TET-Mediated Epigenetic Regulation in Immune Cell Development and Disease

Tsiouplis, Nikolas James; Bailey, David Wesley; Chiou, Lilly; Wissink, Fiona Jane; Tsagaratou, Ageliki

doi:10.3389/fcell.2020.623948

Cited by 40 publications

(32 citation statements)

References 160 publications

(234 reference statements)

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“…Additionally, many small molecules including circular RNAs and methylation modifiers (such as N6-methyladenosine and 5-hydroxymethylcytosine) have not been examined in dNK cells. Whether the RNA modifications [ 84 , 85 ] in dNK cells and pNK cells regulate biological immune functions during pregnancy is worth exploring in the future.…”

Section: Future Directionsmentioning

confidence: 99%

miRNAs in decidual NK cells: regulators worthy of attention during pregnancy

Feng

Zhou

et al. 2021

Reprod Biol Endocrinol

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The critical immune effectors, including T, B, and natural killer (NK) cells, dendritic cells, and macrophages participate in regulating immune responses during pregnancy. Among these immune cells, decidual NK (dNK) cells are involved in key placental development processes at the maternal–fetal interface, such as uterine spiral artery remodeling, trophoblast invasion, and decidualization. Mechanistically, dNK cells significantly influence pregnancy outcome by secreting cytokines, chemokines, and angiogenic mediators and by their interactions with trophoblasts and other decidual cells. MicroRNAs (miRNAs) are small non-coding RNA molecules that participate in the initiation and progression of human diseases. Although the functions of circulating miRNAs in pathological mechanism has been extensively studied, the regulatory roles of miRNAs in NK cells, especially in dNK cells, have been rarely reported. In this review, we analyze the effects of miRNA regulations of dNK cell functions on the immune system during gestation. We discuss aberrant expressions of certain miRNAs in dNK cells that may lead to pathological consequences, such as recurrent pregnancy loss (RPL). Interestingly, miRNA expression patterns are also different between dNK cells and peripheral NK (pNK) cells, and pNK cells in the first- and third‐trimester of gestation. The dysregulation of miRNA plays a pivotal regulatory role in driving immune functions of dNK and pNK cells. Further understanding of the molecular mechanisms of miRNAs in dNK cells may provide new insights into the development of therapeutics to prevent pregnancy failure.

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Section: Future Directionsmentioning

confidence: 99%

miRNAs in decidual NK cells: regulators worthy of attention during pregnancy

Feng

Zhou

et al. 2021

Reprod Biol Endocrinol

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“…The second route is achieved through the actions of a set of proteins (Ten-Eleven-Translocation (TET) family) that further modify the methylgroup on CpG motifs. (Tsiouplis et al, 2020).…”

Section: Enzymes That Regulate Dna Methylationmentioning

confidence: 99%

“…3. A set of 'eraser' enzymes work in effective opposition to the DNA methyl transferases, by modifying the methylation mark (Tsiouplis et al, 2020). 4.…”

Section: Introductionmentioning

confidence: 99%

Could Changing the DNA Methylation Landscape Promote the Destruction of Epstein-Barr Virus-Associated Cancers?

Sinclair

2021

Front. Cell. Infect. Microbiol.

