Epigenetic determinants in rheumatoid arthritis: the influence of DNA methylation and histone modifications

Epigenetics is a field of science which describes external and environmental modifications to DNA without altering their primary sequences of nucleotides. Contrary to genetic changes, epigenetic modifications are reversible. The epigenetic changes appear as a result of the influence of external factors, such as diet or stress. Epigenetic mechanisms alter the accessibility of DNA by methylation of DNA or post-translational modifications of histones (acetylation, methylation, phosphorylation, ubiquitinqation). The extent of DNA methylation depends on the balance between DNA methyltransferases and demethylases. The main histone modifications are stimulated by K-acetyltransferases, histone deacetylases, K-metyltransferases and K-demethylases. There is proof that environmental modifications of this enzymes regulate immunological processes including autoimmunity in rheumatoid arthritis (RA). In this work we present epigenetic mechanisms involved in RA pathogenesis and a range of research presenting the possible impact of its modification in RA patients.

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DNA methylation: dynamic and stable regulation of memory

BioMolecular Concepts ◽

10.1515/bmc.2011.046 ◽

2011 ◽

Vol 2 (6) ◽

pp. 459-467 ◽

Cited By ~ 2

Author(s):

Thomas Vaissière ◽

Courtney A. Miller

Keyword(s):

Dna Methylation ◽

Transcriptional Regulation ◽

Learning And Memory ◽

Gene Transcription ◽

Histone Modifications ◽

Epigenetic Mechanisms ◽

Epigenetic Changes ◽

Central Process ◽

Recent Advances ◽

Epigenetic Events

AbstractEpigenetic mechanisms have emerged as a central process in learning and memory. Histone modifications and DNA methylation are epigenetic events that can mediate gene transcription. Interesting features of these epigenetic changes are their transient and long lasting potential. Recent advances in neuroscience suggest that DNA methylation is both dynamic and stable, mediating the formation and maintenance of memory. In this review, we will further illustrate the recent hypothesis that DNA methylation participates in the transcriptional regulation necessary for memory.

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Expression of ATRA Inducible RARα2 Isoform Is Deregulated in AML.

Blood ◽

10.1182/blood.v106.11.1204.1204 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1204-1204

Author(s):

Annegret Glasow ◽

Angela Barrett ◽

Rajeev Gupta ◽

David Grimwade ◽

Marieke von Lindern ◽

...

Keyword(s):

Dna Methylation ◽

Retinoic Acid ◽

Cell Lines ◽

Histone Deacetylases ◽

Target Genes ◽

Retinoic Acid Receptor ◽

Cell Types ◽

Dna Methyltransferases ◽

Protein Isoforms ◽

Epigenetic Changes

Abstract Retinoids exert a variety of effects on both normal and malignant hematopoietic cells. To date, three different retinoic acid receptor (RAR) and retinoid X receptor (RXR) genes have been characterized, each encoding multiple N-terminal protein isoforms. RXRs serve as co-regulators for RARs, and many other nuclear receptors integrating different signalling pathways. All-trans-retinoic acid (ATRA) signaling pathway is of critical importance for optimal myelomonocytic differentiation and its disruption by translocations of the RARα gene leads to acute promyelocytic leukemia (APL). APL associated fusion oncoproteins, such as PML-RARα and PLZF-RARα, function through recruitment of histone deacetylases (HDACs) and DNA methyltransferases (DNMTs), thus promoting an inactive chromatin state and leading to repression of RARα target genes. Recently, we demonstrated that up-regulation of RARα2 expression by ATRA directly correlates with differentiation of APL and non-APL AML cells and that RARα2 transcription is silenced by DNA methylation in AML cell lines. Using primary AML samples as well as normal cord and peripheral blood derived cells representing different stages of myelomonocytic development we now show that expression of RARα2 increases with maturation of hematopietic cells. Expression of RARα1 on the other hand, which is transcribed from a distinct promoter, remains relatively constant throughout the different stages of myelomonocytic development. The levels of RARα1 expression in various primary AML cell types appear to be similar to those found in normal hematopietic cells. Consistent with data derived from AML cell lines, however, the RARα2 isoform is poorly expressed in all samples. Compared with CD34+/CD133+ or CD34+ progenitors, and more mature CD33+ myeloid cells, RARα2 is expressed at much lower levels in a variety of primary AML cells and its expression is not effectively induced by myelomonocytic growth factors and/or ATRA. Negatively acting epigenetic changes, such as DNA methylation, appear to be responsible for deregulated expression of RARα2 in AML cells, although their pattern and extent differs significantly between AML cell lines and primary AML samples. Taken together our data suggest that agents, which revert negatively acting epigenetic changes may restore expression of the RARα2 isoform in AML cells and render them more responsive to ATRA as well as other differentiation inducers.

