The Roles of H3K4 Methylation Marks

H3K4me1, H3K4me2 and H3K4me3 are generally associated with active gene transcription [116]. Although partially overlapping with H3K4me3 at the 5'-end level of transcribing genes, H3K4me2 decorates genomic regions independently of H3K4me3 [117]. H3Kme2's role as a biomarker in the diagnosis and prognosis of CM patients has been suggested by several studies. For example, Uzdensky at al. found elevated levels of H3K4me2 in tumor samples compared to paired normal skin [118]. Later on, Kampilafkos at al. observed that H3K4me2 and H3K27me3 levels were lower in metastatic compared to primary melanomas and that combined IHC analysis of H3K4me2, H3K27me3, and EZH2 may help identify cancer cells with stem cell-like behaviors, particularly at the invasion front of CM [72]. This study highlighted that the combination of several genetic alterations may be more relevant for characterizing and predicting complex events such as metastasis and that all these epigenetic changes can be integrated as a code that can provide valuable information about the biology of melanocytic tumors.

H3K4me3 is a chromatin landmark of promoters of transcriptionally active genes or genes poised for activation in mammalian cells [116]. In particular, for CM, Cheng at al. observed that human metastatic tissues are highly heterogeneous in terms of H3K4me3 levels [115]. Further analysis showed that metastatic lesions that displayed low levels of H3K4me3 were associated with repressed genes in embryonic stem cells (ESCs) and PRC2-target genes. In contrast, elevated H3K4me3 levels correlated with interferon and inflammatory response genes [115]. However, Terranova at al. found that metastatic melanomas harbor exceptionally wide H3K4me3 domains [119]. These domains can span tens of thousands of kilobases, and appear to be involved in the regulation of several EMT transcription factors (POU3F2, SOX9, and PDGFRA) as well as melanocyte-specific master regulators (MITF, ZEB2, and TFAP2A) [120]. Terranova et al. finally highlighted that particular events such as BRAF or NRAS mutations may employ specific chromatin states (bivalent states and broad H3K4me3 domains) to orchestrate transcriptional changes unique to a genotype, suggesting that epigenetic mechanisms play important roles in regulating CM behaviors [119].
