Context-defined cancer co-dependency mapping identifies a functional interplay between PRC2 and MLL-MEN1 complex in lymphoma

Interplay between chromatin-associated complexes and modifications critically contribute to the partitioning of epigenome into stable and functionally distinct domains. Yet there is a lack of systematic identification of chromatin crosstalk mechanisms, limiting our understanding of the dynamic transition between chromatin states during development and disease. Here we perform co-dependency mapping of genes using CRISPR-Cas9-mediated fitness screens in pan-cancer cell lines to quantify gene-gene functional relationships. We identify 145 co-dependency modules and further define the molecular context underlying the essentiality of these modules by incorporating mutational, epigenome, gene expression and drug sensitivity profiles of cell lines. These analyses assign new protein complex composition and function, and predict new functional interactions, including an unexpected co-dependency between two transcriptionally counteracting chromatin complexes - polycomb repressive complex 2 (PRC2) and MLL-MEN1 complex. We show that PRC2-mediated H3K27 tri-methylation regulates the genome-wide distribution of MLL1 and MEN1. In lymphoma cells with EZH2 gain-of-function mutations, the re-localization of MLL-MEN1 complex drives oncogenic gene expression and results in a hypersensitivity to pharmacologic inhibition of MEN1. Together, our findings provide a resource for discovery of trans-regulatory interactions as mechanisms of chromatin regulation and potential targets of synthetic lethality.

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The gene effect dataset of CRISPR-Cas9 essentiality screens in 1,086 pan-cancer cell lines (gene effect scores derived from CRISPR knockout screens published by Broad's Achilles and Sanger's SCORE projects, release public 2022q2) was downloaded from Cancer Dependency Map portal (DepMap, https://depmap.org/portal/). The number of samples for each assay was indicated in each figure legend. The sample size was determined by using power calculation for a t-test difference between two or three independent means based on a normally distributed population with equal variance.
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We included two replicates for CRISPR knockouts using individual sgRNAs and performed three replicates for cell proliferation experiments. Replicated experiments were successful and support conclusions drawn in this report.
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Files in database submission 6-8 weeks old male athymic nu/nu mice and 6-week-old female NOD-scid IL2Rgammanull (NSG) mice were purchased from The Jackson Laboratory. Number of mice used per experiments are described in manuscript. All mice were housed under specificpathogen free (SPF) condition under controlled temperature (20-26°C) and humidity (40-70%) with 12h/12h light/dark cycle, followed the guideline of Columbia University animal facility.
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