Ten-eleven translocation proteins and their role beyond DNA demethylation - what we can learn from the fly.
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ABSTRACT:
SUBMITTER: Ismail JN
PROVIDER: S-EPMC7595634 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Ten-eleven translocation proteins (TET1-3) are dioxygenases that oxidize 5-methyldeoxycytosine, thus taking part in passive and active demethylation. TETs have shown to be involved in immune cell development, affecting from self-renewal of stem cells and lineage commitment to terminal differentiation. In fact, dysfunction of TET proteins have been vastly associated with both myeloid and lymphoid leukemias. Recently, there has been accumulating evidence suggesting that TETs regulate immune cell function during innate and adaptive immune responses, thereby modulating inflammation. In this work, we pursue to review the current and recent evidence on the mechanistic aspects by which TETs regulate immune cell maturation and function. We will also discuss the complex interplay of TET expression and activity by several factors to modulate a multitude of inflammatory processes. Thus, modulating TET enzymes could be a novel pharmacological approach to target inflammation-related diseases and myeloid and lymphoid leukemias, when their activity is dysregulated.
| S-EPMC8977485 | biostudies-literature
Project description:Increasing evidence indicates that active DNA demethylation is involved in several processes in mammals, resulting in developmental stage-specificity and cell lineage-specificity. The recently discovered Ten-Eleven Translocation (TET) dioxygenases are accepted to be involved in DNA demethylation by initiating 5-mC oxidation. Aberrant DNA methylation profiles are associated with many diseases. For example in cancer, hypermethylation results in silencing of tumor suppressor genes. Such silenced genes can be re-expressed by epigenetic drugs, but this approach has genome-wide effects. In this study, fusions of designer DNA binding domains to TET dioxygenase family members (TET1, -2 or -3) were engineered to target epigenetically silenced genes (ICAM-1, EpCAM). The effects on targeted CpGs' methylation and on expression levels of the target genes were assessed. The results indicated demethylation of targeted CpG sites in both promoters for targeted TET2 and to a lesser extent for TET1, but not for TET3. Interestingly, we observed re-activation of transcription of ICAM-1. Thus, our work suggests that we provided a mechanism to induce targeted DNA demethylation, which facilitates re-activation of expression of the target genes. Furthermore, this Epigenetic Editing approach is a powerful tool to investigate functions of epigenetic writers and erasers and to elucidate consequences of epigenetic marks.
| S-EPMC3919596 | biostudies-literature
Project description:Stable expression of Foxp3 is ensured by demethylation of CpG motifs in the Foxp3 intronic element, the conserved non-coding sequence 2 (CNS2), which persists throughout the lifespan of regulatory T cells (Tregs). However, little is known about the mechanisms on how CNS2 demethylation is sustained. In this study, we found that Ten-Eleven-Translocation (Tet) DNA dioxygenase protects the CpG motifs of CNS2 from re-methylation by DNA methyltransferases (Dnmts) and prevents Tregs from losing Foxp3 expression under inflammatory conditions. Upon stimulation of Tregs by interleukin-6 (IL6), Dnmt1 was recruited to CNS2 and induced methylation, which was inhibited by Tet2 recruited by IL2. Tet2 prevented CNS2 re-methylation by not only the occupancy of the CNS2 locus but also by its enzymatic activity. These results show that the CNS2 methylation status is dynamically regulated by a balance between Tets and Dnmts which influences the expression of Foxp3 in Tregs.
| S-EPMC5223106 | biostudies-literature
Project description:BackgroundRheumatoid arthritis (RA) patients present with abnormal methylation patterns in their fibroblast-like synoviocytes (FLS). Given that DNA demethylation is critical for producing DNA methylation patterns, we hypothesized that DNA demethylation may facilitate RA progression. Therefore, we designed this study to examine the role of DNA dioxygenase family, Ten-Eleven translocation (TET1/2/3), in the pathological process of RA.MethodsSynovial tissues and FLS were obtained from patients with RA and Osteoarthritis. K/BxN serum-induced arthritis was induced in Wild-type (WT) and TET3 heterozygous-deficient (TET3+/-) C57BL/6 mice.ResultsWe found that both TET3 and 5-hydroxymethylcytosine (5hmC) were upregulated in synovitis tissues from RA patients and confirmed this upregulation in the cultured FLS derived from synovitis tissues. Tumor necrosis factor α (TNFα) upregulated TET3 and 5hmC levels in cultured FLS, and the stimulated FLS exhibited high cell mobility with increased transcription of cellular migration-related factors such as C-X-C motif chemokine ligand 8 (CXCL8) and C-C motif chemokine ligand 2 (CCL2) in a TET3-dependent manner. In addition, TET3 haploinsufficiency lowered RA progression in a mouse model of serum-induced arthritis.ConclusionsBased on these findings, we can assume that TET3-mediated DNA demethylation acts as an epigenetic regulator of RA progression.
