCA4 (BRG1) subunit being one of the most frequently mutated. The SWI/SNF complex modulates chromatin remodeling through the activity of two mutually exclusive catalytic subunits, SMARCA4 and SMARCA2 (BRM). Here, we show that a SMARCA2-containing residual SWI/SNF complex underlies the oncogenic activity of SMARCA4 mutant cancers. We demonstrate that a residual SWI/SNF complex exists in SMARCA4 mutant cell lines and plays essential roles in cellular proliferation. Further, using data from loss-of-function screening of 165 cancer cell lines, we identify SMARCA2 as an essential gene in SMARCA4 mutant cancer cell lines. Mechanistically, we reveal that Smarca4 inactivation leads to greater incorporation of the nonessential SMARCA2 subunit into the SWI/SNF complex. Collectively, these results reveal a role for SMARCA2 in oncogenesis caused by SMARCA4 loss and identify the ATPase and bromodomain-containing SMARCA2 as a potential therapeutic target in these cancers.

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“…For example, many candidate therapeutic targets identified from shRNA screens have failed validation in independent assays (Babij et al, 2011;Begley and Ellis, 2012;Prinz et al, 2011). Among the possible reasons for lack of robustness, one must consider RNAi off-target effects, variable potency and knock-down/out efficiency of RNAi and CRISPR reagents, biological and technical noise in highthroughput screens (Echeverri et al, 2006;Hart et al, 2014;Shao et al, 2013), cell line-specific efficiency of viral pool infection and toxicity from additional viral vector expression cassettes (e.g. fluorescence reporter proteins).…”

Section: Introductionmentioning

confidence: 99%

ScreenBEAM: a novel meta-analysis algorithm for functional genomics screens via Bayesian hierarchical modeling

Silva

Califano

2015

Bioinformatics

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Motivation: Functional genomics (FG) screens, using RNAi or CRISPR technology, have become a standard tool for systematic, genome-wide loss-of-function studies for therapeutic target discovery. As in many large-scale assays, however, off-target effects, variable reagents' potency and experimental noise must be accounted for appropriately control for false positives. Indeed, rigorous statistical analysis of high-throughput FG screening data remains challenging, particularly when integrative analyses are used to combine multiple sh/sgRNAs targeting the same gene in the library. Method: We use large RNAi and CRISPR repositories that are publicly available to evaluate a novel meta-analysis approach for FG screens via Bayesian hierarchical modeling, Screening Bayesian Evaluation and Analysis Method (ScreenBEAM). Results: Results from our analysis show that the proposed strategy, which seamlessly combines all available data, robustly outperforms classical algorithms developed for microarray data sets as well as recent approaches designed for next generation sequencing technologies. Remarkably, the ScreenBEAM algorithm works well even when the quality of FG screens is relatively low, which accounts for about 80-95% of the public datasets. Availability and implementation: R package and source code are available at: https://github.com/

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ATARiS: Computational quantification of gene suppression phenotypes from multisample RNAi screens

Cited by 118 publications

References 57 publications

Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers

Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers

Residual Complexes Containing SMARCA2 (BRM) Underlie the Oncogenic Drive of SMARCA4 (BRG1) Mutation

ScreenBEAM: a novel meta-analysis algorithm for functional genomics screens via Bayesian hierarchical modeling

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