Tet methylcytosine dioxygenase 1

Tet methylcytosine dioxygenase 1
Identifiers
Symbols	TET1 ; CXXC6; LCX; MLL-TET1; TET1-MLL; bA119F7.1
External IDs	OMIM: 607790 HomoloGene: 12735 GeneCards: TET1 Gene
EC number	1.14.11.n2
Gene ontology Molecular function • iron ion binding • zinc ion binding • structure-specific DNA binding • methylcytosine dioxygenase activity Cellular component • nucleus Biological process • inner cell mass cell differentiation • transcription, DNA-templated • protein O-linked glycosylation • gene expression • chromatin modification • stem cell maintenance • oxidative DNA demethylation • regulation of gene expression, epigenetic • regulation of DNA methylation • positive regulation of transcription from RNA polymerase II promoter • DNA demethylation • negative regulation of methylation-dependent chromatin silencing • regulation of genetic imprinting Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	80312	52463
Ensembl	ENSG00000138336	ENSMUSG00000047146
UniProt	Q8NFU7	Q3URK3
RefSeq (mRNA)	NM_030625	NM_001253857
RefSeq (protein)	NP_085128	NP_001240786
Location (UCSC)	Chr 10: 68.56 – 68.69 Mb	Chr 10: 62.8 – 62.9 Mb
PubMed search

Ten-eleven translocation methylcytosine dioxygenase 1 (TET1) is a member of the TET family of enzymes that in humans is encoded by the TET1 gene.^[1][2]

Discovery

TET1 was first discovered in a 61 year old patient with a rare variation of t(10;11)(q22;q23) acute myeloid leukemiaa(AML)s a zinc-finger binding protein (specifically on the CXXC domain) that fuses to the gene MLL.^[3] 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.^[4]

Function

TET1 catalyzes the conversion of the modified DNA base 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC).^[5] TET1 produces 5-hmC by oxidation of 5-mC in an iron and alpha-ketoglutarate dependent manner.^[6] The conversion of 5-mC to 5-hmC has been proposed as the initial step of active DNA demethylation in mammals.^[6] Additionally, downgrading TET1 has decreased levels of 5-formylcytosine (5-fC) and 5-carboxylcytosine (5-caC) in both cell cultures and mice.^[6]

Applications

TET1 appears to facilitate nuclear reprogramming of somatic cells to iPS cells.^[7][8]

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.^[9]

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.^{[10][11][12][13]} 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.^[11]

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.^[14] TET1 levels could be used to detect breast cancer metastasis.^[14] 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.^[15] Breast cancer patients with high TET1 levels had significantly higher survival probabilities than patients with low TET1 levels.^[13]

Degradation of TET1 in hypoxnia-induced EMT lung cancer cells led to reduced metastasis rates and cells.^[16] Healthy cells transitioning to cancer cells have decreased levels of TET1 but decreasing TET1 expression does not lead to malignancy.^[17] Cancer cells using the KRAS pathway had decreased invasive potential after reintroducing TET1, likewise downgrading KRAS increased TET1 levels.^[18]

