De novo identification of essential protein domains from CRISPR-Cas9 tiling-sgRNA knockout screens

Wei He, Liang Zhang, Oscar D. Villarreal, Rongjie Fu, Ella Bedford, Jingzhuang Dou, Anish Y. Patel, Mark T. Bedford, Xiaobing Shi, Taiping Chen, Blaine Bartholomew and Han Xu ()
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Wei He: The University of Texas MD Anderson Cancer Center
Liang Zhang: The University of Texas MD Anderson Cancer Center
Oscar D. Villarreal: The University of Texas MD Anderson Cancer Center
Rongjie Fu: The University of Texas MD Anderson Cancer Center
Ella Bedford: The University of Texas MD Anderson Cancer Center
Jingzhuang Dou: The University of Texas MD Anderson Cancer Center
Anish Y. Patel: The University of Texas MD Anderson Cancer Center
Mark T. Bedford: The University of Texas MD Anderson Cancer Center
Xiaobing Shi: Van Andel Research Institute
Taiping Chen: The University of Texas MD Anderson Cancer Center
Blaine Bartholomew: The University of Texas MD Anderson Cancer Center
Han Xu: The University of Texas MD Anderson Cancer Center

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: Abstract High-throughput CRISPR-Cas9 knockout screens using a tiling-sgRNA design permit in situ evaluation of protein domain function. Here, to facilitate de novo identification of essential protein domains from such screens, we propose ProTiler, a computational method for the robust mapping of CRISPR knockout hyper-sensitive (CKHS) regions, which refer to the protein regions associated with a strong sgRNA dropout effect in the screens. Applied to a published CRISPR tiling screen dataset, ProTiler identifies 175 CKHS regions in 83 proteins. Of these CKHS regions, more than 80% overlap with annotated Pfam domains, including all of the 15 known drug targets in the dataset. ProTiler also reveals unannotated essential domains, including the N-terminus of the SWI/SNF subunit SMARCB1, which is validated experimentally. Surprisingly, the CKHS regions are negatively correlated with phosphorylation and acetylation sites, suggesting that protein domains and post-translational modification sites have distinct sensitivities to CRISPR-Cas9 mediated amino acids loss.

Date: 2019
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DOI: 10.1038/s41467-019-12489-8

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