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]
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]
TET1 catalyzes the conversion of the modified DNA base 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC). [9]
TET1 produces 5-hmC by oxidation of 5-mC in an iron and alpha-ketoglutarate dependent manner. [10] The conversion of 5-mC to 5-hmC has been proposed as the initial step of active DNA demethylation in mammals. [10] Additionally, downgrading TET1 has decreased levels of 5-formylcytosine (5-fC) and 5-carboxylcytosine (5-caC) in both cell cultures and mice. [10]
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]
TET1 appears to facilitate nuclear reprogramming of somatic cells to iPS cells. [13] [14]
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.
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]
5-Methylcytosine is a methylated form of the DNA base cytosine (C) that regulates gene transcription and takes several other biological roles. When cytosine is methylated, the DNA maintains the same sequence, but the expression of methylated genes can be altered. 5-Methylcytosine is incorporated in the nucleoside 5-methylcytidine.
The CpG sites or CG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5' → 3' direction. CpG sites occur with high frequency in genomic regions called CpG islands.
In biology, reprogramming refers to erasure and remodeling of epigenetic marks, such as DNA methylation, during mammalian development or in cell culture. Such control is also often associated with alternative covalent modifications of histones.
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For molecular biology in mammals, DNA demethylation causes replacement of 5-methylcytosine (5mC) in a DNA sequence by cytosine (C). DNA demethylation can occur by an active process at the site of a 5mC in a DNA sequence or, in replicating cells, by preventing addition of methyl groups to DNA so that the replicated DNA will largely have cytosine in the DNA sequence.
5-Hydroxymethylcytosine (5hmC) is a DNA pyrimidine nitrogen base derived from cytosine. It is potentially important in epigenetics, because the hydroxymethyl group on the cytosine can possibly switch a gene on and off. It was first seen in bacteriophages in 1952. However, in 2009 it was found to be abundant in human and mouse brains, as well as in embryonic stem cells. In mammals, it can be generated by oxidation of 5-methylcytosine, a reaction mediated by TET enzymes. Its molecular formula is C5H7N3O2.
Tet methylcytosine dioxygenase 2 (TET2) is a human gene. It resides at chromosome 4q24, in a region showing recurrent microdeletions and copy-neutral loss of heterozygosity (CN-LOH) in patients with diverse myeloid malignancies.
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Anjana Rao is a cellular and molecular biologist of Indian ethnicity, working in the US. She uses immune cells as well as other types of cells to understand intracellular signaling and gene expression. Her research focuses on how signaling pathways control gene expression.
The TET enzymes are a family of ten-eleven translocation (TET) methylcytosine dioxygenases. They are instrumental in DNA demethylation. 5-Methylcytosine is a methylated form of the DNA base cytosine (C) that often regulates gene transcription and has several other functions in the genome.
