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

Area of Science:

• Epigenetics and Chromatin Biology
• Cancer Genomics
• Systems Biology

Background:

• Chromatin modifications and complexes define epigenome domains, but crosstalk mechanisms remain poorly understood.
• Understanding dynamic chromatin state transitions is crucial for development and disease research.

Purpose of the Study:

• To systematically identify gene-gene functional relationships and chromatin crosstalk mechanisms.
• To define the molecular context of essential gene modules in cancer.

Main Methods:

• CRISPR-Cas9-mediated fitness screens for co-dependency mapping in pan-cancer cell lines.
• Integration of mutational, epigenome, gene expression, and drug sensitivity data.
• Analysis of protein complex composition and function.

Main Results:

• Identified 145 co-dependency modules and novel functional interactions.
• Discovered an unexpected co-dependency between Polycomb Repressive Complex 2 (PRC2) and MLL-MEN1 complex.
• Demonstrated PRC2-mediated H3K27 tri-methylation regulates MLL1/MEN1 genome-wide distribution.
• Showed EZH2 mutations in lymphoma cells lead to MLL-MEN1 re-localization, driving oncogenesis and MEN1 inhibitor sensitivity.

Conclusions:

• Provides a resource for discovering trans-regulatory interactions in chromatin regulation.
• Highlights PRC2-MLL-MEN1 crosstalk as a mechanism of chromatin regulation.
• Identifies potential synthetic lethality targets, particularly MEN1 inhibition in specific lymphoma contexts.