Epigenetics of T lymphocytes in health and disease

Leoni, Cristina; Vincenzetti, Lucia; Emming, Stefan; Monticelli, Silvia

doi:10.4414/smw.2015.14191

Cited by 13 publications

(20 citation statements)

References 103 publications

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“…Similarly, differences in genomic DNA methylation have been described between ethnic groups within the United States, and these differences may contribute to natural variations in disease susceptibility . Epigenetic changes can distinguish genetically identical and genetically dissimilar individuals, and these distinctions may accrue as environmental cues drive an “epigenetic drift” .…”

Section: Resultsmentioning

confidence: 99%

Epigenetic changes and their implications in autoimmune hepatitis

Czaja

2018

Eur J Clin Investigation

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Background: The genetic risk of autoimmune hepatitis is insufficient to explain the observed risk, and epigenetic changes may explain disparities in disease occurrence in different populations within and between countries. The goal of this review was to examine how epigenetic changes induced by the environment or inherited as a phenotypic trait may affect autoimmune hepatitis and be amenable to therapeutic intervention. Materials and methods: Pertinent abstracts were identified in PubMed by multiple search terms. The number of abstracts reviewed was 1689, and the number of full-length articles reviewed exceeded 150. Results: Activation of pro-inflammatory genes in autoimmune disease is associated with hypomethylation of deoxyribonucleic acid and modification of histones within chromatin. Organ-specific microribonucleic acids can silence genes by marking messenger ribonucleic acids for degradation, and they can promote inflammatory activity or immunosuppression. High circulating levels of the microribonucleic acids 21 and 122 have been demonstrated in autoimmune hepatitis, and they may increase production of pro-inflammatory cytokines. Microribonucleic acids are also essential for maintaining regulatory T cells. Drugs, pollutants, infections, diet and ageing can induce inheritable epigenetic changes favouring autoimmunity. Reversal is feasible by manipulating enzymes, transcription factors, gene-silencing molecules and toxic exposures or by administering methyl donors and correcting vitamin D deficiency. Gene targets, site specificity, efficacy and consequences are uncertain. Conclusions: Potentially reversible epigenetic changes may affect the occurrence and outcome of autoimmune hepatitis, and investigations are warranted to determine the nature of these changes, key genomic targets, and feasible interventions and their consequences.

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Section: Resultsmentioning

confidence: 99%

Epigenetic changes and their implications in autoimmune hepatitis

Czaja

2018

Eur J Clin Investigation

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“…Although the role of DNA methylation in general and DNMT3A in particular in allergy, asthma, and mast cell activation disorders is far from being completely understood, several studies have investigated the role of Dnmt3a in regulating cytokine production in T lymphocytes (reviewed in ref. 5). For example, the Il2, Il4, and Ifng cytokine genes are regulated by DNA methylation in T cells (46)(47)(48) and, in the absence of Dnmt1 or Dnmt3a (but not Dnmt3b), T lymphocytes were unable to appropriately silence the expression of Ifng or Il4, resulting in unrestrained cytokine expression (49)(50)(51).…”

Section: Dysregulated Dna Methylation Activity Leads To Increased Masmentioning

confidence: 99%

“…Such a process is carried out by three DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B), and has a critical role in the control of gene expression (1,2). In general, high levels of DNA methylation are associated with transcriptional silencing (3), especially when present at promoter regions and at repetitive elements (4), although the function of DNA methylation at other genomic features and its correlation with gene expression are more uncertain (3)(4)(5). Whereas DNMT1 is thought to be primarily responsible for copying the preexisting methylation to the newly synthesized DNA strand during replication, DNMT3A and DNMT3B display significant affinity also for unmethylated DNA, and are therefore considered de novo methyltransferases (6,7).…”

