What is TET DNA demethylation

Tet DNA demethylation refers to the process by which methyl groups are removed from cytosines in DNA, primarily through the action of TET (Ten-Eleven Translocation) enzymes.

These enzymes play a key role in epigenetic regulation by catalyzing the oxidation of 5-methylcytosine (5mC), an important DNA modification, leading to DNA demethylation.

Overview of TET Enzymes

There are three TET enzymes in mammals:

1. TET1
2. TET2
3. TET3

These enzymes are dioxygenases that require cofactors such as Fe²⁺ (iron) and α-ketoglutarate to function.

---

Mechanism of TET-Mediated DNA Demethylation

The process of TET-mediated DNA demethylation occurs in following steps:

1. TET enzymes catalyze the oxidation of 5-methylcytosine (5mC) to form:
   • 5-hydroxymethylcytosine (5hmC)
   • 5-formylcytosine (5fC)
   • 5-carboxylcytosine (5caC)
2. Base Excision Repair (BER) Pathway
   • 5fC and 5caC can be recognized and excised by the enzyme thymine DNA glycosylase (TDG).
   • The gap left in the DNA is then filled with an unmodified cytosine through the base excision repair pathway.
3. In some cases, the oxidized forms (e.g., 5hmC) are not immediately removed but instead diluted out during DNA replication. This is called passive demethylation and occurs because the DNA methyltransferase enzymes fail to methylate the oxidized bases during replication.
4. When the oxidized cytosines are removed via the BER pathway, the process is called active demethylation because it doesn’t rely on DNA replication.

---

What is the Biological Functions of TET-Mediated DNA Demethylation

1. Ten-Eleven Translocation enzymes regulate gene expression by altering DNA methylation patterns, especially in developmental and stem cells.
   
2. TET activity is essential for embryonic development and differentiation of stem cells into various cell types.
   
3. Mutations in TET2 are commonly found in hematological cancers like myelodysplastic syndromes and acute myeloid leukemia (AML). These mutations often lead to hypermethylation and silencing of tumor suppressor genes.
   
4. TET enzymes and 5hmC are highly enriched in the brain, where they are involved in neurodevelopment, synaptic plasticity, and memory formation.