Abstract 4314: Chromatin state alterations during melanoma progression

The extent and nature of epigenomic changes associated with melanoma progression is poorly understood. To determine chromatin state patterns of human metastatic melanomas, we defined epigenome of melanoma by profiling 6 histone modification marks (H3K4me, H3K27Ac, H3K4me3, H3K79me2, H3K27me3 and H3K9me3) in 48 metastatic melanoma tumors, cell lines and short-term cultures. Computation of chromatin states identified specific chromatin state aberrations in human tumors and their relationship with specific genotypes. Specifically, we defined patterns of enhancer elements, broad H3K4me3 domains and bivalent chromatin states enriched in specific genotypes of BRAF, NRAS, and WT groups of melanomas. Importantly, we identified switch from specific bivalent chromatin states in melanocytes to active states leading to upregulation of EMT genes in NRAS mutant melanomas. Similarly, we noted gains of broad H3K4me3 domains in particular classes of oncogenes in specific gentoypes as well as during transitions from melanocytes to melanomas. Finally, we identified clusters of enhancers that are specifically enriched in subset of melanoma samples defining intertumor epigenetic heterogeneity in melanoma tumors. In addition, to investigate chromatin state changes associated with early stages of melanoma progression, we systematically profiled 35 epigenetic modifications in a cell phenotypic model of non-tumorigenic and tumorigenic states (and verified in human nevi and melanoma samples). Specific chromatin state transitions featuring loss of histone acetylations and H3K4me2/3 were observed on specific promoter and enhancer elements targeting cancer-regulatory genes in important melanoma-driving cell signaling pathways. Intriguingly, only a small fraction of chromatin state transitions correlated with expected changes in gene expression patterns. Restoration of acetylation levels on deacetylated loci by histone deacetylase (HDAC) inhibitors selectively blocked excessive proliferation in tumorigenic cells and human melanoma cells, suggesting functional roles of observed chromatin state transitions in driving hyperproliferative phenotype. Overall, our study reveals principles of epigenetic reprogramming in melanoma progression stages and how they may establish transcriptional programs that impart aggressive characteristics to melanomas. Citation Format: Kunal Rai, Christopher Terranova, Mayinuer Maitituoheti, Ming Tang, Kadir Akdemir, Elias Orouji, Lynda Chin, Petko Fiziev, Mayura Dhamdhere, Neha S. Samant, Amikhsha Shah, Sneha Sharma, Jason Ernst. Chromatin state alterations during melanoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4314.