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DNA methylation at CpG motifs provides an epigenetic route to regulate gene expression. In general, an inverse correlation between DNA hypermethylation at CpG motifs and gene expression is observed. Epstein Barr-virus (EBV) infects people and the EBV genome resides in the nucleus where either its replication cycle initiates or it enters a long-term latency state where the viral genome becomes hypermethylated at CpG motifs. Viral gene expression shows a largely inverse correlation with DNA hypermethylation. DNA methylation occurs through the action of DNA methyl transferase enzymes: writer DNA methyl transferases add methyl groups to specific regions of unmethylated DNA; maintenance DNA methyl transferases reproduce the pattern of DNA methylation during genome replication. The impact of DNA methylation is achieved through the association of various proteins specifically with methylated DNA and their influence on gene regulation. DNA methylation can be changed through altering DNA methyl transferase activity or through the action of enzymes that further modify methylated CpG motifs. Azacytidine prodrugs that are incorporated into CpG motifs during DNA replication are recognized by DNA methyl transferases and block their function resulting in hypomethylation of DNA. EBV-associated cancers have hypermethylated viral genomes and many carcinomas also have highly hypermethylated cellular genomes. Decitabine, a member of the azacytidine prodrug family, reactivates viral gene expression and promotes the recognition of lymphoma cells by virus-specific cytotoxic T-cells. For EBV-associated cancers, the impact of decitabine on the cellular genome and the prospect of combining decitabine with other therapeutic approaches is currently unknown but exciting.

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“…In addition to being an general antioxidant, VC has an unique property to reduce Fe(III) to Fe(II) for epigenetic enzymes, including Ten-Eleven Translocation (TET). family proteins (TET1, TET2, TET3) are essential for DNA demethylation by oxidizing 5-methylcytosine (5mC) to mainly 5-hydroxymethylcytosine (5hmC) 39,40,52 . Previous studies have shown that TET2 and TET3 are required for B cell development and function [53][54][55][56][57][58][59] .…”

Section: The Effect Of Vc Is Dependent On Either Tet2 or Tet3mentioning

confidence: 99%

“…TET enzymes oxidize 5mC into oxidized bases including 5hmC, a stable epigenetic medication and an intermediate for DNA demethylation 40,52,60 . To confirm VC indeed enhances TET activity, we used DNA dot blot to semi-quantitatively measure the level of 5hmC in B cells.…”

Section: Vc Remodels the Genome-wide 5hmc Modificationmentioning

confidence: 99%

Epigenetic Remodeling by Vitamin C Potentiates the Differentiation of Mouse and Human Plasma Cells

Chen

Alamonte-Loya

Lay

et al. 2021

Preprint

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Ascorbate (vitamin C) is an essential micronutrient in humans. The chronic severe deficiency of ascorbate, termed scurvy, has long been associated with increased susceptibility to infections. How ascorbate affects the immune system at the cellular and molecular levels remained unclear. Here, from a micronutrient screen, we identified ascorbate as a potent enhancer for antibody response by facilitating the IL-21/STAT3-dependent plasma cell differentiation in mouse and human B cells. The effect of ascorbate is unique, as other antioxidants failed to promote plasma cell differentiation. Ascorbate is critical during early B cell activation by poising the cells to plasma cell lineage without affecting the proximal IL-21/STAT3 signaling and the overall transcriptome. Consistent with its role as a cofactor for epigenetic enzymes, ascorbate potentiates plasma cell differentiation by remodeling the epigenome via TET (Ten Eleven Translocation), the enzymes responsible for DNA demethylation by oxidizing 5-methylcytosines into 5-hydroxymethylcytosine (5hmC). Genome-wide 5hmC profiling identified ascorbate responsive elements (EAR) at the Prdm1 locus, including a distal element with a STAT3 motif overlapped with a CpG that was methylated and modified by TET in the presence of ascorbate. The results suggest that an adequate level of VC is required for antibody response and highlight how micronutrients regulate the activity of epigenetic enzymes to regulate gene expression. Our findings imply that epigenetic enzymes can function as sensors to gauge the availability of metabolites and influence cell fate decisions.

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TET-Mediated Epigenetic Regulation in Immune Cell Development and Disease

Cited by 40 publications

References 160 publications

miRNAs in decidual NK cells: regulators worthy of attention during pregnancy

miRNAs in decidual NK cells: regulators worthy of attention during pregnancy

Could Changing the DNA Methylation Landscape Promote the Destruction of Epstein-Barr Virus-Associated Cancers?

Epigenetic Remodeling by Vitamin C Potentiates the Differentiation of Mouse and Human Plasma Cells

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