TET proteins in natural and induced differentiation

Abstract

The ten-eleven-translocation (TET) proteins oxidize 5-methylcytosine in DNA. Alterations in TET protein function have been linked to cancer, but TETs have also been observed to influence many cell differentiation processes. Here we review recent work assessing the contribution of TET proteins to natural and induced differentiation. Altogether these analyses have helped characterize how TETs and their enzymatic products influence DNA methylation patterns, regulatory element activity, DNA binding protein specificity and gene expression.

Figure 1

Model for enhancer regulation by TET proteins. (a) Prior to activation, enhancer DNA is tightly associated with nucleosomes and is not accessible to most transcription factors (TFs) except for pioneer TFs that are relatively insensitive to the presence of nucleosomes and DNA methylation and can recruit TET proteins to oxidize 5mC in the vicinity into 5hmC and other oxi-mC, resulting in DNA demethylation. 5hmC deposition and DNA demethylation are associated with increased accessibility of enhancers and acetylation of H3 lysine 27. By increasing enhancer accessibility and altering DNA modification landscapes, TET proteins assist the binding of additional TFs such as those that prefer unmodified C (5mC-sensitive) or 5hmC (5hmC-dependent). In addition, 5hmC may be recognized by specific reader(s), whose function may depend on the local chromatin environment. (b) Schematic representation of 5mC and 5hmC dynamics during enhancer activation. The 5mC (black) and 5hmC (green) levels are shown for the corresponding stages of enhancer activation/development/maturation in (a). Top, enhancer DNA is fully methylated before activation. Middle, TET proteins recruited by pioneer TFs convert 5mC into 5hmC and other oxi-mC. Bottom, Prolonged TET activity results in complete cytosine demethylation and depletion of both 5mC and 5hmC at the center of enhancers.