Systematic Epigenomic Analysis Reveals Chromatin States Associated with Melanoma Progression

Abstract

Summary The extent and nature of epigenomic changes associated with melanoma progression is poorly understood. Through systematic epigenomic profiling of 35 epigenetic modifications and transcriptomic analysis, we define chromatin state changes associated with melanomagenesis using a cell phenotypic model of non-tumorigenic and tumorigenic states. Computation of specific chromatin state transitions showed loss of histone acetylations and H3K4me2/3 on regulatory regions proximal to specific cancer-regulatory genes in important melanoma-driving cell signaling pathways. Importantly, such acetylation changes were also observed between benign nevi and malignant melanoma human tissues. 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 HDAC inhibitors selectively blocked excessive proliferation in tumorigenic cells and human melanoma cells suggesting functional roles of observed chromatin state transitions in driving hyper-proliferative phenotype. Taken together, we define functionally relevant chromatin states associated with melanoma progression.

MC1R CpG island regulates MC1R expression and is methylated in a subset of melanoma tumours

“…To investigate this we looked at histone modification datasets in melanocytes from two datasets. The first study (Fiziev et al, 2017;GSE58953) found the region around the CGI is annotated as a weak enhancer weakly acetylated in one To further characterise the methylation pattern, we analysed the cutaneous skin melanoma cohort from The Cancer Genome Atlas (TCGA). Total of 460 samples contained data for DNA methylation and mRNA expression of MC1R, as well as survival data.…”

“…To investigate this we looked at histone modification datasets in melanocytes from two datasets. The first study (Fiziev et al, ; GSE58953) found the region around the CGI is annotated as a weak enhancer weakly acetylated in one melanocyte cell line. The second study (Fontanals‐Cirera et al, ; GSE94488) reported markers of enhancers were present within the region of MC1R in melanocytes but not directly overlapping with the CGI in our study.…”

Chromatin-state discovery and genome annotation with ChromHMM

“…In the context of human disease, ChromHMM annotations have been analyzed in conjunction with genome-wide association studies (GWAS) for predicting the cell types relevant to human traits or predicting mechanism of individual GWAS identified loci 1,4,27,28 . ChromHMM has had applications to studying diseases such as Alzheimer’s disease 29,30 , neurodegeneration 31 , type 2 diabetes 32 and cancer 33–36 , among many other diseases. ChromHMM has also been used for studying chromatin state variation across individuals 37 , chromatin state changes across different Drosophila species 38 , and aging 39,40 , among many other applications.…”

Epigenetics in Melanoma Development and Drug Resistance

“…Specifically, chromatin state transitions characterized by loss of histone acetylation marks like H3K27Ac, H2BK5Ac and H4K5Ac and di-/trimethylation of H3K4 in regulatory domains associated with signaling pathways important for melanoma including phosphatidylinositol 3-kinase (PI3K), interferon (IFN) γ-, LKB1-, TRAILand platelet-derived growth factor (PDGF)-mediated signaling was observed, again emphasizing the link between epigenetic changes and melanoma development and progression [52].…”