Figure 3. The evolving “TETris playground”.

A picture is emerging in which TETs build up specific “DNA modification blocks” (hmC, fC, caC) through their coordinated regulation at multiple levels. The following sequence of events can therefore be suggested: (i) Transcription factors will result in (ii) 5hmC, 5fC, and 5caC formation with 5hmC being more abundant in gene bodies. (iii) These modifications can be further bound by various “binders” or “readers” that will either participate in DNA demethylation or translate the epigenetic signal to transcriptional activation or repression. Other active players are transcriptional regulators and small molecules such as vitamin C that directly affect TET activity and hence the deposition of 5hmC, 5fC, and 5caC. These DNA modification blocks, TETs, and TET regulators can assemble in a gene- and/or a cell-state-dependent manner creating precise landscapes which will ultimately affect gene expression.