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Genome Res. 2016 Dec;26(12):1730-1741. Epub 2016 Oct 13.

Whole-genome analysis of the methylome and hydroxymethylome in normal and malignant lung and liver.

Li X1, Liu Y1,2,3, Salz T1, Hansen KD1,4,5, Feinberg A1,6,7,8.

Author information

1
Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
2
The Ministry of Education Key Laboratory of Metabolism and Molecular Medicine, Fudan University, Shanghai, China, 200032.
3
Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai, China, 200032.
4
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
5
Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA.
6
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
7
Department of Biomedical Engineering, Johns Hopkins Whiting School of Engineering, Baltimore, Maryland 21205, USA.
8
Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA.

Abstract

DNA methylation at the 5-position of cytosine (5mC) is an epigenetic modification that regulates gene expression and cellular plasticity in development and disease. The ten-eleven translocation (TET) gene family oxidizes 5mC to 5-hydroxymethylcytosine (5hmC), providing an active mechanism for DNA demethylation, and it may also provide its own regulatory function. Here we applied oxidative bisulfite sequencing to generate whole-genome DNA methylation and hydroxymethylation maps at single-base resolution in human normal liver and lung as well as paired tumor tissues. We found that 5hmC is significantly enriched in CpG island (CGI) shores while depleted in CGIs themselves, especially in active genes, which exhibit a bimodal distribution of 5hmC around CGI that corresponds to H3K4me1 modifications. Hydroxymethylation on promoters, gene bodies, and transcription termination regions (TTRs) showed strong positive correlation with gene expression within and across tissues, suggesting that 5hmC is a marker of active genes and could play a role in gene expression mediated by DNA demethylation. Comparative analysis of methylomes and hydroxymethylomes revealed that 5hmC is significantly enriched in both tissue-specific DMRs (t-DMRs) and cancer-specific DMRs (c-DMRs), and 5hmC is negatively correlated with methylation changes, especially in non-CGI-associated DMRs. These findings revealed novel reciprocity between epigenetic markers at CGI shores corresponding to differential gene expression in normal tissues and matching tumors. Overall, our study provided a comprehensive analysis of the interplay between the methylome, hydroxymethylome, and histone modifications during tumorigenesis.

PMID:
27737935
PMCID:
PMC5131824
DOI:
10.1101/gr.211854.116
[Indexed for MEDLINE]
Free PMC Article

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