title: Loss of Tet1-Associated 5-Hydroxymethylcytosine Is Concomitant with Aberrant Promoter Hypermethylation in Liver Cancer.
abstract: Aberrant hypermethylation of CpG islands (CGI) in human tumors occurs predominantly at repressed genes in the host tissue, but the preceding events driving this phenomenon are poorly understood. In this study, we temporally tracked epigenetic and transcriptomic perturbations that occur in a mouse model of liver carcinogenesis. Hypermethylated CGI events in the model were predicted by enrichment of the DNA modification 5-hydroxymethylcytosine (5hmC) and the histone H3 modification H3K27me3 at silenced promoters in the host tissue. During cancer progression, selected CGIs underwent hypo-hydroxymethylation prior to hypermethylation, while retaining H3K27me3. In livers from mice deficient in Tet1, a tumor suppressor involved in cytosine demethylation, we observed a similar loss of promoter core 5hmC, suggesting that reduced Tet1 activity at CGI may contribute to epigenetic dysregulation during hepatocarcinogenesis. Consistent with this possibility, mouse liver tumors exhibited reduced Tet1 protein levels. Similar to humans, DNA methylation changes at CGI in mice did not appear to be direct drivers of hepatocellular carcinoma progression, rather, dynamic changes in H3K27me3 promoter deposition correlated strongly with tumor-specific activation and repression of transcription. Overall, our results suggest that loss of promoter-associated 5hmC in liver tumors licenses reprograming of DNA methylation at silent CGI during progression. Cancer Res; 76(10); 3097-108. ©2016 AACR.
authors.affiliation: MRC Human Genetics Unit at the Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: John P
authors.initials: JP
authors.lastname: Thomson
authors.affiliation: MRC Human Genetics Unit at the Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Ottaviano
authors.affiliation: Department of Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Tübingen, Tübingen, Germany.
authors.forename: Elif B
authors.initials: EB
authors.lastname: Unterberger
authors.affiliation: Preclinical Safety, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Harri
authors.initials: H
authors.lastname: Lempiäinen
authors.affiliation: Preclinical Safety, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Arne
authors.initials: A
authors.lastname: Muller
authors.affiliation: Preclinical Safety, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Remi
authors.initials: R
authors.lastname: Terranova
authors.affiliation: MRC Human Genetics Unit at the Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Illingworth
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Shaun
authors.initials: S
authors.lastname: Webb
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Alastair R W
authors.initials: AR
authors.lastname: Kerr
authors.affiliation: University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Lyall
authors.affiliation: University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Drake
authors.affiliation: Medical Research Institute, University of Dundee, Ninewells Hospital & Medical School, Dundee, United Kingdom.
authors.forename: C Roland
authors.initials: CR
authors.lastname: Wolf
authors.affiliation: Preclinical Safety, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Moggs
authors.affiliation: Department of Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Tübingen, Tübingen, Germany. Richard.Meehan@igmm.ed.ac.uk michael.schwarz@uni-tuebingen.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Schwarz
authors.affiliation: MRC Human Genetics Unit at the Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, United Kingdom. Richard.Meehan@igmm.ed.ac.uk michael.schwarz@uni-tuebingen.de.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Meehan
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives* / Q000633:toxicity; D000818:Animals; D006528:Carcinoma, Hepatocellular; D002454:Cell Differentiation; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C540839:TET1 protein, mouse; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine