Genome-wide DNA methylation changes in Oral Submucous Fibrosis.

Abstract

OBJECTIVE\nOral submucous fibrosis (OSF) is a debilitating potentially malignant condition of the buccal cavity characterized by extensive extracellular matrix deposition resulting in stiffness and trismus. As OSF is a progressive disease we hypothesized that there would be extensive epigenetic changes in OSF tissues.\n\n\nMATERIALS AND METHODS\nUsing the Infinium HumanMethylation450 BeadChip Array, we analyzed gross DNA methylation changes in seven OSF tissues compared to five controls. Comparison with transcriptomic data and pathway analyses were conducted to find commonly regulated genes.\n\n\nRESULTS\nA total of 3294 differentially methylated regions mapping to 857 genes were identified. Comparison with transcriptome data revealed 38 downregulated-hypermethylated genes; and 55 hypomethylated-upregulated genes. Using methylation specific- and qRT-PCR, aberrant hypomethylation and increased expression of FGF13, RPS6KA3 and ACSL4 genes was confirmed. Pathways involved in Insulin signaling, Ubiquitin-mediated proteolysis, nicotine addiction, and RAS/MAPK pathways were dysregulated, among others. Intriguingly, numerous genes located on the X chromosome were dysregulated in OSF tissues as the transcript for XIST gene was downregulated due to hypermethylation of the XIST promoter.\n\n\nCONCLUSIONS\nThis study highlights global epigenetic dysregulation of tissues of the oral cavity in OSF patients, and hints at possible X chromosomal dysregulation, previously not implicated in the pathogenesis of OSF.