DNA Demethylation: Where Genetics Meets Epigenetics

Zhang, Xiaofei; Fu, Rongguo; Yu, Jie; Wu, Xiaosheng

doi:10.2174/13816128113199990546

Cited by 18 publications

(11 citation statements)

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“…DNA methylation is the covalent methylation of the C5 position of cytosine residues in CpG dinucleotides, which leads to transcriptional repression of genes [ 24 ]. DNA methylation, typically associated with gene silencing, along with post-translational modifications of histone tails (associated with gene activation or silencing), are the most common mechanisms affecting accessibility of DNA to and binding of transcription factors.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic regulation of inflammation in localized aggressive periodontitis

et al. 2017

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BackgroundWe have previously demonstrated a Toll-like receptor (TLR)-mediated hyper-responsive phenotype in our cohort of localized aggressive periodontitis (LAP) individuals. However, mechanisms related to this phenotype are still not clear in the literature. The objective of this cross-sectional study is to examine the role of epigenetic regulation, specifically DNA methylation status of genes in the TLR pathway in this cohort. Peripheral blood was collected from 20 LAP patients and 20 healthy unrelated controls. Whole blood was stimulated with 1 μl (100 ng/μl) of purified Escherichia coli lipopolysaccharide (LPS) for 24 h and cyto/chemokines in the supernatants analyzed by Luminex multiplex assays. Genomic DNA extracted from buffy coats prepared from a second tube of whole blood was used for DNA methylation analysis by pyrosequencing of seven TLR signaling genes (FADD, MAP3K7, MYD88, IL6R, PPARA, IRAK1BP1, RIPK2).ResultsSignificant differences in the methylation status were observed at specific CpG positions in LAP patients compared to healthy controls and interestingly also between severe and moderate LAP. Specifically, subjects with moderate LAP presented hypermethylation of both the upregulating (MAP3K7, MYD88, IL6R, and RIPK2) and downregulating (FADD, IRAK, and PPARA) genes, while severe LAP presented hypomethylation of these genes. Further analysis on CpG sites with significant differences in methylation status correlates with an increased pro-inflammatory cytokine profile for LAP patients.ConclusionsOur findings suggest that epigenetic modifications of genes in the TLR pathway may orchestrate the thresholds for balancing induction and prevention of tissue destruction during the course of disease, and thus differ significantly at different stages of the disease, where moderate LAP shows hypermethylation and severe LAP shows hypomethylation of several genes.Trial registration https://clinicaltrials.gov, NCT01330719

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Section: Discussionmentioning

confidence: 99%

Epigenetic regulation of inflammation in localized aggressive periodontitis

et al. 2017

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“…DNA methylation plays a key role in proper HSPC self-renewal and lineage differentiation, and its dysregulation can lead to aberrant stem cell function and cellular transformation [37]. TET2 plays a crucial role in epigenetic modulation by promoting DNA demethylation [38]. DNA hypermethylation resulting from TET2 mutation is associated with CHIP, increased risk of MDS progression, and poor prognosis in AML [35].…”

Section: Tet2 and Dnmt3a Mutations And Their Impactmentioning

confidence: 99%

Age-Associated TET2 Mutations: Common Drivers of Myeloid Dysfunction, Cancer and Cardiovascular Disease

Ferrone

Blydt-Hansen

Rauh

2020

IJMS

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Acquired, inactivating mutations in Tet methylcytosine dioxygenase 2 (TET2) are detected in peripheral blood cells of a remarkable 5%–10% of adults greater than 65 years of age. They impart a hematopoietic stem cell advantage and resultant clonal hematopoiesis of indeterminate potential (CHIP) with skewed myelomonocytic differentiation. CHIP is associated with an overall increased risk of transformation to a hematological malignancy, especially myeloproliferative and myelodysplastic neoplasms (MPN, MDS) and acute myeloid leukemia (AML), of approximately 0.5% to 1% per year. However, it is becoming increasingly possible to identify individuals at greatest risk, based on CHIP mutational characteristics. CHIP, and particularly TET2-mutant CHIP, is also a novel, significant risk factor for cardiovascular diseases, related in part to hyper-inflammatory, progeny macrophages carrying TET2 mutations. Therefore, somatic TET2 mutations contribute to myeloid expansion and innate immune dysregulation with age and contribute to prevalent diseases in the developed world—cancer and cardiovascular disease. Herein, we describe the impact of detecting TET2 mutations in the clinical setting. We also present the rationale and promise for targeting TET2-mutant and other CHIP clones, and their inflammatory environment, as potential means of lessening risk of myeloid cancer development and dampening CHIP-comorbid inflammatory diseases.

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“…DNA methylation is regulated by DNA methyltransferases, a family of enzymes that catalyze the transfer of a methyl group to DNA. This family encompasses Dnmt1 that is thought to participate in maintenance DNA methylation, and Dnmt3a , involved in de novo DNA methylation in response to external stimuli [ 36 ]. At PND49, neither TCE exposure appreciably altered expression of Dnmt1 or Dnmt3a in CD4 + T cells.…”

Section: Resultsmentioning

confidence: 99%

Differential Immunotoxicity Induced by Two Different Windows of Developmental Trichloroethylene Exposure

Gilbert

Woodruff

Blossom

2014

Autoimmune Diseases

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Developmental exposure to environmental toxicants may induce immune system alterations that contribute to adult stage autoimmune disease. We have shown that continuous exposure of MRL+/+ mice to trichloroethylene (TCE) from gestational day (GD) 0 to postnatal day (PND) 49 alters several aspects of CD4+ T cell function. This window of exposure corresponds to conception-adolescence/young adulthood in humans. More narrowly defining the window of TCE developmental exposure causes immunotoxicity that would establish the stage at which avoidance and/or intervention would be most effective. The current study divided continuous TCE exposure into two separate windows, namely, gestation only (GD0 to birth (PND0)) and early-life only (PND0-PND49). The mice were examined for specific alterations in CD4+ T cell function at PND49. One potentially long-lasting effect of developmental exposure, alterations in retrotransposon expression indicative of epigenetic alterations, was found in peripheral CD4+ T cells from both sets of developmentally exposed mice. Interestingly, certain other effects, such as alterations in thymus cellularity, were only found in mice exposed to TCE during gestation. In contrast, expansion of memory/activation cell subset of peripheral CD4+ T cells were only found in mice exposed to TCE during early life. Different windows of developmental TCE exposure can have different functional consequences.

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DNA Demethylation: Where Genetics Meets Epigenetics

Cited by 18 publications

References 0 publications

Epigenetic regulation of inflammation in localized aggressive periodontitis

Epigenetic regulation of inflammation in localized aggressive periodontitis

Age-Associated TET2 Mutations: Common Drivers of Myeloid Dysfunction, Cancer and Cardiovascular Disease

Differential Immunotoxicity Induced by Two Different Windows of Developmental Trichloroethylene Exposure

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