| S-EPMC9479255 | biostudies-literature
Project description:A precise balance of DNA methylation and demethylation is required for epigenetic control of cell identity, development, and growth. DNA methylation marks are introduced by de novo DNA methyltransferases DNMT3a/b and are maintained throughout cell divisions by DNA methyltransferase 1 (DNMT1), which adds methyl groups to hemimethylated CpG dinucleotides generated during DNA replication. Ten eleven translocation (TET) dioxygenases oxidize 5-methylcytosine (mC) to 5-hydroxymethylcytosine (hmC), 5-formylcytosine (fC), and 5-carboxylcytosine (caC), a process known to induce DNA demethylation and gene reactivation. In this study, we investigated the catalytic activity of human DNMT1 in the presence of oxidized forms of mC. A mass spectrometry-based assay was employed to study the kinetics of DNMT1-mediated cytosine methylation in CG dinucleotides containing C, mC, hmC, fC, or caC across from the target cytosine. Homology modeling, coupled with molecular dynamics simulations, was used to explore the structural consequences of mC oxidation with regard to the geometry of protein-DNA complexes. The DNMT1 enzymatic activity was strongly affected by the oxidation status of mC, with the catalytic efficiency decreasing in the following order: mC > hmC > fC > caC. Molecular dynamics simulations revealed that DNMT1 forms an unproductive complex with DNA duplexes containing oxidized forms of mC as a consequence of altered interactions of the target recognition domain of the protein with the C-5 substituent on cytosine. Our results provide new structural and mechanistic insight into TET-mediated DNA demethylation.
| S-EPMC6310613 | biostudies-literature
Project description:The ten-eleven translocation family of proteins (Tet1/2/3, Tets) converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which can be further oxidized and repaired by thymine DNA glycosylase (TDG), to influence gene transcription in embryonic and adult tissues. However the mechanisms of how Tets and TDG levels are regulated are unknown. We show that miR-29 can directly regulate Tet1-3 and TDG mRNA levels through binding to their 3'UTRs. miR-29 mimic decreases global 5hmC levels, a hallmark of Tet activity. Moreover, the mRNA levels for Tet3 and TDG are inversely correlated with the levels of miR-29 in aged mouse aorta implying that aging may affect methylation patterns via miRNA. In summary, our data show that Tets and TDG are direct targets of miR-29 and unravel a novel regulatory role for this miRNA in epigenetic DNA demethylation pathways.
| S-EPMC3767426 | biostudies-literature
Project description:DNA cytosine methylation (5-methylcytosine, 5mC) is the most important epigenetic mark in higher eukaryotes. 5mC in genomes is dynamically controlled by writers and erasers. DNA (cytosine-5)-methyltransferases (DNMTs) are responsible for the generation and maintenance of 5mC in genomes. Active demethylation of 5-methylcytosine (5mC) is achieved by ten-eleven translocation (TET) dioxygenase-mediated oxidation of 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). 5fC and 5caC are further processed by thymine DNA glycosylase (TDG)-initiated base excision repair (BER) to restore unmodified cytosines. The TET-TDG-BER pathway could cause the production of DNA strand breaks and therefore jeopardize the integrity of genomes. Here, we investigated the direct decarboxylation of 5caC in mammalian genomes by using metabolic labeling with 2'-fluorinated 5caC (F-5caC) and mass spectrometry analysis. Our results clearly demonstrated the decarboxylation of 5caC occurring in mammalian genomes, which unveiled that, in addition to the TET-TDG-BER pathway, the direct decarboxylation of TET-produced 5caC constituted a new pathway for active demethylation of 5mC in mammalian genomes.
