The discovery of Ten-eleven translocation (TET) enzymes was one of the biggest recent discovery in epigenetics. They provided a mechanistic basis for a mostly hypothetical pathway, active DNA demethylation. The enzymes are named for a common translocation in cancers. A translocation can occur between chromosomes 10 and 11 creating a MLL-TET1 fusion protein (Lorsbach et al., 2003). Until recently this was what the protein was known for. In the last 5 years, TET proteins have been shown to catalyze the steps of the iterative demethylation of 5-methylcytosine (5mC) (Ito et al., 2010; Tahiliani et al., 2009). 5mC is first converted to 5-hydroxymethyl cytosine (5hmC), then 5-formylcytosine (5fC), then 5-carboxylcytosine (5caC), each by TET1-3 (Ito et al., 2011). 5fC and 5caC can both be converted to unmodified C by Terminal deoxynucleotidyl transferase (TdT).
All three TET enzymes have a CD (Cys-rich and DSBH regions) domain that uses O2 to decarboxylate α-ketoglutaric acid generating a high-valet iron oxide that converts 5mC to 5hmC (as well as 5hmC à 5fC à5caC). TET1 and TET3 also have a CXXC domain, though TET2 does not. CXXC domains typically bind unmethylated CpG dinucleotides, but in TET enzymes they bind 5mC and 5hmC (Xu et al., 2011). The exact role of the CXXC domain is not fully understood, but it is likely involved in targeting the enzyme to specific regions of the genome. The expression levels and cell-type distribution for the TET enzymes differ as well. TET1/2 are found in embryonic stem cells, while TET3 is found in the germ line (Ito et al., 2010). The significance of these differences, and the mechanisms of how TETs are regulated remain largely unknown.
The potential biological roles of these enzymes are becoming clear. It is suspected that TETs and 5mc derivatives are important in development. Active DNA demethylation of the paternal chromosomes is an important part of the early development of the fertilized zygote. TET-mediated DNA demethylation is likely to be critical for this process. The most intriguing finding regarding 5hmC is its significant enrichment in the human brain (Khare et al., 2012). It is thought that it plays a role in regulation of gene expression, but much about this base is still speculative.
TET Additional Reading
This is one the best reviews on TET proteins out there. It is specific and detailed without being difficult to read; a great intro. The authors give a good history of the discovery of the enzymes as well as their structure and function.
This is another good TET and 5hmC review. These authors speculate more on the potential roles of TET proteins and 5hmC than other reviews, but still give a nice overview of what is known about the 5hmC pathway.
- Ito, S., D’Alessio, A.C., Taranova, O.V., Hong, K., Sowers, L.C., and Zhang, Y. (2010). Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 466, 1129-1133.
- Ito, S., Shen, L., Dai, Q., Wu, S.C., Collins, L.B., Swenberg, J.A., He, C., and Zhang, Y. (2011). Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333, 1300-1303.
- Khare, T., Pai, S., Koncevicius, K., Pal, M., Kriukiene, E., Liutkeviciute, Z., Irimia, M., Jia, P., Ptak, C., Xia, M., et al. (2012). 5-hmC in the brain is abundant in synaptic genes and shows differences at the exon-intron boundary. Nat. Struct. Mol. Biol. 19, 1037-1043.
- Lorsbach, R.B., Moore, J., Mathew, S., Raimondi, S.C., Mukatira, S.T., and Downing, J.R. (2003). TET1, a member of a novel protein family, is fused to MLL in acute myeloid leukemia containing the t(10;11)(q22;q23). Leukemia 17, 637-641.
- Tahiliani, M., Koh, K.P., Shen, Y., Pastor, W.A., Bandukwala, H., Brudno, Y., Agarwal, S., Iyer, L.M., Liu, D.R., Aravind, L., and Rao, A. (2009). Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324, 930-935.
- Xu, Y., Wu, F., Tan, L., Kong, L., Xiong, L., Deng, J., Barbera, A.J., Zheng, L., Zhang, H., Huang, S., et al. (2011). Genome-wide regulation of 5hmC, 5mC, and gene expression by Tet1 hydroxylase in mouse embryonic stem cells. Mol. Cell 42, 451-464.