title: 5-Hydroxymethylcytosine localizes to enhancer elements and is associated with survival in glioblastoma patients.
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.
authors.affiliation: 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.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Johnson
authors.affiliation: Department of Biostatistics, College of Public Health and Human Sciences, Oregon State University, Corvallis, Oregon 97331, USA.
authors.forename: E Andres
authors.initials: EA
authors.lastname: Houseman
authors.affiliation: 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.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: King
authors.affiliation: 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.
authors.forename: Katharine M
authors.initials: KM
authors.lastname: von Herrmann
authors.affiliation: Department of Neurology, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Camilo E
authors.initials: CE
authors.lastname: Fadul
authors.affiliation: 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.
authors.forename: Brock C
authors.initials: BC
authors.lastname: Christensen
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics* / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D005909:Glioblastoma / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D017397:Prefrontal Cortex / Q000378:metabolism / Q000473:pathology; D016019:Survival Analysis; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D004273:DNA, Neoplasm; D014157:Transcription Factors; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human