| S-EPMC8409474 | biostudies-literature
Project description:Liver-specific ten-eleven translocation (Tet) methylcytosine dioxygenases 2 and 3 (Tet2 plus Tet3)-deficient hepatitis B virus (HBV) transgenic mice fail to support viral biosynthesis. The levels of viral transcription and replication intermediates are dramatically reduced. Hepatitis B core antigen is only observed in a very limited number of pericentral hepatocytes in a pattern that is similar to glutamate-ammonia ligase (Glul), a β-catenin target gene. HBV transcript abundance in adult Tet-deficient mice resembles that observed in wild-type neonatal mice. Furthermore, the RNA levels of several β-catenin target genes including Glul, Lhpp, Notun, Oat, Slc1a2, and Tbx3 in Tet-deficient mice were also similar to that observed in wild-type neonatal mice. As HBV transcription is regulated by β-catenin, these findings support the suggestion that neonatal Tet deficiency might limit β-catenin target gene expression, limiting viral biosynthesis. Additionally, HBV transgene DNA displays increased 5-methylcytosine (5mC) frequency at CpG sequences consistent with neonatal Tet deficiency being responsible for decreased developmental viral DNA demethylation mediated by 5mC oxidation to 5-hydroxymethylcytosine, a process that might be responsible for the reduction in cellular β-catenin target gene expression and viral transcription and replication.IMPORTANCEChronic hepatitis B virus (HBV) infection causes significant worldwide morbidity and mortality. There are no curative therapies available to resolve chronic HBV infections, and the small viral genome limits molecular targets for drug development. An alternative approach to drug development is to target cellular genes essential for HBV biosynthesis. In the liver, ten-eleven translocation (Tet) genes encode cellular enzymes that are not essential for postnatal mouse development but represent essential activities for viral DNA demethylation and transcription. Consequently, Tet inhibitors may potentially be developed into therapeutic agents capable of inducing and/or maintaining HBV covalently closed circular DNA methylation, resulting in transcriptional silencing and the resolution of chronic viral infection.
| S-EPMC10878274 | biostudies-literature
Project description:Ten-eleven translocation (TET) family proteins (TETs), specifically, TET1, TET2 and TET3, can modify DNA by oxidizing 5-methylcytosine (5mC) iteratively to yield 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxycytosine (5caC), and then two of these intermediates (5fC and 5caC) can be excised and return to unmethylated cytosines by thymine-DNA glycosylase (TDG)-mediated base excision repair. Because DNA methylation and demethylation play an important role in numerous biological processes, including zygote formation, embryogenesis, spatial learning and immune homeostasis, the regulation of TETs functions is complicated, and dysregulation of their functions is implicated in many diseases such as myeloid malignancies. In addition, recent studies have demonstrated that TET2 is able to catalyze the hydroxymethylation of RNA to perform post-transcriptional regulation. Notably, catalytic-independent functions of TETs in certain biological contexts have been identified, further highlighting their multifunctional roles. Interestingly, by reactivating the expression of selected target genes, accumulated evidences support the potential therapeutic use of TETs-based DNA methylation editing tools in disorders associated with epigenetic silencing. In this review, we summarize recent key findings in TETs functions, activity regulators at various levels, technological advances in the detection of 5hmC, the main TETs oxidative product, and TETs emerging applications in epigenetic editing. Furthermore, we discuss existing challenges and future directions in this field.
| S-EPMC10415333 | biostudies-literature
Project description:Studies from human cells, rats, and zebrafish have documented that hyperglycemia (HG) induces the demethylation of specific cytosines throughout the genome. We previously documented that a subset of these changes become permanent and may provide, in part, a mechanism for the persistence of complications referred to as the metabolic memory phenomenon. In this report, we present studies aimed at elucidating the molecular machinery that is responsible for the HG-induced DNA demethylation observed. To this end, RNA expression and enzymatic activity assays indicate that the ten-eleven translocation (Tet) family of enzymes are activated by HG. Furthermore, through the detection of intermediates generated via conversion of 5-methyl-cytosine back to the unmethylated form, the data were consistent with the use of the Tet-dependent iterative oxidation pathway. In addition, evidence is provided that the activity of the poly(ADP-ribose) polymerase (Parp) enzyme is required for activation of Tet activity because the use of a Parp inhibitor prevented demethylation of specific loci and the accumulation of Tet-induced intermediates. Remarkably, this inhibition was accompanied by a complete restoration of the tissue regeneration deficit that is also induced by HG. The ultimate goal of this work is to provide potential new avenues for therapeutic discovery.
| S-EPMC4141369 | biostudies-literature