PT  - JOURNAL ARTICLE
AU  - Ryan D. Chow
AU  - Guangchuan Wang
AU  - Adan Codina
AU  - Lupeng Ye
AU  - Sidi Chen
TI  - Mapping <em>in vivo</em> genetic interactomics through Cpf1 crRNA array screening
AID  - 10.1101/153486
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 153486
4099  - http://biorxiv.org/content/early/2017/06/21/153486.short
4100  - http://biorxiv.org/content/early/2017/06/21/153486.full
AB  - Genetic interactions lay the foundation of biological networks in virtually all organisms. Due to the complexity of mammalian genomes and cellular architectures, unbiased mapping of genetic interactions in vivo is challenging. Cpf1 is a single effector RNA-guided nuclease that enables multiplexed genome editing using crRNA arrays. Here we designed a Cpf1 crRNA array library targeting all pairwise permutations of the most significantly mutated nononcogenes, and performed double knockout screens in mice using a model of malignant transformation as well as a model of metastasis. CrRNA array sequencing revealed a quantitative landscape of all single and double knockouts. Enrichment, synergy and clonal analyses identified many unpredicted drivers and co-drivers of transformation and metastasis, with epigenetic factors as hubs of these highly connected networks. Our study demonstrates a powerful yet simple approach for in vivo mapping of unbiased genetic interactomes in mammalian species at a phenotypic level.