TETology: Epigenetic Mastermind in Action

Cytosine methylation is a well-explored epigenetic modification mediated by DNA methyltransferases (DNMTs) which are considered "methylation writers"; cytosine methylation is a reversible process. The process of removal of methyl groups from DNA remained unelucidated until the discovery of ten-eleven translocation (TET) proteins which are now considered "methylation editors." TET proteins are a family of Fe(II) and alpha-ketoglutarate-dependent 5-methyl cytosine dioxygenases-they convert 5-methyl cytosine to 5-hydroxymethyl cytosine, and to further oxidized derivatives. In humans, there are three TET paralogs with tissue-specific expression, namely TET1, TET2, and TET3. Among the TETs, TET2 is highly expressed in hematopoietic stem cells where it plays a pleiotropic role. The paralogs also differ in their structure and DNA binding. TET2 lacks the CXXC domain which mediates DNA binding in the other paralogs; thus, TET2 requires interactions with other proteins containing DNA-binding domains for effectively binding to DNA to bring about the catalysis. In addition to its role as methylation editor of DNA, TET2 also serves as methylation editor of RNA. Thus, TET2 is involved in epigenetics as well as epitranscriptomics. TET2 mutations have been found in various malignant hematological disorders like acute myeloid leukemia, and non-malignant hematological disorders like myelodysplastic syndromes. Increasing evidence shows that TET2 plays an important role in the non-hematopoietic system as well. Hepatocellular carcinoma, gastric cancer, prostate cancer, and melanoma are some non-hematological malignancies in which a role of TET2 has been implicated. Loss of TET2 is also associated with atherosclerotic vascular lesions and endometriosis. The current review elaborates on the role of structure, catalysis, physiological functions, pathological alterations, and methods to study TET2, with specific emphasis on epigenomics and epitranscriptomics.