A TET2–DNMT1 Complex Prevents Abnormal DNA Methylation

The TET proteins promote DNA demethylation by converting 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). TET2 is frequently mutated or inactivated in cancer, and it has been suggested that the TET proteins may protect against abnormal DNA methylation at promoters. Zhang and colleagues found that the enzymatic activity of TET2 was enhanced by acetylation at K110 by p300, and, conversely, that TET2 activity was reduced by HDAC1/2-mediated deacetylation. Acetylation stabilized TET2 by preventing its ubiquitination and subsequent proteasomal degradation, thereby increasing TET2 activity. Mechanistically, TET2 acetylation enhanced the interaction between TET2 and the DNA methyltransferase DNMT1, which increased the stability of both proteins. Oxidative stress has been previously associated with abnormal methylation and recruitment of DNMT complexes to promoter CpG islands, and, consistent with these findings, acetylation of TET2 promoted its DNMT1-dependent association with chromatin under conditions of oxidative stress. TET2 bound to thymine-DNA glycosylase (TDG), which is required for TET2-mediated demethylation. The TET2–TDG interaction was independent of TET2 acetylation, but oxidative stress recruited acetylated TET2–TDG to chromatin in a DNMT-dependent manner. Enhanced TET2 activity and chromatin binding was associated with increased global levels of 5hmC and a global decrease in DNA methylation. Depletion of TET2 induced DNA hypermethylation especially at promoter CpG islands, resulting in downregulation of genes including those with bivalent chromatin in embryonic stem cells, many of which are involved in development, differentiation, or transcriptional regulation. Taken together, these results indicate that TET2 may oppose the function of DNMT1 in TET2–DNMT1 complexes, and suggest that TET2 activity may protect against abnormal DNA methylation under conditions of oxidative stress. Further, these findings raise the possibility that HDAC inhibitors may potentially be used to maintain TET2 activity and prevent aberrant DNA methylation in patients with cancer.

Zhang YW, Wang Z, Xie W, Cai Y, Xia L, Easwaran H, et al. Acetylation enhances TET2 function in protecting against abnormal DNA methylation during oxidative stress. Mol Cell 2017;65:323–35.

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