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CRISPRi enables isoform-specific loss-of-function screens and identification of gastric cancer-specific isoform dependencies

Davies, Rebecca
Liu, Ling
Taotao, Sheng
Tuano, Natasha
Chaturvedi, Richa
Huang, Kie Kyon
Itman, Catherine
Mandoli, AmitQamra, Aditi
Hu, Changyuan
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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).
Keywords
Source Title
Genome Biology
Publisher
BioMed Central Ltd
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Rights
Attribution 4.0 International
Date
2021-01-26
DOI
10.1186/s13059-021-02266-6
Type
Article
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