References

1. "Entrez Gene: Tet methylcytosine dioxygenase 1". Retrieved 2012-07-26.
2. Coulter JB, O'Driscoll CM, Bressler JP (October 2013). "Hydroquinone increases 5-hydroxymethylcytosine formation through ten eleven translocation 1 (TET1) 5-methylcytosine dioxygenase". The Journal of Biological Chemistry 288 (40): 28792–800. doi:10.1074/jbc.M113.491365. PMC 3789975. PMID 23940045.
3. 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): 4075–80. PMID 12124344.
4. 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): 637–41. doi:10.1038/sj.leu.2402834. PMID 12646957.
5. Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L, Rao A (May 2009). "Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1". Science 324 (5929): 930–5. doi:10.1126/science.1170116. PMC 2715015. PMID 19372391.
6. Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, He C, Zhang Y (September 2011). "Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine". Science 333 (6047): 1300–3. doi:10.1126/science.1210597. PMC 3495246. PMID 21778364.
7. Pera MF (December 2013). "Epigenetics, vitamin supplements and cellular reprogramming". Nature Genetics 45 (12): 1412–3. doi:10.1038/ng.2834. PMID 24270443.
8. Chen J, Gao Y, Huang H, Xu K, Chen X, Jiang Y, Li H, Gao S, Tao Y, Wang H, Zhang Y, Wang H, Cai T, Gao S (March 2015). "The combination of Tet1 with Oct4 generates high-quality mouse-induced pluripotent stem cells". Stem Cells 33 (3): 686–98. doi:10.1002/stem.1879. PMID 25331067.
9. Dong E, Gavin DP, Chen Y, Davis J (2012-09-01). "Upregulation of TET1 and downregulation of APOBEC3A and APOBEC3C in the parietal cortex of psychotic patients". Translational Psychiatry 2 (9): e159. doi:10.1038/tp.2012.86. PMC 3565208. PMID 22948384.
10. Yang H, Liu Y, Bai F, Zhang JY, Ma SH, Liu J, Xu ZD, Zhu HG, Ling ZQ, Ye D, Guan KL, Xiong Y (January 2013). "Tumor development is associated with decrease of TET gene expression and 5-methylcytosine hydroxylation". Oncogene 32 (5): 663–9. doi:10.1038/onc.2012.67. PMC 3897214. PMID 22391558.
11. Neri F, Dettori D, Incarnato D, Krepelova A, Rapelli S, Maldotti M, Parlato C, Paliogiannis P, Oliviero S (August 2015). "TET1 is a tumour suppressor that inhibits colon cancer growth by derepressing inhibitors of the WNT pathway". Oncogene 34 (32): 4168–76. doi:10.1038/onc.2014.356. PMID 25362856.
12. Liu C, Liu L, Chen X, Shen J, Shan J, Xu Y, Yang Z, Wu L, Xia F, Bie P, Cui Y, Bian XW, Qian C (2013-05-09). "Decrease of 5-hydroxymethylcytosine is associated with progression of hepatocellular carcinoma through downregulation of TET1". PloS One 8 (5): e62828. doi:10.1371/journal.pone.0062828. PMC 3650038. PMID 23671639.
13. Hsu CH, Peng KL, Kang ML, Chen YR, Yang YC, Tsai CH, Chu CS, Jeng YM, Chen YT, Lin FM, Huang HD, Lu YY, Teng YC, Lin ST, Lin RK, Tang FM, Lee SB, Hsu HM, Yu JC, Hsiao PW, Juan LJ (September 2012). "TET1 suppresses cancer invasion by activating the tissue inhibitors of metalloproteinases". Cell Reports 2 (3): 568–79. doi:10.1016/j.celrep.2012.08.030. PMID 22999938.
14. Sang Y, Cheng C, Tang XF, Zhang MF, Lv XB (2015-01-01). "Hypermethylation of TET1 promoter is a new diagnosic marker for breast cancer metastasis". Asian Pacific Journal of Cancer Prevention 16 (3): 1197–200. PMID 25735355.
15. "TET1 partially mediates HDAC inhibitor-induced suppression of breast cancer invasion". www.spandidos-publications.com. Retrieved 2016-04-07.
16. Tsai YP, Chen HF, Chen SY, Cheng WC, Wang HW, Shen ZJ, Song C, Teng SC, He C, Wu KJ (2014-01-01). "TET1 regulates hypoxia-induced epithelial-mesenchymal transition by acting as a co-activator". Genome Biology 15 (12): 513. doi:10.1186/s13059-014-0513-0. PMC 4253621. PMID 25517638.
17. Kudo Y, Tateishi K, Yamamoto K, Yamamoto S, Asaoka Y, Ijichi H, Nagae G, Yoshida H, Aburatani H, Koike K (April 2012). "Loss of 5-hydroxymethylcytosine is accompanied with malignant cellular transformation". Cancer Science 103 (4): 670–6. doi:10.1111/j.1349-7006.2012.02213.x. PMID 22320381.
18. Wu BK, Brenner C (December 2014). "Suppression of TET1-dependent DNA demethylation is essential for KRAS-mediated transformation". Cell Reports 9 (5): 1827–40. doi:10.1016/j.celrep.2014.10.063. PMC 4268240. PMID 25466250.

Further reading

• Abdel-Wahab O, Mullally A, Hedvat C, Garcia-Manero G, Patel J, Wadleigh M, Malinge S, Yao J, Kilpivaara O, Bhat R, Huberman K, Thomas S, Dolgalev I, Heguy A, Paietta E, Le Beau MM, Beran M, Tallman MS, Ebert BL, Kantarjian HM, Stone RM, Gilliland DG, Crispino JD, Levine RL (July 2009). "Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies". Blood 114 (1): 144–7. doi:10.1182/blood-2009-03-210039. PMC 2710942. 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): 637–41. doi:10.1038/sj.leu.2402834. PMID 12646957.
• Morgan AR, Hamilton G, Turic D, Jehu L, Harold D, Abraham R, Hollingworth P, Moskvina V, Brayne C, Rubinsztein DC, Lynch A, Lawlor B, Gill M, O'Donovan M, Powell J, Lovestone S, Williams J, Owen MJ (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): 727–31. doi:10.1002/ajmg.b.30670. PMID 18163421.
• 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): 4075–80. PMID 12124344.
• Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, Ito S, Yang C, Wang P, Xiao MT, Liu LX, Jiang WQ, Liu J, Zhang JY, Wang B, Frye S, Zhang Y, Xu YH, Lei QY, Guan KL, Zhao SM, Xiong Y (January 2011). "Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases". Cancer Cell 19 (1): 17–30. doi:10.1016/j.ccr.2010.12.014. PMC 3229304. 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): 423–34. doi:10.1016/j.cell.2011.03.022. PMC 3088758. PMID 21496894.
• Frauer C, Rottach A, Meilinger D, Bultmann S, Fellinger K, Hasenöder S, Wang M, Qin W, Söding J, Spada F, Leonhardt H (2011). "Different binding properties and function of CXXC zinc finger domains in Dnmt1 and Tet1". PloS One 6 (2): e16627. doi:10.1371/journal.pone.0016627. PMC 3032784. PMID 21311766.
• Langemeijer SM, Aslanyan MG, Jansen JH (December 2009). "TET proteins in malignant hematopoiesis". Cell Cycle 8 (24): 4044–8. doi:10.4161/cc.8.24.10239. PMID 19923888.
• 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): 272–81. doi:10.1016/j.exphem.2010.12.004. PMID 21168469.