TET enzymes, DNA demethylation and pluripotency

Abstract Ten-eleven translocation (TET) methylcytosine dioxygenases (TET1, TET2, TET3) actively cause demethylation of 5-methylcytosine (5mC) and produce and safeguard hypomethylation at key regulatory regions across the genome. This 5mC erasure is particularly important in pluripotent embryonic stem cells (ESCs) as they need to maintain self-renewal capabilities while retaining the potential to generate different cell types with diverse 5mC patterns. In this review, we discuss the multiple roles of TET proteins in mouse ESCs, and other vertebrate model systems, with a particular focus on TET functions in pluripotency, differentiation, and developmental DNA methylome reprogramming. Furthermore, we elaborate on the recently described non-catalytic roles of TET proteins in diverse biological contexts. Overall, TET proteins are multifunctional regulators that through both their catalytic and non-catalytic roles carry out myriad functions linked to early developmental processes.