-
Clinical Epigenetics Aug 2023Loss of epigenetic control is a hallmark of aging. Among the most prominent roles of epigenetic mechanisms is the inactivation of one of two copies of the X chromosome...
BACKGROUND
Loss of epigenetic control is a hallmark of aging. Among the most prominent roles of epigenetic mechanisms is the inactivation of one of two copies of the X chromosome in females through DNA methylation. Hence, age-related disruption of X-chromosome inactivation (XCI) may contribute to the aging process in women.
METHODS
We analyzed 9,777 CpGs on the X chromosome in whole blood samples from 2343 females and 1688 males (Illumina 450k methylation array) and replicated findings in duplicate using one whole blood and one purified monocyte data set (in total, 991/924 females/males). We used double generalized linear models to detect age-related differentially methylated CpGs (aDMCs), whose mean methylation level differs with age, and age-related variably methylated CpGs (aVMCs), whose methylation level becomes more variable with age.
RESULTS
In females, aDMCs were relatively uncommon (n = 33) and preferentially occurred in regions known to escape XCI. In contrast, many CpGs (n = 987) were found to display an increased variance with age (aVMCs). Of note, the replication rate of aVMCs was also high in purified monocytes (94%), indicating an independence of cell composition. aVMCs accumulated in CpG islands and regions subject to XCI suggesting that they stemmed from the inactive X. In males, carrying an active copy of the X chromosome only, aDMCs (n = 316) were primarily driven by cell composition, while aVMCs replicated well (95%) but were infrequent (n = 37).
CONCLUSIONS
Our results imply that age-related DNA methylation differences at the inactive X chromosome are dominated by the accumulation of variability.
Topics: Male; Female; Humans; DNA Methylation; X Chromosome; X Chromosome Inactivation; Aging; Epigenesis, Genetic
PubMed: 37626340
DOI: 10.1186/s13148-023-01549-y -
Organic & Biomolecular Chemistry Jul 2022The clinically used DNA-alkylating drug streptozotocin (STZ) was investigated using a simple work-up as an -methylating agent to transform various carboxylic acids,...
The clinically used DNA-alkylating drug streptozotocin (STZ) was investigated using a simple work-up as an -methylating agent to transform various carboxylic acids, sulfonic acids and phosphorous acids into corresponding methyl esters, and did so with yields of up to 97% in 4 h at room temperature. Good substrate tolerance was observed, and benefited from the mild conditions and compatibility of the reaction with water.
Topics: Carboxylic Acids; DNA; Esters; Methylation; Streptozocin
PubMed: 35621003
DOI: 10.1039/d2ob00578f -
Toxicology Jun 2021Between 1990 and 2020, our understanding of the significance of arsenic biomethylation changed in remarkable ways. At the beginning of this period, the conversion of... (Review)
Review
Between 1990 and 2020, our understanding of the significance of arsenic biomethylation changed in remarkable ways. At the beginning of this period, the conversion of inorganic arsenic into mono- and di-methylated metabolites was viewed primarily as a process that altered the kinetic behavior of arsenic. By increasing the rate of clearance of arsenic, the formation of methylated metabolites reduced exposure to this toxin; that is, methylation was detoxification. By 2020, it was clear that at least some of the toxic effects associated with As exposure depended on formation of methylated metabolites containing trivalent arsenic. Because the trivalent oxidation state of arsenic is associated with increased potency as a cytotoxin and clastogen, these findings were consistent with methylation-related changes in the dynamic behavior of arsenic. That is, methylation was activation. Our current understanding of the role of methylation as a modifier of kinetic and dynamic behaviors of arsenic is the product of research at molecular, cellular, organismic, and population levels. This information provides a basis for refining our estimates of risk associated with long term exposure to inorganic arsenic in environmental media, food, and water. This report summarizes the growth of our knowledge of enzymatically catalyzed methylation of arsenic over this period and considers the prospects for new discoveries.
Topics: Animals; Arsenic; Arsenic Poisoning; Environmental Exposure; Humans; Methylation; Oxidation-Reduction
PubMed: 33901604
DOI: 10.1016/j.tox.2021.152800 -
Communications Biology Apr 2022The global dietary supplement market is valued at over USD 100 billion. One popular dietary supplement, S-adenosylmethionine, is marketed to improve joints, liver health...
