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

Xiao Chen, Yinglu Li, Fang Zhu, Xinjing Xu, Brian Estrella, Manuel A. Pazos, John T. McGuire, Dimitris Karagiannis, Varun Sahu, Mustafo Mustafokulov, Claudio Scuoppo, Francisco J. Sánchez-Rivera, Yadira M. Soto-Feliciano, Laura Pasqualucci, Alberto Ciccia, Jennifer E. Amengual and Chao Lu ()
Additional contact information
Xiao Chen: Columbia University Irving Medical Center
Yinglu Li: Columbia University Irving Medical Center
Fang Zhu: Columbia University Irving Medical Center
Xinjing Xu: Columbia University Irving Medical Center
Brian Estrella: Columbia University Irving Medical Center
Manuel A. Pazos: Columbia University Irving Medical Center
John T. McGuire: Columbia University Irving Medical Center
Dimitris Karagiannis: Columbia University Irving Medical Center
Varun Sahu: Columbia University Irving Medical Center
Mustafo Mustafokulov: Columbia University Irving Medical Center
Claudio Scuoppo: Columbia University Irving Medical Center
Francisco J. Sánchez-Rivera: Massachusetts Institute of Technology
Yadira M. Soto-Feliciano: Massachusetts Institute of Technology
Laura Pasqualucci: Columbia University Irving Medical Center
Alberto Ciccia: Columbia University Irving Medical Center
Jennifer E. Amengual: Columbia University Irving Medical Center
Chao Lu: Columbia University Irving Medical Center

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-39990-5

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