Biology:Tet methylcytosine dioxygenase 1

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Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[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 leukemia (AML) as 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]

Reaction catalyzed by Tet methylcytosine dioxygenase 1 - en.svg

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]

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.[7]

TET1 may play a role in memory extinction. TET1-knockout mice show markedly impaired memory extinction, despite maintaining normal memory acquisition.[8]

Applications

TET1 appears to facilitate nuclear reprogramming of somatic cells to iPS cells.[9][10]

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.[11]

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.[12][13][14][15] 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.[13]

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.[16] TET1 levels could be used to detect breast cancer metastasis.[16] 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.[17] Breast cancer patients with high TET1 levels had significantly higher survival probabilities than patients with low TET1 levels.[15]

Degradation of TET1 in hypoxia-induced EMT lung cancer cells led to reduced metastasis rates and cells.[18] Healthy cells transitioning to cancer cells have decreased levels of TET1 but decreasing TET1 expression does not lead to malignancy.[19] Cancer cells using the KRAS pathway had decreased invasive potential after reintroducing TET1, likewise downgrading KRAS increased TET1 levels.[20]

References

  1. ↑ "Entrez Gene: Tet methylcytosine dioxygenase 1". https://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=retrieve&list_uids=80312. 
  2. ↑ "Hydroquinone increases 5-hydroxymethylcytosine formation through ten eleven translocation 1 (TET1) 5-methylcytosine dioxygenase". The Journal of Biological Chemistry 288 (40): 28792–28800. October 2013. doi:10.1074/jbc.M113.491365. PMID 23940045. 
  3. ↑ "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. July 2002. PMID 12124344. 
  4. ↑ "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. March 2003. doi:10.1038/sj.leu.2402834. PMID 12646957. 
  5. ↑ "Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1". Science 324 (5929): 930–935. May 2009. doi:10.1126/science.1170116. PMID 19372391. Bibcode: 2009Sci...324..930T. 
  6. ↑ 6.0 6.1 6.2 "Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine". Science 333 (6047): 1300–1303. September 2011. doi:10.1126/science.1210597. PMID 21778364. Bibcode: 2011Sci...333.1300I. 
  7. ↑ "5-hydroxymethylcytosine accumulation in postmitotic neurons results in functional demethylation of expressed genes". Proceedings of the National Academy of Sciences of the United States of America 114 (37): E7812–E7821. September 2017. doi:10.1073/pnas.1708044114. PMID 28847947. Bibcode: 2017PNAS..114E7812M. 
  8. ↑ "Tet1 is critical for neuronal activity-regulated gene expression and memory extinction". Neuron 79 (6): 1109–1122. September 2013. doi:10.1016/j.neuron.2013.08.003. PMID 24050401. 
  9. ↑ "Epigenetics, vitamin supplements and cellular reprogramming". Nature Genetics 45 (12): 1412–1413. December 2013. doi:10.1038/ng.2834. PMID 24270443. 
  10. ↑ "The combination of Tet1 with Oct4 generates high-quality mouse-induced pluripotent stem cells". Stem Cells 33 (3): 686–698. March 2015. doi:10.1002/stem.1879. PMID 25331067. 
  11. ↑ "Upregulation of TET1 and downregulation of APOBEC3A and APOBEC3C in the parietal cortex of psychotic patients". Translational Psychiatry 2 (9): e159. September 2012. doi:10.1038/tp.2012.86. PMID 22948384. 
  12. ↑ "Tumor development is associated with decrease of TET gene expression and 5-methylcytosine hydroxylation". Oncogene 32 (5): 663–669. January 2013. doi:10.1038/onc.2012.67. PMID 22391558. 
  13. ↑ 13.0 13.1 "TET1 is a tumour suppressor that inhibits colon cancer growth by derepressing inhibitors of the WNT pathway". Oncogene 34 (32): 4168–4176. August 2015. doi:10.1038/onc.2014.356. PMID 25362856. 
  14. ↑ "Decrease of 5-hydroxymethylcytosine is associated with progression of hepatocellular carcinoma through downregulation of TET1". PLOS ONE 8 (5): e62828. 2013-05-09. doi:10.1371/journal.pone.0062828. PMID 23671639. Bibcode: 2013PLoSO...862828L. 
  15. ↑ 15.0 15.1 "TET1 suppresses cancer invasion by activating the tissue inhibitors of metalloproteinases". Cell Reports 2 (3): 568–579. September 2012. doi:10.1016/j.celrep.2012.08.030. PMID 22999938. 
  16. ↑ 16.0 16.1 "Hypermethylation of TET1 promoter is a new diagnosic marker for breast cancer metastasis". Asian Pacific Journal of Cancer Prevention 16 (3): 1197–1200. 2015-01-01. doi:10.7314/apjcp.2015.16.3.1197. PMID 25735355. 
  17. ↑ "TET1 partially mediates HDAC inhibitor-induced suppression of breast cancer invasion". Molecular Medicine Reports 10 (5): 2595–2600. November 2014. doi:10.3892/mmr.2014.2517. PMID 25175940. 
  18. ↑ "TET1 regulates hypoxia-induced epithelial-mesenchymal transition by acting as a co-activator". Genome Biology 15 (12): 513. December 2014. doi:10.1186/s13059-014-0513-0. PMID 25517638. 
  19. ↑ "Loss of 5-hydroxymethylcytosine is accompanied with malignant cellular transformation". Cancer Science 103 (4): 670–676. April 2012. doi:10.1111/j.1349-7006.2012.02213.x. PMID 22320381. 
  20. ↑ "Suppression of TET1-dependent DNA demethylation is essential for KRAS-mediated transformation". Cell Reports 9 (5): 1827–1840. December 2014. doi:10.1016/j.celrep.2014.10.063. PMID 25466250. 

Further reading



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