The global dietary supplement market is valued at over USD 100 billion. One popular dietary supplement, S-adenosylmethionine, is marketed to improve joints, liver health and emotional well-being in the US since 1999, and has been a prescription drug in Europe to treat depression and arthritis since 1975, but recent studies questioned its efficacy. In our body, S-adenosylmethionine is critical for the methylation of nucleic acids, proteins and many other targets. The marketing of SAM implies that more S-adenosylmethionine is better since it would stimulate methylations and improve health. Previously, we have shown that methylation reactions regulate biological rhythms in many organisms. Here, using biological rhythms to assess the effects of exogenous S-adenosylmethionine, we reveal that excess S-adenosylmethionine disrupts rhythms and, rather than promoting methylation, is catabolized to adenine and methylthioadenosine, toxic methylation inhibitors. These findings further our understanding of methyl metabolism and question the safety of S-adenosylmethionine as a supplement.
Topics: Adenine; Dietary Supplements; Liver; Methylation; S-Adenosylmethionine
PubMed: 35383287
DOI: 10.1038/s42003-022-03280-5 -
Molecular Biology and Evolution Feb 2022Considerable attention has recently been focused on the potential involvement of DNA methylation in regulating gene expression in cnidarians. Much of this work has been...
Considerable attention has recently been focused on the potential involvement of DNA methylation in regulating gene expression in cnidarians. Much of this work has been centered on corals, in the context of changes in methylation perhaps facilitating adaptation to higher seawater temperatures and other stressful conditions. Although first proposed more than 30 years ago, the possibility that DNA methylation systems function in protecting animal genomes against the harmful effects of transposon activity has largely been ignored since that time. Here, we show that transposons are specifically targeted by the DNA methylation system in cnidarians, and that the youngest transposons (i.e., those most likely to be active) are most highly methylated. Transposons in longer and highly active genes were preferentially methylated and, as transposons aged, methylation levels declined, reducing the potentially harmful side effects of CpG methylation. In Cnidaria and a range of other invertebrates, correlation between the overall extent of methylation and transposon content was strongly supported. Present transposon burden is the dominant factor in determining overall level of genomic methylation in a range of animals that diverged in or before the early Cambrian, suggesting that genome defense represents the ancestral role of CpG methylation.
Topics: Animals; Cnidaria; CpG Islands; DNA Methylation; Genome; Invertebrates
PubMed: 35084499
DOI: 10.1093/molbev/msac018 -
Journal of Plant Research May 2021Differential epigenetic (DNA cytosine methylation) and gene expression patterns were investigated in reproductive and vegetative organs from Ilex paraguariensis and I....
Differential epigenetic (DNA cytosine methylation) and gene expression patterns were investigated in reproductive and vegetative organs from Ilex paraguariensis and I. dumosa, at distinct developmental stages. We aimed at contributing towards elucidating major molecular changes underlying the sexual differentiation processes which, in these dioecious species, are completely unknown. Simultaneously, as a first step towards the development of an early sexing system, we searched for promising molecular markers. This was assessed through Methylation Sensitive Amplified Polymorphism (MSAP) and Amplified Fragment Length Polymorphism on cDNA (cDNA-AFLP) techniques, applying discriminant multivariate analyses, and bioinformatic characterization of differential fragments. A significant positive correlation was found between epigenetic and indirect 'genetic' information for both species, indicating influence of the genetic background on the epigenetic variation. Higher epigenetic than genetic diversities were estimated. Our outcomes showed up to 1.86 times more representation of mCG subepiloci than mCCG in all organs sampled. Along the maturing stages of floral buds, the frequency of mCG evidenced an incremental trend, whereas mCCG and unmethylated conditions showed opposite tendencies. Reproductive and vegetative samples tended to cluster apart based on epigenetic patterns; at gene expression level, organs exhibited clear-cut distinctive patterns, nonetheless profiles of young leaves and floral primordia resemble. Epigenetic and expression data allowed discrimination of I. dumosa´s samples according to the gender of the donor; more elusive patterns were observed for I. paraguariensis. In total, 102 differentially methylated and expressed fragments were characterized bioinformatically. Forty-three were annotated in various functional categories; four candidate markers were validated through qPCR, finding statistical differences among organs but not among sexes. The methylation condition of epilocus C13m33 appears as indicative of gender in both species. Thirty-three organ-specific and 34 gender-specific methylated markers were discriminated and deserve further research, particularly those expressed in leaves. Our study contributes concrete candidate markers with potential for practical application.