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DNA Methyltransferases in Malar Melasma and Their Modification by Sunscreen in Combination with 4% Niacinamide, 0.05% Retinoic Acid, or Placebo

BioMed Research International ◽

10.1155/2019/9068314 ◽

2019 ◽

Vol 2019 ◽

pp. 1-7 ◽

Cited By ~ 3

Author(s):

Andres Eduardo Campuzano-García ◽

Bertha Torres-Alvarez ◽

Diana Hernández-Blanco ◽

Cornelia Fuentes-Ahumada ◽

Juan Diego Cortés-García ◽

...

Keyword(s):

Dna Methylation ◽

Retinoic Acid ◽

Dna Methyltransferases ◽

Epigenetic Changes ◽

Dna Hypermethylation ◽

Lesional Skin ◽

Methylation Of Dna ◽

Unaffected Skin ◽

Initial Results ◽

Perilesional Skin

Background. Malar melasma has a chronic and recurrent character that may be related to epigenetic changes. Objective. To recognize the expression and DNA methylation of DNA methyltransferases (DNMTs) in malar melasma and perilesional skin, as well as the changes in DNMTs after their treatment with sunscreen in combination with 4% niacinamide, 0.05% retinoic acid, or placebo. Methods. Thirty female patients were clinically evaluated for the expression of DNMT1 and DNMT3b using real-time PCR and immunofluorescence. These initial results were compared to results after eight weeks of treatment with sunscreen in combination with niacinamide, retinoic acid, or placebo. Results. The relative expression of DNMT1 was significantly elevated in melasma compared with unaffected skin in all subjects, indicating DNA hypermethylation. After treatment, it was decreased in all groups: niacinamide (7 versus 1; p<0.01), retinoic acid (7 versus 2; p<0.05), and placebo (7 versus 3; p<0.05), which correlates with clinical improvement. DNMT3b was not overexpressed in lesional skin but reduced in all groups. Conclusions. We found DNA hypermethylation in melasma lesions. Environmental factors such as solar radiation may induce cellular changes that trigger hyperpigmentation through the activation of pathways regulated by epigenetic modifications. However, limiting or decreasing DNA methylation through sunscreen, niacinamide, and retinoic acid treatments that provide photoprotection and genetic transcription can counteract this.

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Epigenetic regulation of peroxiredoxins: Implications in the pathogenesis of cancer

Experimental Biology and Medicine ◽

10.1177/1535370216669834 ◽

2016 ◽

Vol 242 (2) ◽

pp. 140-147 ◽

Cited By ~ 8

Author(s):

Suet-Hui Ow ◽

Pei-Jou Chua ◽

Boon-Huat Bay

Keyword(s):

Dna Methylation ◽

Histone Modifications ◽

Epigenetic Regulation ◽

Histone Deacetylases ◽

Epigenetic Mechanisms ◽

Epigenetic Regulators ◽

Future Treatments ◽

Peroxiredoxin I ◽

Reversible Nature

Peroxiredoxin I to VI (PRX I–VI), a family of highly conserved antioxidants, has been implicated in numerous diseases. There have been reports that PRXs are expressed aberrantly in a variety of tumors, implying that they could play an important role in carcinogenesis. Epigenetic mechanisms such as DNA methylation, histone modifications, and microRNAs have been reported to modulate expression of PRXs. In addition, the use of epigenetic regulators, such as histone deacetylases, has been demonstrated to restore PRX to normal levels, indicating that the reversible nature of epigenetics can be exploited for future treatments.

