Figure 2. Modulation of TET protein expression and function.

In addition to the coding region mutations in TET genes, TET protein expression and activity can be modulated in a variety of ways. TET transcription or translation could be inhibited by promoter methylation, microRNAs, mutations in regulatory sequences (i.e. promoters, enhancers or splice sites) or altered transcription factor expression or function. TET protein levels could be regulated by proteolysis mediated by caspase or calpain. Ubiquitylation of TET2 protein by E3 ligases CRL4^VprBP and interactions with other proteins such as WT1, IDAX and PGC7 that are important for recruiting TET proteins to specific chromatin regions are known to regulate its DNA binding activity. TET function can also be modulated by IDH mutations leading to the production of 2-hydroxyglutarate or alterations in cellular metabolic status (i.e. hypoxia, Fe²⁺ levels or redox state).