Insights into the Biochemistry, Evolution, and Biotechnological Applications of the Ten-Eleven Translocation (TET) Enzymes

Abstract

A tight link exists between patterns of DNA methylation at carbon 5 of cytosine and differential gene expression in mammalian tissues. Indeed, aberrant DNA methylation results in various human diseases, including neurologic and immune disorders, and contributes to the initiation and progression of various cancers. Proper DNA methylation depends on the fidelity and control of the underlying mechanisms that write, maintain, and erase these epigenetic marks. In this Perspective, we address one of the key players in active demethylation: the ten-eleven translocation enzymes or TETs. These enzymes belong to the Fe²⁺/α-ketoglutarate-dependent dioxygenase superfamily and iteratively oxidize 5-methylcytosine (5mC) in DNA to produce 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxycytosine. The latter three bases may convey additional layers of epigenetic information in addition to being intermediates in active demethylation. Despite the intense interest in understanding the physiological roles TETs play in active demethylation and cell regulation, less has been done, in comparison, to illuminate details of the chemistry and factors involved in regulating the three-step oxidation mechanism. Herein, we focus on what is known about the biochemical features of TETs and explore questions whose answers will lead to a more detailed understanding of the in vivo modus operandi of these enzymes. We also summarize the membership and evolutionary history of the TET/JBP family and highlight the prokaryotic homologues as a reservoir of potentially diverse functionalities awaiting discovery. Finally, we spotlight sequencing methods that utilize TETs for mapping 5mC and its oxidation products in genomic DNA and comment on possible improvements in these approaches.