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Distinct and overlapping control of 5-methylcytosine and 5-hydroxymethylcytosine by the TET proteins in human cancer cells

Emily L Putiri1, Rochelle L Tiedemann12, Joyce J Thompson1, Chunsheng Liu1, Thai Ho3, Jeong-Hyeon Choi2 and Keith D Robertson1*

Author Affiliations

1 Department of Molecular Pharmacology and Experimental Therapeutics and Center for Individualized Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA

2 Cancer Center, Georgia Regents University, 1411 Laney Walker Blvd, Augusta, GA 30912, USA

3 Department of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ 85259, USA

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Genome Biology 2014, 15:R81  doi:10.1186/gb-2014-15-6-r81

Published: 23 June 2014

Abstract

Background

The TET family of dioxygenases catalyze conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), but their involvement in establishing normal 5mC patterns during mammalian development and their contributions to aberrant control of 5mC during cellular transformation remain largely unknown. We depleted TET1, TET2, and TET3 in a pluripotent embryonic carcinoma cell model and examined the impact on genome-wide 5mC, 5hmC, and transcriptional patterns.

Results

TET1 depletion yields widespread reduction of 5hmC, while depletion of TET2 and TET3 reduces 5hmC at a subset of TET1 targets suggesting functional co-dependence. TET2 or TET3 depletion also causes increased 5hmC, suggesting these proteins play a major role in 5hmC removal. All TETs prevent hypermethylation throughout the genome, a finding dramatically illustrated in CpG island shores, where TET depletion results in prolific hypermethylation. Surprisingly, TETs also promote methylation, as hypomethylation was associated with 5hmC reduction. TET function is highly specific to chromatin environment: 5hmC maintenance by all TETs occurs at polycomb-marked chromatin and genes expressed at moderate levels; 5hmC removal by TET2 is associated with highly transcribed genes enriched for H3K4me3 and H3K36me3. Importantly, genes prone to hypermethylation in cancer become depleted of 5hmC with TET deficiency, suggesting that TETs normally promote 5hmC at these loci. Finally, all three TETs, but especially TET2, are required for 5hmC enrichment at enhancers, a condition necessary for expression of adjacent genes.

Conclusions

These results provide novel insight into the division of labor among TET proteins and reveal important connections between TET activity, the chromatin landscape, and gene expression.