TET dioxygenases

TET dioxygenases (TET stands for: Ten-Eleven-Translocation-Dioxygenases). TET dioxygenases are key enzymes for the dynamic control of DNA methylation. By oxidizing 5mC, they enable both active DNA demethylation and the establishment of new epigenetic states and are therefore essential for development, cell identity and disease development.

It is an enzyme class of Fe(II)/alpha-ketoglutarate-dependent dioxygenases that are mainly localized in the cell nucleus.

Family and members (in mammals)

• TET1
• TET2
• TET3

Its substrate in DNA is 5-methylcytosine (5mC). This leads to a stepwise oxidation of 5mC to 5-hydroxymethylcytosine (5hmC) to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC)

Molecular biological significance:

• Initiation of active DNA demethylation
• Generation of stable epigenetic marks (e.g. 5hmC as a separate epigenetic signal)

Biological role

• Development: early development, stem cell pluripotency, reprogramming
• Gene regulation: influence on chromatin structure and transcriptional activity
• Immunology and hematopoiesis: Important for differentiation and function of immune cells
• Brain: High 5hmC levels in neurons; relevant for learning and memory processes

Regulation

• Cofactors: Fe²⁺, α-ketoglutarate (from the citrate cycle), O₂
• Modulators: Vitamin C (ascorbate) can increase activity; oncogenic mutations (e.g. in IDH1/2) can inhibit via altered α-KG/succinate ratio.
• Post-translational modifications: phosphorylation, O-GlcNAcylation, etc.

Tumor diseases: TET2 mutations common in myeloid neoplasms (e.g. AML, MDS), alteration of 5hmC profiles in solid tumors

Neurological diseases: Associations with neurodegenerative diseases and psychiatric disorders

Therapeutic potential: target structure for epigenetic therapies, biomarker for disease diagnosis

1. Ginno PA et al. (2020) A Genome-Scale Map of DNA Methylation Turnover Identifies Site-Specific Dependencies of DNMT and TET Activity. Nature Communications 11: 2680.
2. Schubeler D (2015) Function and Information Content of DNA Methylation. Nature 517: 321-326.
3. Yin Y et al. (2017) Impact of Cytosine Methylation on DNA Binding Specificities of Human Transcription Factors. Science 356: eaaj2239.