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. 2024 Feb 1;15:963. doi: 10.1038/s41467-024-45128-y

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© The Author(s) 2024

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — a Design of the CRISPR-based screen to identify vulnerabilities in MYC-driven HCC. A genome-wide sgRNA library (colored bars) is introduced in Cas9-expressing MYC-driven HCC cells to generate a baseline cell pool. Cells are then cultured under MYC^high or MYC^low conditions resulting in a MYC synthetic lethal (MYC-SL) cell pool and a control cell pool, respectively. Deep sequencing of sgRNAs identifies genes that are essential only when MYC is highly expressed but not essential when MYC transgene expression is shut off. b Scatter plot of Beta scores (gene essentiality scores) in the control (MYC^low; x-axis) versus MYC-SL (MYC^high; y-axis) condition. Loss of genes highlighted in red significantly reduced fitness of MYC^high HCC cells but had no significant effect on MYC^low control cells. c Gene set enrichment analysis (GSEA) of essential and non-essential genes. Left and middle: Hart et al. Mol Syst Biol, 2014; Right: Bartha et al. Nat Rev Genet, 2017. d Venn diagram of essential genes identified in EC4 cells with high and low MYC levels. KEGG pathway analysis of MYC-SL genes (only essential in MYC^high condition) is shown. e Comparison of essential gene hits between our genome-wide CRISPR screen (MYC^high and MYC^low control conditions) and essential genes identified in 13 human HCC cell lines (DepMap, CCLE-liver) and human pluripotent stem cells (hPSC). UpSet plot and numbers of overlapping essential genes between indicated genome-wide CRISPR screens are shown. f Correlation analysis of gene essentiality scores from our genome-wide CRISPR screen in MYC-driven murine HCC and essentiality scores in human HCC cell lines (DepMap, CCLE-liver). Pearson’s correlation coefficient (r), two-tailed p-value, and R² of linear regression (blue line) are shown. For this figure, source data are provided as a Source Data file.