Structure and Function of TET Enzymes

Mammalian DNA methylation mainly occurs at the carbon-C5 position of cytosine (5mC). TET enzymes were discovered to successively oxidize 5mC to 5-hydromethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). Ten-eleven translocation (TET) enzymes and oxidized 5mC derivatives play important roles in various biological and pathological processes, including regulation of DNA demethylation, gene transcription, embryonic development, and oncogenesis. In this chapter, we will discuss the discovery of TET-mediated 5mC oxidation and the structure, function, and regulation of TET enzymes. We start with brief descriptions of the mechanisms of TET-mediated 5mC oxidation and TET-dependent DNA demethylation. We then discuss the TET-mediated epigenetic reprogramming in pluripotency maintenance and embryogenesis, as well as in tumorigenesis and neural system. We further describe the structural basis for substrate recognition and preference in TET-mediated 5mC oxidation. Finally, we summarize the chemical molecules and interacting proteins that regulate TET’s activity.