Tet methylcytosine dioxygenase 1
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| Location (UCSC) | Chr 10: 68.56 – 68.69 Mb | Chr 10: 62.64 – 62.74 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
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Ten-eleven translocation methylcytosine dioxygenase 1 (TET1) is a member of the TET family of enzymes, in humans it is encoded by the TET1 gene. Its function, regulation, and utilizable pathways remain a matter of current research while it seems to be involved in DNA demethylation and therefore gene regulation.[5][6]
Discovery
TET1 was first discovered in a 61-year-old patient with a rare variation of t(10;11)(q22;q23) acute myeloid leukemia (AML) as a zinc-finger binding protein (specifically on the CXXC domain) that fuses to the gene MLL.[7] Another study confirmed that this protein was a translocation partner of MLL in an 8-year-old patient with t(10;11)(q22;q23) AML and named the protein Ten-Eleven Translocation 1.[8]
Function
TET1
TET1 produces 5-hmC by
A site with a 5-hmC base already has increased transcriptional activity, a state termed "functional demethylation". This state is common in post-mitotic neurons.[11]
TET1 may play a role in memory extinction. TET1-knockout mice show markedly impaired memory extinction, despite maintaining normal memory acquisition.[12]
Applications
TET1 appears to facilitate nuclear
The enzyme is also utilized as part of TET-Assisted Bisulfite Sequencing (TAB-seq) to quantify levels of hydroxymethylation in the genome and to distinguish 5-hydroxymethylcytosine (5hmc) from 5-methylcytosine (5mc) at single base resolution. The technique was developed by Chuan He and rectifies the inability of traditional bisulfite sequencing to decipher between the two modified bases. In this technique, TET1 is responsible for the oxidation of 5mc allowing it to be read as thymine following treatment with bisulfite. This is not the case for 5hmc as it is glucosylated in the initial step inhibiting its oxidation by TET1.
Clinical significance
Patients with schizophrenia or bipolar disorder have shown increased levels of TET1 mRNA and protein expression in the inferior parietal lobule, indicating these diseases may be caused by mistakes in gene expression regulation.[15]
Colon, breast, prostate and liver tumors have significantly reduced levels of TET1 compared to the healthy colon cells and normal epithelial colon cells with downgraded TET1 levels have greater levels of proliferation.[16][17][18][19] Additionally, increasing TET1 expression levels in colon cancer cells decreased cell proliferation in both cell cultures and mice through demethylation of promoters of the WNT signaling pathway.[17]
Breast cancer cell lines with silenced TET1 expression have increased rates of invasion and breast cancers that spread to the lymph nodes are characterized by lower TET1 levels.[20] TET1 levels could be used to detect breast cancer metastasis.[20] A histone deacetylase inhibitor Trichostatin A increased levels of TET1 in breast cancer tissues but was a less effective tumor suppressor in patients with low TET1 expression.[21] Breast cancer patients with high TET1 levels had significantly higher survival probabilities than patients with low TET1 levels.[19]
Degradation of TET1 in hypoxia-induced EMT lung cancer cells led to reduced metastasis rates and cells.[22] Healthy cells transitioning to cancer cells have decreased levels of TET1 but decreasing TET1 expression does not lead to malignancy.[23] Cancer cells using the KRAS pathway had decreased invasive potential after reintroducing TET1, likewise downgrading KRAS increased TET1 levels.[24]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000138336 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000047146 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Entrez Gene: Tet methylcytosine dioxygenase 1". Retrieved 2012-07-26.
- PMID 23940045.
- PMID 12124344.
- S2CID 1202064.
- PMID 19372391.
- ^ PMID 21778364.
- PMID 28847947.
- PMID 24050401.
- S2CID 11597504.
- S2CID 42714024.
- PMID 22948384.
- PMID 22391558.
- ^ S2CID 22017396.
- PMID 23671639.
- ^ PMID 22999938.
- ^ PMID 25735355.
- PMID 25175940.
- PMID 25517638.
- S2CID 5823834.
- PMID 25466250.
Further reading
- Abdel-Wahab O, Mullally A, Hedvat C, Garcia-Manero G, Patel J, Wadleigh M, et al. (July 2009). "Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies". Blood. 114 (1): 144–147. PMID 19420352.
- Lorsbach RB, Moore J, Mathew S, Raimondi SC, Mukatira ST, Downing JR (March 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 (3): 637–641. S2CID 1202064.
- Morgan AR, Hamilton G, Turic D, Jehu L, Harold D, Abraham R, et al. (September 2008). "Association analysis of 528 intra-genic SNPs in a region of chromosome 10 linked to late onset Alzheimer's disease". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics. 147B (6): 727–731. S2CID 13916214.
- Ono R, Taki T, Taketani T, Taniwaki M, Kobayashi H, Hayashi Y (July 2002). "LCX, leukemia-associated protein with a CXXC domain, is fused to MLL in acute myeloid leukemia with trilineage dysplasia having t(10;11)(q22;q23)". Cancer Research. 62 (14): 4075–4080. PMID 12124344.
- Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, et al. (January 2011). "Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases". Cancer Cell. 19 (1): 17–30. PMID 21251613.
- Guo JU, Su Y, Zhong C, Ming GL, Song H (April 2011). "Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain". Cell. 145 (3): 423–434. PMID 21496894.
- Frauer C, Rottach A, Meilinger D, Bultmann S, Fellinger K, Hasenöder S, et al. (February 2011). "Different binding properties and function of CXXC zinc finger domains in Dnmt1 and Tet1". PLOS ONE. 6 (2): e16627. PMID 21311766.
- Langemeijer SM, Aslanyan MG, Jansen JH (December 2009). "TET proteins in malignant hematopoiesis". Cell Cycle. 8 (24): 4044–4048. S2CID 27430810.
- Mohr F, Döhner K, Buske C, Rawat VP (March 2011). "TET genes: new players in DNA demethylation and important determinants for stemness". Experimental Hematology. 39 (3): 272–281. PMID 21168469.
