Reprogramming of bivalent chromatin states in NRAS-mutant melanoma suggests PRC2 inhibition as a therapeutic strategy

The dynamic evolution of chromatin state patterns during metastasis, their relationship with bona fide genetic drivers and therapeutic vulnerabilities are not completely understood. Combinatorial chromatin state profiling of 46 melanoma samples reveals an association of NRAS-mutants with bivalent H3K27me3 and Polycomb Repressive Complex 2. Reprogramming of bivalent domains during metastasis occurs on master transcription factors of a mesenchymal phenotype, including ZEB1, TWIST1 and CDH1. Resolution of bivalency using pharmacological inhibition of EZH2 decreases invasive capacity of melanoma cells and markedly reduces tumor burden in vivo, specifically in NRAS-mutants. Coincident with bivalent reprogramming the increased expression of pro-metastatic and melanocyte-specific cell identity genes are associated with exceptionally wide H3K4me3 domains, suggesting a role for this epigenetic element. Overall, we demonstrate that reprogramming of bivalent and broad domains represents key epigenetic alterations in metastatic melanoma, and that EZH2 plus MEK inhibition may provide a promising therapeutic strategy for NRAS-mutant melanoma patients. Comprehensive chromatin state profiling and analysis of metastatic melanoma by performing ChIP-sequencing of 6 core histone modifications. Chromatin profiling for H3K4me3 and H3K27me3 in NRAS-mutant MSTC and NRAS-mutant isogenic melanocytes.