Abstract IA05: Massively parallel search for synthetic lethal vulnerabilities using CRISPRi and CRISPRa

We present a robust technology enabling systematic investigation of the cellular consequences of repressing or inducing individual transcripts. We identify rules for specific targeting of transcriptional repressors (CRISPRi), typically achieving 90-99% knockdown with minimal off-target effects, and activators (CRISPRa) to endogenous genes via endonuclease-deficient Cas9. Together they enable modulation of gene expression over a ~1000-fold range. Using these rules, we construct and validate genome-scale CRISPRi and CRISPRa libraries that enable systematic analysis of gene function including both essential and nonessential as well as long noncoding RNAs. Our results establish CRISPRi and CRISPRa as powerful tools that provide rich and complementary information for mapping complex pathways. We have now adpated this approach to allow the largescale analysis of double knockdowns. This enables the systematic search for synthetic lethal interactions that will inform the rational design of combination drug therapies.Citation Format: Jonathan Weissman. Massively parallel search for synthetic lethal vulnerabilities using CRISPRi and CRISPRa [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr IA05.

Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Weissman, J. Tags: New Technology and Bioinformatics: Oral Presentations - Invited Abstracts Source Type: research