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Loss of Tet1 associated 5-hydroxymethylcytosine is concomitant with aberrant promoter hypermethylation in liver cancer.

Thomson, JP and Ottaviano, R and Unterberger, E and Lempiainen, H and Mueller, Arne and Terranova, Remi and Illingworth, RS and Webb, S and Kerr, AR and Drake, A and Lyall, M and Wolf, CR and Moggs, Jonathan and Schwarz, M and Meehan, R (2016) Loss of Tet1 associated 5-hydroxymethylcytosine is concomitant with aberrant promoter hypermethylation in liver cancer. Cancer Research.

Abstract

We have previously shown that aberrant hyper-methylation of CpG islands (CGIs) in human cancers occurs
predominantly at repressed genes in the host tissue. We report that hyper-methylated CGI events in mice
occurring in hepatocarcinogenesis are also predicated by silent promoters in the host tissue that are enriched for the DNA modification 5-hydroxymethylcytosine (5hmC) and the histone modification H3K27me3. During cancer progression these CGIs undergo hypo-hydroxymethylation, prior to subsequent hyper-methylation; whilst retaining H3K27me3. A similar loss of promoter-core 5hmC is observed in Tet1 deficient mouse livers indicating that reduced Tet1 activity at CGIs may be responsible for the epigenetic dysregulation observed during hepatocarcinogenesis. Consistent with this, reduced Tet1 protein levels are observed in mouse liver tumour lesions. As in human, DNA methylation changes at CGIs do not appear to be direct drivers of hepatocellular carcinoma progression in mice. Instead dynamic changes in H3K27me3 promoter deposition are strongly associated with tumour-specific activation and repression of transcription. Our data suggests that loss of promoter associated 5hmC in diverse liver tumours licences DNA methylation reprogramming at silent CGIs during cancer progression.

Item Type: Article
Keywords: non-genotoxic carcinogenesis; DNA methylation; phenobarbital; rodent; tumor, Tet1, 5-hydroxymethylcytosine
Date Deposited: 12 Feb 2016 00:45
Last Modified: 12 Feb 2016 00:45
URI: https://oak.novartis.com/id/eprint/25446

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