TET family dioxygenases and DNA demethylation in stem cells and cancers

The methylation of cytosine and subsequent oxidation constitutes a fundamental epigenetic modification in mammalian genomes, and its abnormalities are intimately coupled to various pathogenic processes including cancer development. Enzymes of the Ten–eleven translocation (TET) family catalyze the stepwise oxidation of 5-methylcytosine in DNA to 5-hydroxymethylcytosine and further oxidation products. These oxidized 5-methylcytosine derivatives represent intermediates in the reversal of cytosine methylation, and also serve as stable epigenetic modifications that exert distinctive regulatory roles. It is becoming increasingly obvious that TET proteins and their catalytic products are key regulators of embryonic development, stem cell functions and lineage specification. Over the past several years, the function of TET proteins as a barrier between normal and malignant states has been extensively investigated. Dysregulation of TET protein expression or function is commonly observed in a wide range of cancers. Notably, TET loss-of-function is causally related to the onset and progression of hematologic malignancy in vivo. In this review, we focus on recent advances in the mechanistic understanding of DNA methylation–demethylation dynamics, and their potential regulatory functions in cellular differentiation and oncogenic transformation. Proteins that remove chemical tags from DNA play key regulatory roles in cell development and the initiation of cancer. In a review article, Myunggon Ko from the Ulsan National Institute of Science and Technology in South Korea and colleagues describe how enzymes of the Ten-eleven translocation (TET) family reverse the methylation of cytosine in DNA, affecting cellular differentiation, embryonic development and cancer. The researchers detail the mechanisms by which TET proteins remove methyl groups from cytosine residues in a stepwise manner. The absence of functional TET has been implicated in a wide range of human cancers, in particular, cancers of the blood cells. In mouse models, reintroducing TET activity into blood stem cells helped prevent leukemia, suggesting that restoring TET function in people could have therapeutic benefit for cancer patients.