DNA demethylation, Tet proteins and 5-hydroxymethylcytosine in epigenetic reprogramming: An emerging complex story

•Tet enzymes and 5hmC are implicated in epigenetic reprogramming in vivo and in vitro.•The relationship between 5hmC and DNA demethylation isn’t as simple as models suggest.•5hmC-independent functions of Tet(1-3) should be considered in future investigations.

Epigenetic reprogramming involves processes that lead to the erasure of epigenetic information, reverting the chromatin template to a less differentiated state. Extensive epigenetic reprogramming occurs both naturally during mammalian development in the early embryo and the developing germ line, and artificially in various in vitro reprogramming systems. Global DNA demethylation appears to be a shared attribute of reprogramming events, and understanding DNA methylation dynamics is thus of considerable interest. Recently, the Tet enzymes, which catalyse the iterative oxidation of 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxylcytosine, have emerged as potential drivers of epigenetic reprogramming. Although some of the recent studies point towards the direct role of Tet proteins in the removal of DNA methylation, the accumulating evidence suggests that the processes underlying DNA methylation dynamics might be more complex. Here, we review the current evidence, highlighting the agreements and the discrepancies between the suggested models and the experimental evidence.