DrugThatGene: integrative analysis to streamline the identification of druggable genes, pathways and protein complexes from CRISPR screens

MOTIVATION The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) nuclease system has allowed for high-throughput, large scale pooled screens for functional genomic studies. To aid in the translation of functional genomics to therapeutics, we developed DrugThatGene (DTG) as a web-based application that streamlines analysis of potential therapeutic targets identified from functional genetic screens. RESULTS Starting from a gene list as input, DTG offers automated identification of small molecules along with supporting information from human genetic and other relevant databases. Furthermore, DTG aids in the identification of common biological pathways and protein complexes in conjunction with associated small molecule inhibitors. Taken together, DTG aims to expedite the identification of small molecules from the abundance of functional genetic data generated from CRISPR screens. AVAILABILITY AND IMPLEMENTATION DTG is an open-source and free software available as a website at http://drugthatgene.pinellolab.org. Source code is available at: https://github.com/pinellolab/DrugThatGene, which can be downloaded in order to run DTG locally.

[1]  Ada Hamosh,et al.  7. Online Mendelian Inheritance in Man (OMIM): A Directory of Human Genes and Genetic Disorders , 2002 .

[2]  J. Kinney,et al.  Discovery of cancer drug targets by CRISPR-Cas9 screening of protein domains , 2015, Nature Biotechnology.

[3]  Oliver Pelz,et al.  caRpools: an R package for exploratory data analysis and documentation of pooled CRISPR/Cas9 screens , 2016, Bioinform..

[4]  Christian von Mering,et al.  STRING: known and predicted protein–protein associations, integrated and transferred across organisms , 2004, Nucleic Acids Res..

[5]  Jiyang Yu,et al.  ScreenBEAM: a novel meta-analysis algorithm for functional genomics screens via Bayesian hierarchical modeling , 2015, Bioinform..

[6]  Jun S. Liu,et al.  Quality control, modeling, and visualization of CRISPR screens with MAGeCK-VISPR , 2015, Genome Biology.

[7]  Deng Pan,et al.  DGIdb 2.0: mining clinically relevant drug–gene interactions , 2015, Nucleic Acids Res..

[8]  Max A. Horlbeck,et al.  Parallel shRNA and CRISPR-Cas9 screens enable antiviral drug target identification , 2016, Nature chemical biology.

[9]  Deanna M. Church,et al.  ClinVar: public archive of relationships among sequence variation and human phenotype , 2013, Nucleic Acids Res..

[10]  M. Rehmsmeier,et al.  Comprehensive analysis of high-throughput screens with HiTSeekR , 2016, Nucleic acids research.

[11]  Timothy K Lu,et al.  Multiplexed barcoded CRISPR-Cas9 screening enabled by CombiGEM , 2016, Proceedings of the National Academy of Sciences.

[12]  Susan Tweedie,et al.  Genenames.org: the HGNC and VGNC resources in 2017 , 2016, Nucleic Acids Res..

[13]  N. Perrimon,et al.  Identification of potential drug targets for tuberous sclerosis complex by synthetic screens combining CRISPR-based knockouts with RNAi , 2015, Science Signaling.

[14]  Joshua F. McMichael,et al.  DGIdb - Mining the druggable genome , 2013, Nature Methods.

[15]  Rajarshi Guha,et al.  Pharos: Collating protein information to shed light on the druggable genome , 2016, Nucleic Acids Res..

[16]  Luca Pinello,et al.  Genome-wide CRISPR-Cas9 Screen Identifies Leukemia-Specific Dependence on a Pre-mRNA Metabolic Pathway Regulated by DCPS. , 2018, Cancer cell.

[17]  Neville E. Sanjana,et al.  Genome-Scale CRISPR-Cas9 Knockout Screening in Human Cells , 2014, Science.

[18]  James Y. Zou Analysis of protein-coding genetic variation in 60,706 humans , 2015, Nature.

[19]  J. Poirier,et al.  Design, execution, and analysis of pooled in vitro CRISPR/Cas9 screens , 2016, The FEBS journal.

[20]  Susumu Goto,et al.  KEGG: Kyoto Encyclopedia of Genes and Genomes , 2000, Nucleic Acids Res..

[21]  Jun S. Liu,et al.  MAGeCK enables robust identification of essential genes from genome-scale CRISPR/Cas9 knockout screens , 2014, Genome Biology.

[22]  Hans-Werner Mewes,et al.  CORUM: the comprehensive resource of mammalian protein complexes , 2007, Nucleic Acids Res..