Tet Enzymes, Variants, and Differential Effects on Function

Melamed, Philippa; Yosefzon, Yahav; David, Cfir; Tsukerman, Anna; Pnueli, Lilach

doi:10.3389/fcell.2018.00022

Cited by 103 publications

(79 citation statements)

References 56 publications

(100 reference statements)

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“…A potential explanation for the unique role of each TET is their ability to bind to different gene sequences, with TET1 directly binding to DNA via its CXXC domain, which is not present in TET2 (Wu and Zhang, 2011;Zhang et al, 2016). Alternatively, TET1 and TET2 could use distinct binding partners and co-factors, which in turn modulate their enzymatic activity (Melamed et al, 2018;Zhang et al, 2017). Together with the lack of compensation, these potential explanations highlight important functional differences between TET1 and TET2 which may deserve future investigation.…”

Section: Discussionmentioning

confidence: 99%

TET1-mediated DNA hydroxy-methylation regulates adult remyelination

Moyon

Frawley

Marshall-Phelps³

et al. 2019

Preprint

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Highlights:-DNA hydroxy-methylation (5hmC) regulates gene expression in adult OPC (aOPC) -TET1, the enzyme catalyzing 5hmC in aOPC regulates myelin regenerative potential -Age-related TET1 decline results in decreased 5hmC and inefficient remyelination -Tet1 loss in aOPC impairs solute carrier expression and mimics remyelination in aging SummaryAdult myelination is essential for brain function and response to injury, but the molecular mechanisms remain elusive. Here we identify DNA hydroxy-methylation, an epigenetic mark catalyzed by Ten-Eleven translocation (TET) enzymes, as necessary for adult myelin repair.While DNA hydroxy-methylation and high levels of TET1 are detected in young adult mice during myelin regeneration after demyelination, this process is defective in old mice. Constitutive or inducible lineage-specific ablation of Tet1 (but not of Tet2) recapitulate the age-related decline of DNA hydroxy-methylation and inefficient remyelination. Genome-wide hydroxy-methylation and transcriptomic analysis identify numerous TET1 targets, including several members of the solute carrier (Slc) gene family. Lower transcripts for Slc genes, including Slc12a2, are observed in Tet1 mutants and old mice and are associated with swelling at the neuroglial interface, a phenotype detected also in zebrafish slc12a2b mutants.We conclude that TET1-mediated DNA hydroxy-methylation is necessary for adult myelination after injury.

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Section: Discussionmentioning

confidence: 99%

TET1-mediated DNA hydroxy-methylation regulates adult remyelination

Moyon

Frawley

Marshall-Phelps³

et al. 2019

Preprint

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“…Structural studies confirmed that these catalytic domains specifically bind to cytosines in CG dinucleotides in DNA, known as CpG sites and do not bind to other DNA bases and have almost no specificity to the flanking DNA sequences [114]. The three family members of the TET family-TET1, TET2 and TE3-catalyze the successive hydroxylation of DNA methyl cytosine 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC), 5-formylcytosine (5-fC) and 5-carboxycytosine (5-caC) [115]. These 5-mC oxidation products 5-fC-and 5-caC-modified cytosine are the intermediates that are formed during the conversion of 5-mC to unmodified cytosine, impending for the first step for active DNA demethylation pathway [114,115].…”