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Epigenetic regulation of the human mucin gene MUC4 in epithelial cancer cell lines involves both DNA methylation and histone modifications mediated by DNA methyltransferases and histone deacetylases

The FASEB Journal ◽

10.1096/fj.07-103390 ◽

2008 ◽

Vol 22 (8) ◽

pp. 3035-3045 ◽

Cited By ~ 41

Author(s):

Audrey Vincent ◽

Marie‐Paule Ducourouble ◽

Isabelle Van Seuningen

Keyword(s):

Dna Methylation ◽

Cell Lines ◽

Cancer Cell ◽

Histone Modifications ◽

Epigenetic Regulation ◽

Histone Deacetylases ◽

Cancer Cell Lines ◽

Dna Methyltransferases ◽

Epithelial Cancer ◽

Mucin Gene

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DNA Methylation and Immune Memory Response

Cells ◽

10.3390/cells10112943 ◽

2021 ◽

Vol 10 (11) ◽

pp. 2943

Author(s):

Nathalia Noschang Mittelstaedt ◽

André Luiz Becker ◽

Deise Nascimento de Freitas ◽

Rafael F. Zanin ◽

Renato T. Stein ◽

...

Keyword(s):

Dna Methylation ◽

Adaptive Immune Response ◽

Dna Methyltransferases ◽

Immune Memory ◽

Epigenetic Changes ◽

Cpg Dinucleotides ◽

Memory Response ◽

Methylation Of Dna ◽

Complex Process ◽

And Function

The generation of memory is a cardinal feature of the adaptive immune response, involving different factors in a complex process of cellular differentiation. This process is essential for protecting the second encounter with pathogens and is the mechanism by which vaccines work. Epigenetic changes play important roles in the regulation of cell differentiation events. There are three types of epigenetic regulation: DNA methylation, histone modification, and microRNA expression. One of these epigenetic changes, DNA methylation, occurs in cytosine residues, mainly in CpG dinucleotides. This brief review aimed to analyse the literature to verify the involvement of DNA methylation during memory T and B cell development. Several studies have highlighted the importance of the DNA methyltransferases, enzymes that catalyse the methylation of DNA, during memory differentiation, maintenance, and function. The methylation profile within different subsets of naïve activated and memory cells could be an interesting tool to help monitor immune memory response.

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Influence of Benzo(a)pyrene on Different Epigenetic Processes

International Journal of Molecular Sciences ◽

10.3390/ijms222413453 ◽

2021 ◽

Vol 22 (24) ◽

pp. 13453

Author(s):

Bożena Bukowska ◽

Paulina Sicińska

Keyword(s):

