Methylcytosine dioxygenase TET3 (TET3) (TET3)

Methylcytosine dioxygenase TET3 (TET3) is a member of the Ten-eleven translocation family of enzymes that play a central role in epigenetic regulation through active DNA demethylation [1, 11]. It functions as a Fe(II)- and 2-oxoglutarate-dependent dioxygenase, sequentially oxidizing 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) [1, 5, 11]. TET3 is specifically critical for zygotic paternal DNA reprogramming and is induced during the differentiation of embryonic stem cells to regulate lineage specification and neuronal plasticity [12, 16]. In clinical contexts, TET3 dysregulation is associated with numerous pathologies: its inactivation or deficiency causes Beck-Fahrner syndrome (a neurodevelopmental disorder), while its overexpression in specific macrophage populations drives chronic inflammation in conditions like metabolic dysfunction-associated steatohepatitis (MASH) and endometriosis [10, 15, 19]. Though direct therapeutic targeting is in early stages, Vitamin C is a known cofactor that enhances its activity, and experimental small-molecule inhibitors and degraders are being developed to modulate its epigenetic function in cancer and inflammatory diseases [5, 6, 10, 17].

Other names

Ten-eleven translocation 3Ten-eleven translocation methylcytosine dioxygenase 3TET3 methylcytosine dioxygenaseCXXC-type zinc finger protein 10

TET3 activity is modulated by cofactors like Vitamin C that enhance its catalytic oxidation of 5-methylcytosine, or by small-molecule inhibitors and degraders that prevent its association with target promoters or reduce its protein levels to suppress pathogenic gene expression and global DNA demethylation [5, 6, 10, 17].