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Nat Commun. 2016 Nov 25;7:13177. doi: 10.1038/ncomms13177.

5-Hydroxymethylcytosine localizes to enhancer elements and is associated with survival in glioblastoma patients.

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Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756, USA.
Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756, USA.
Department of Biostatistics, College of Public Health and Human Sciences, Oregon State University, Corvallis, Oregon 97331, USA.
Department of Neurology, University of Virginia, Charlottesville, Virginia 22908, USA.


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.

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