Lung Cancer ◽

Dna Methylation ◽

Histone Deacetylases ◽

Polyaromatic Hydrocarbons ◽

Methylation Status ◽

Underlying Mechanism ◽

Epidemiological Studies ◽

Dna Methyltransferases ◽

Epigenetic Changes ◽

Marine Medaka

Epigenetic changes constitute one of the processes that is involved in the mechanisms of carcinogenicity. They include dysregulation of DNA methylation processes, disruption of post-translational patterns of histone modifications, and changes in the composition and/or organization of chromatin. Benzo(a)pyrene (BaP) influences DNA methylation and, depending on its concentrations, as well as the type of cell, tissue and organism it causes hypomethylation or hypermethylation. Moreover, the exposure to polyaromatic hydrocarbons (PAHs), including BaP in tobacco smoke results in an altered methylation status of the offsprings. Researches have indicated a potential relationship between toxicity of BaP and deregulation of the biotin homeostasis pathway that plays an important role in the process of carcinogenesis. Animal studies have shown that parental-induced BaP toxicity can be passed on to the F1 generation as studied on marine medaka (Oryzias melastigma), and the underlying mechanism is likely related to a disturbance in the circadian rhythm. In addition, ancestral exposure of fish to BaP may cause intergenerational osteotoxicity in non-exposed F3 offsprings. Epidemiological studies of lung cancer have indicated that exposure to BaP is associated with changes in methylation levels at 15 CpG; therefore, changes in DNA methylation may be considered as potential mediators of BaP-induced lung cancer. The mechanism of epigenetic changes induced by BaP are mainly due to the formation of CpG-BPDE adducts, between metabolite of BaP—BPDE and CpG, which leads to changes in the level of 5-methylcytosine. BaP also acts through inhibition of DNA methyltransferases activity, as well as by increasing histone deacetylases HDACs, i.e., HDAC2 and HDAC3 activity. The aim of this review is to discuss the mechanism of the epigenetic action of BaP on the basis of the latest publications.

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Epigenetics, Nutrition, Disease and Drug Development

Current Drug Discovery Technologies ◽

10.2174/1570163815666180419154954 ◽

2019 ◽

Vol 16 (4) ◽

pp. 386-391 ◽

Cited By ~ 1

Author(s):

Kenneth Lundstrom

Keyword(s):

Dna Methylation ◽

Drug Discovery ◽

Rna Interference ◽

Nutritional Requirements ◽

Signal Pathways ◽

Disease Development ◽

Epigenetic Mechanisms ◽

Epigenetic Changes ◽

Health And Disease ◽

Novel Drug

Epigenetic mechanisms comprising of DNA methylation, histone modifications and gene silencing by RNA interference have been strongly linked to the development and progression of various diseases. These findings have triggered research on epigenetic functions and signal pathways as targets for novel drug discovery. Dietary intake has also presented significant influence on human health and disease development and nutritional modifications have proven important in prevention, but also the treatment of disease. Moreover, a strong link between nutrition and epigenetic changes has been established. Therefore, in attempts to develop novel safer and more efficacious drugs, both nutritional requirements and epigenetic mechanisms need to be addressed.

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Neuroblastoma and the epigenome

Cancer and Metastasis Reviews ◽

10.1007/s10555-020-09946-y ◽

2021 ◽

Author(s):

Irfete S. Fetahu ◽

Sabine Taschner-Mandl

Keyword(s):

Dna Methylation ◽

Histone Modifications ◽

Disease Diagnosis ◽

Dna Methyltransferases ◽

Epigenetic Alterations ◽

Aberrant Expression ◽

Tet Proteins ◽

Relative Paucity ◽

Underlying Causes ◽

Aberrant Dna Methylation

AbstractNeuroblastoma (NB) is a pediatric cancer of the sympathetic nervous system and one of the most common solid tumors in infancy. Amplification of MYCN, copy number alterations, numerical and segmental chromosomal aberrations, mutations, and rearrangements on a handful of genes, such as ALK, ATRX, TP53, RAS/MAPK pathway genes, and TERT, are attributed as underlying causes that give rise to NB. However, the heterogeneous nature of the disease—along with the relative paucity of recurrent somatic mutations—reinforces the need to understand the interplay of genetic factors and epigenetic alterations in the context of NB. Epigenetic mechanisms tightly control gene expression, embryogenesis, imprinting, chromosomal stability, and tumorigenesis, thereby playing a pivotal role in physio- and pathological settings. The main epigenetic alterations include aberrant DNA methylation, disrupted patterns of posttranslational histone modifications, alterations in chromatin composition and/or architecture, and aberrant expression of non-coding RNAs. DNA methylation and demethylation are mediated by DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) proteins, respectively, while histone modifications are coordinated by histone acetyltransferases and deacetylases (HATs, HDACs), and histone methyltransferases and demethylases (HMTs, HDMs). This article focuses predominately on the crosstalk between the epigenome and NB, and the implications it has on disease diagnosis and treatment.

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