Abstract
Glioblastomas exhibit widespread molecular alterations including a highly distorted epigenome. Here, we resolve genome-wide 5-methylcytosine and 5-hydroxymethylcytosine in glioblastoma through parallel processing of DNA with bisulfite and oxidative bisulfite treatments. We apply a statistical algorithm to estimate 5-methylcytosine, 5-hydroxymethylcytosine and unmethylated proportions from methylation array data. We show that 5-hydroxymethylcytosine is depleted in glioblastoma compared with prefrontal cortex tissue. In addition, the genomic localization of 5-hydroxymethylcytosine in glioblastoma is associated with features of dynamic cell-identity regulation such as tissue-specific transcription and super-enhancers. Annotation of 5-hydroxymethylcytosine genomic distribution reveal significant associations with RNA regulatory processes, immune function, stem cell maintenance and binding sites of transcription factors that drive cellular proliferation. In addition, model-based clustering results indicate that patients with low-5-hydroxymethylcytosine patterns have significantly poorer overall survival. Our results demonstrate that 5-hydroxymethylcytosine patterns are strongly related with transcription, localizes to disease-critical genes and are associated with patient prognosis.
Highlights
Glioblastomas exhibit widespread molecular alterations including a highly distorted epigenome
Gliomas that carry mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes have been shown to harbour a pattern of DNA hypermethylation at certain promoter regions which results in a glioma CpG island methylator phenotype (G-CIMP)[8]
Our study provides evidence that a perturbed hydroxymethylome in glioblastoma may reflect progressive disruption of genomic stability and that loss of 5 hmC regulation is a potential indicator of disease progression
Summary
Glioblastomas exhibit widespread molecular alterations including a highly distorted epigenome. The genomic localization of 5-hydroxymethylcytosine in glioblastoma is associated with features of dynamic cell-identity regulation such as tissue-specific transcription and super-enhancers. Our results demonstrate that 5-hydroxymethylcytosine patterns are strongly related with transcription, localizes to disease-critical genes and are associated with patient prognosis. Systematic molecular analyses have advanced our understanding of glioblastoma pathobiology through the identification of common mutations, structural-based genetic alterations and dysregulated epigenomes[3,4,5]. Among these molecular alterations, severe disturbance of the glioblastoma epigenome has been observed, especially perturbations to global DNA 5-methylcytosine (5 mC) patterns[6,7,8,9]. It has been demonstrated that use of paired BS and oxBS treatment on the same samples followed by hybridization to the Infinium DNA methylation array reliably permits accurate quantification of 5 hmC and 5 mC19,20
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