Genome wide profiling of 5-formylcytosine and 5-carboxylcytosine in melanoma
Rabidou, Kimberlie Ann Marques
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Malignant melanoma, which comprises only 2% of skin cancers cases, but is the most lethal form of skin cancer. With the prevalence of melanoma continuing to rise, there is a greater need to elucidate the mechanisms underlying disease initiation and progression. Because mutations in melanoma-associated genes account for only 10% of cases, epigenome-altering environmental factors must have a role in pathogenesis. DNA methylation and demethylation are key epigenetics processes which govern cell differentiation and development. 5-methylcytosine (5mC) is a key epigenetic mark, which undergoes oxidation to 5-hydroxymethylcytosine (5hmC), 5formylcytosine (5fC) and 5carboxycytosine (5caC) during demethylation. In melanoma, it has been established that the loss of 5hmC is a cancer hallmark and is associated with poor prognostic outcome. The roles of 5fC/5caC, however, are not known. Here, I aimed to investigate the role of 5fC/5caC in melanoma and its contribution to disease development. Using methylase-assisted bisulfite sequencing, I have mapped the genome-wide distribution of 5fC/5caC at base pair resolution in two melanoma cell lines, A2058 and Mel Juso. In both cell lines, this modification is enriched at distal regulatory elements. Comparisons of differentially methylated sites and regions between the cell lines revealed that the products of 5fC/5caC enriched genes participate in cell adhesion and cell signaling, both of which are altered during melanoma initiation and progression. Increased levels of 5fC/5caC in these genes may be a contributing factor to this deregulation. Through these studies, we aim to identify distinct regions undergoing alterations in melanoma, which can serve as diagnostic and prognostic biomarkers.