RT Journal
A1 Li, Xin
A1 Liu, Yun
A1 Salz, Tal
A1 Hansen, Kasper D.
A1 Feinberg, Andrew
T1 Whole-genome analysis of the methylome and hydroxymethylome in normal and malignant lung and liver
JF Genome Research 
JO Genome Research 
YR 2016 
FD December 01 
VO 26 
IS 12 
SP 1730 
OP 1741 
DO 10.1101/gr.211854.116 
UL http://genome.cshlp.org/content/26/12/1730.abstract 
AB 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.