TET enzymes
5-Methylcytosine (see first Figure) is a methylated form of the DNA base cytosine (C) that often regulates gene transcription and has several other functions in the genome.
TET enzymes have central roles in DNA demethylation required during embryogenesis, gametogenesis, memory, learning, addiction and pain perception.
IDAX is thought to play a role in regulating TET2 activity by facilitating its recruitment to unmethylated CpGs.
The dominant TET1 isoform in most somatic tissues, at least in the mouse, arises from alternative promoter usage which gives rise to a short transcript and a truncated protein designated TET1s.
[11] Then EGR1 and TET1 appear to cooperate in demethylating and thereby activating the expression of genes downstream of the EGR1 binding sites in DNA.
Physical processivity refers to the ability of a TET protein to slide along the DNA from one CpG site to another.
Chemical processivity refers to the ability of TET to catalyze the oxidation of 5mC iteratively to 5caC without releasing its substrate.
The TET enzymes each harbor a core catalytic domain with a double-stranded β-helix fold that contains the crucial metal-binding residues found in the family of Fe(II)/α-KG- dependent oxygenases.
[16] α-KG coordinates as a bidentate ligand (connected at two points) to Fe(II) (see Figure), while the 5mC is held by a noncovalent force in close proximity.
[17] These include, for instance, TET2 interaction with O-linked N-acetylglucosamine (O-GlcNAc) transferase to promote histone O-GlcN acylation to affect transcription of target genes.
[19] After fertilization, early in the first day of embryogenesis, the paternal chromosomes are almost completely demethylated in six hours by an active TET-dependent process, before DNA replication begins (blue line in Figure).
As reviewed by Messerschmidt et al.,[21] the majority of PGCs are arrested in the G2 phase of the cell cycle while they migrate toward the hindgut during embryo days 7.5 to 8.5.
One particular TET enzyme, TET1, and TDG are present at high levels from embryo day 9.5 to 13.5,[22] and are employed in active TET-dependent demethylation during gametogenesis.
[21] PGC genomes display the lowest levels of DNA methylation of any cells in the entire life cycle of the mouse by embryonic day 13.5.
[23] Learning and memory have levels of permanence, differing from other mental processes such as thought, language, and consciousness, which are temporary in nature.
Learning and memory can be either accumulated slowly (multiplication tables) or rapidly (touching a hot stove), but once attained, can be recalled into conscious use for a long time.
There were 1,223 differentially methylated genes in the anterior cingulate cortex (see Figure) of mice four weeks after contextual fear conditioning.
Li et al.[27] reported one example of the relationship between expression of a TET protein, demethylation and memory while using extinction training.
Extinction training led to a significant increase in TET3 messenger RNA levels within cortical neurons.
Reduced Tet1 expression caused by shRNA injected into the NAc robustly enhanced cocaine place conditioning.
Nociception triggers a variety of physiological and behavioral responses and usually results in a subjective experience, or perception, of pain.
On the other hand, forced overexpression of TET1 or TET3 for 2 consecutive days significantly produced pain-like behavior as evidenced by a decrease in the mouse of the thermal pain threshold.
They further showed that the nociceptive pain effects occurred through TET mediated conversion of 5-methylcytosine to 5-hydroxymethylcytosine in the promoter of a microRNA designated miR-365-3p, thus increasing its expression.
This microRNA, in turn, ordinarily targets (decreases expression of) the messenger RNA of Kcnh2, that codes for a protein known as Kv11.1 or KCNH2.
