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Title: CRISPRi enables isoform-specific loss-of-function screens and identification of gastric cancer-specific isoform dependencies
Authors: Davies, Rebecca
Liu, Ling
Taotao, Sheng 
Tuano, Natasha
Chaturvedi, Richa
Huang, Kie Kyon
Itman, Catherine
Mandoli, Amit 
Qamra, Aditi 
Hu, Changyuan
Powell, David
Daly, Roger J.
Tan, Patrick 
Rosenbluh, Joseph
Issue Date: 26-Jan-2021
Publisher: BioMed Central Ltd
Citation: Davies, Rebecca, Liu, Ling, Taotao, Sheng, Tuano, Natasha, Chaturvedi, Richa, Huang, Kie Kyon, Itman, Catherine, Mandoli, Amit, Qamra, Aditi, Hu, Changyuan, Powell, David, Daly, Roger J., Tan, Patrick, Rosenbluh, Joseph (2021-01-26). CRISPRi enables isoform-specific loss-of-function screens and identification of gastric cancer-specific isoform dependencies. Genome Biology 22 (1) : 47. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
Abstract: Introduction: Genes contain multiple promoters that can drive the expression of various transcript isoforms. Although transcript isoforms from the same gene could have diverse and non-overlapping functions, current loss-of-function methodologies are not able to differentiate between isoform-specific phenotypes. Results: Here, we show that CRISPR interference (CRISPRi) can be adopted for targeting specific promoters within a gene, enabling isoform-specific loss-of-function genetic screens. We use this strategy to test functional dependencies of 820 transcript isoforms that are gained in gastric cancer (GC). We identify a subset of GC-gained transcript isoform dependencies, and of these, we validate CIT kinase as a novel GC dependency. We further show that some genes express isoforms with opposite functions. Specifically, we find that the tumour suppressor ZFHX3 expresses an isoform that has a paradoxical oncogenic role that correlates with poor patient outcome. Conclusions: Our work finds isoform-specific phenotypes that would not be identified using current loss-of-function approaches that are not designed to target specific transcript isoforms. © 2021, The Author(s).
Source Title: Genome Biology
ISSN: 1474-7596
DOI: 10.1186/s13059-021-02266-6
Rights: Attribution 4.0 International
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