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confidence: 99%

“…More specific to the hematopoietic compartment, loss of Dnmt1 in hematopoietic stem cells (HSCs) led to defects in self-renewal, niche retention, as well as altered cell differentiation, especially toward the myeloid lineage (10), whereas loss of both Dnmt3a and Dnmt3b impaired HSC self-renewal capabilities (11). Importantly, aberrant DNA methylation is a hallmark of many diseases, including autoimmune diseases and especially various types of cancer (4,5). Mutations in DNMT3A have been found in a variety of hematological malignancies (4,12,13), including systemic mastocytosis, a clonal proliferative disorder of mast cells (14), pointing toward a role for DNMT3A in modulating mast cell biology.…”

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confidence: 99%

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Dnmt3a restrains mast cell inflammatory responses

Leoni

Montagner

Rinaldi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

119

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DNA methylation and specifically the DNA methyltransferase enzyme DNMT3A are involved in the pathogenesis of a variety of hematological diseases and in regulating the function of immune cells. Although altered DNA methylation patterns and mutations in DNMT3A correlate with mast cell proliferative disorders in humans, the role of DNA methylation in mast cell biology is not understood. By using mast cells lacking Dnmt3a, we found that this enzyme is involved in restraining mast cell responses to acute and chronic stimuli, both in vitro and in vivo. The exacerbated mast cell responses observed in the absence of Dnmt3a were recapitulated or enhanced by treatment with the demethylating agent 5-aza-2′-deoxycytidine as well as by down-modulation of Dnmt1 expression, further supporting the role of DNA methylation in regulating mast cell activation. Mechanistically, these effects were in part mediated by the dysregulated expression of the scaffold protein IQGAP2, which is characterized by the ability to regulate a wide variety of biological processes. Altogether, our data demonstrate that DNMT3A and DNA methylation are key modulators of mast cell responsiveness to acute and chronic stimulation.DNA methylation | epigenetics | inflammation | mast cells

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“…Epigenetic mechanisms of gene regulation translate the modifications caused by the environment into stable modifications in gene expression . Although DNA methylation is one of the most studied and mechanistically understood epigenetic mechanisms, there is a paucity of data regarding the role of methylation in the regulation of the immune response in OLP. Therefore, this cross‐sectional study aimed to analyse the DNA methylation patterns of immune response‐related genes in the different clinical forms of OLP.…”

Section: Discussionmentioning

confidence: 99%

DNA methylation patterns of genes related to immune response in the different clinical forms of oral lichen planus

Cruz

Resende

Lacerda

et al. 2017

J Oral Pathology Medicine

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Background The oral lichen planus is a chronic inflammatory disease. Although its aetiology is not well understood, the role of T lymphocytes in its inflammatory events is recognised. Identifying the epigenetic mechanisms involved in the pathogenesis of this immune‐mediated condition is fundamental for understanding the inflammatory reaction that occurs in the disease. The purpose of this work was to evaluate the methylation pattern of 21 immune response‐related genes in the different clinical forms of oral lichen planus. Methods A cross‐sectional study was performed to analyse the DNA methylation patterns in three distinct groups of oral lichen planus: (i) reticular/plaque lesions; (ii) erosive lesions; (iii) normal oral mucosa (control group). After DNA extraction from biopsies, the samples were submitted to digestions by methylation‐sensitive and methylation‐dependent enzymes and double digestion. The relative percentage of methylated DNA for each gene was provided using real‐time polymerase chain reaction arrays. Results Hypermethylation of the STAT5A gene was observed only in the control group (59.0%). A higher hypermethylation of the ELANE gene was found in reticular/plaque lesions (72.1%) compared to the erosive lesions (50.0%). Conclusion Our results show variations in the methylation profile of immune response‐related genes, according to the clinical type of oral lichen planus after comparing with the normal oral mucosa. Further studies are necessary to validate these findings using gene expression analysis.

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Epigenetics of T lymphocytes in health and disease

Cited by 13 publications

References 103 publications

Epigenetic changes and their implications in autoimmune hepatitis

Epigenetic changes and their implications in autoimmune hepatitis

Dnmt3a restrains mast cell inflammatory responses

DNA methylation patterns of genes related to immune response in the different clinical forms of oral lichen planus

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