Section: Ten Eleven Translocation (Tet)-cancer and Effect Of Vitc (Tmentioning

confidence: 99%

Combination Therapy with Vitamin C Could Eradicate Cancer Stem Cells

2020

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Cancer remains one of the most feared and dreaded diseases in this era of modern medicine, claiming the lives of many, and affecting the quality of life of several others around the globe despite major advances in the diagnosis, treatment, palliative care and the immense resources invested into cancer research. While research in cancer has largely focused on the neoplasm/tumor and the cancerous cells that make up the tumor, more recently, the existence, proliferation, differentiation, migration and invasion of cancer stem cells (CSCs) and the role that CSCs play in tumor initiation, progression, metastasis, drug resistance and relapse/recurrence of the disease has gained widespread interest in cancer research. Although the conventional therapeutic approaches such as surgery, chemotherapy and radiation therapy are effective cancer treatments, very often these treatment modalities fail to target the CSCs, which then later become the source of disease recurrence. A majority of the anti-cancer agents target rapidly dividing cancer cells and normal cells and hence, have side effects that are not expected. Targeting CSCs remains a challenge due to their deviant nature with a low proliferation rate and increased drug resistance mechanism. Ascorbic acid/Vitamin C (Vit.C), a potent antioxidant, is a cofactor for several biosynthetic and gene regulatory enzymes and a vital contributor to immune defense of the body, and was found to be deficient in patients with advanced stages of cancer. Vit.C has gained importance in the treatment of cancer due to its ability to modulate the redox status of the cell and influence epigenetic modifications and significant roles in HIF1α signaling. Studies have reported that intravenous administration of Vit.C at pharmacological doses selectively kills tumor cells and targets CSCs when administered along with chemotherapeutic drugs. In the current article, we provide an in-depth review of how Vit.C plays an important role in targeting CSCs and its possible use as an adjuvant, neoadjuvant or co-treatment in the treatment of cancers.

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“…As described by Jin et al [27] and Melamed et al [28], there are a number of TET enzymes, including at least two isoforms of TET1, one of TET2 and three isoforms of TET3. As reviewed [28], the full-length canonical TET1 isoform appears virtually restricted to early embryos, embryonic stem cells and PGCs. The dominant TET1 isoform in most somatic tissues, at least in the mouse, arises from alternative promoter usage which gives rise to a short transcript and a truncated protein designated TET1s.…”

Section: Tet Enzymesmentioning

confidence: 99%

“…TET2 does not have an affinity for 5-methylcytosine in DNA [31]. The CXXC domain of the full-length TET3, which is the predominant form expressed in neurons, binds most strongly to CpGs modified by 5-carboxycytosine (5caC) (Figure 3), although it does also bind to un-methylated CpGs [28].…”

Section: Tet Enzymesmentioning

confidence: 99%

Demethylation in Early Embryonic Development and Memory

Bernstein¹,

Bernstein²

2020

DNA Methylation Mechanism

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DNA repair processes arose early in evolution. During evolution, DNA base excision repair apparently acquired additional roles in demethylation of cytosines in DNA. Demethylation is central to two mammalian fundamental processes. Embryonic reprogramming and neuronal memory require rapid gene expression alterations depending in part on demethylations. The active demethylation reactions in both processes primarily depend, first, on the family of 5-methylcytosine oxidases sharing the acronym ten-eleven translocation (TET methylcytosine dioxygenases) and, second, on DNA base excision repair enzymes. In mice, within 6 h of fertilization, the paternal chromosomes are close to 100% actively demethylated through TET and repair activity. (Methylation of maternal DNA is blocked during subsequent cycles of replication, so methyl groups on maternal DNA, passively, becomes highly diluted over the next 4 days.) Rats subjected to one instance of contextual fear conditioning create an especially strong long-term memory. At 24 h after training, 9.2% of the genes in the rat genomes of hippocampus neurons are differentially methylated, including over 500 genes with demethylation. The emergence of embryonic development in evolution depended on preexisting DNA methylation/demethylation pathways to modify gene expression. The further emergence of memory likely evolved from the earlier set of methylation/demethylation capabilities associated with embryonic development.

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Tet Enzymes, Variants, and Differential Effects on Function

Cited by 103 publications

References 56 publications

TET1-mediated DNA hydroxy-methylation regulates adult remyelination

TET1-mediated DNA hydroxy-methylation regulates adult remyelination

Combination Therapy with Vitamin C Could Eradicate Cancer Stem Cells

Demethylation in Early Embryonic Development and Memory

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