Topics: Amplified Fragment Length Polymorphism Analysis; DNA; DNA Methylation; DNA, Plant; Epigenesis, Genetic; Gene Expression; Ilex
PubMed: 33759060
DOI: 10.1007/s10265-021-01279-3 -
Journal of Biological Rhythms Jun 2022Methylation, that is, the transfer or synthesis of a -CH group onto a target molecule, is a pervasive biochemical modification found in organisms from bacteria to...
Methylation, that is, the transfer or synthesis of a -CH group onto a target molecule, is a pervasive biochemical modification found in organisms from bacteria to humans. In mammals, a complex metabolic pathway powered by the essential nutrients vitamin B9 and B12, methionine and choline, synthesizes -adenosylmethionine, the methyl donor in the methylation of nucleic acids, proteins, fatty acids, and small molecules by over 200 substrate-specific methyltransferases described so far in humans. Methylations not only play a key role in scenarios for the origin and evolution of life, but they remain essential for the development and physiology of organisms alive today, and methylation deficiencies contribute to the etiology of many pathologies. The methylation of histones and DNA is important for circadian rhythms in many organisms, and global inhibition of methyl metabolism similarly affects biological rhythms in prokaryotes and eukaryotes. These observations, together with various pieces of evidence scattered in the literature on circadian gene expression and metabolism, indicate a close mutual interdependence between biological rhythms and methyl metabolism that may originate from prebiotic chemistry. This perspective first proposes an abiogenetic scenario for rhythmic methylations and then outlines mammalian methyl metabolism, before reanalyzing previously published data to draw a tentative map of its profound connections with the circadian clock.
Topics: Animals; Circadian Rhythm; Folic Acid; Humans; Mammals; Methionine; Methylation; S-Adenosylmethionine
PubMed: 35382619
DOI: 10.1177/07487304221083507 -
Tree Physiology Sep 2023DNA methylation (5mC) and N6-methyladenosine (m6A) are two important epigenetics regulators, which have a profound impact on plant growth development. Phyllostachys...
DNA methylation (5mC) and N6-methyladenosine (m6A) are two important epigenetics regulators, which have a profound impact on plant growth development. Phyllostachys edulis (P. edulis) is one of the fastest spreading plants due to its well-developed root system. However, the association between 5mC and m6A has seldom been reported in P. edulis. In particular, the connection between m6A and several post-transcriptional regulators remains uncharacterized in P. edulis. Here, our morphological and electron microscope observations showed the phenotype of increased lateral root under RNA methylation inhibitor (DZnepA) and DNA methylation inhibitor (5-azaC) treatment. RNA epitranscriptome based on Nanopore direct RNA sequencing revealed that DZnepA treatment exhibits significantly decreased m6A level in the 3'-untranslated region (3'-UTR), which was accompanied by increased gene expression, full-length ratio, higher proximal poly(A) site usage and shorter poly(A) tail length. DNA methylation levels of CG and CHG were reduced in both coding sequencing and transposable element upon 5-azaC treatment. Cell wall synthesis was impaired under methylation inhibition. In particular, differentially expressed genes showed a high percentage of overlap between DZnepA and 5-azaC treatment, which suggested a potential correlation between two methylations. This study provides preliminary information for a better understanding of the link between m6A and 5mC in root development of moso bamboo.
Topics: Methylation; Poaceae; RNA; DNA; Gene Expression Regulation, Plant
PubMed: 37294626
DOI: 10.1093/treephys/tpad074 -
Cells Aug 2019Rheumatoid arthritis (RA) is a long-term autoimmune disease of unknown etiology that leads to progressive joint destruction and ultimately to disability. RA affects as... (Review)
Review
Rheumatoid arthritis (RA) is a long-term autoimmune disease of unknown etiology that leads to progressive joint destruction and ultimately to disability. RA affects as much as 1% of the population worldwide. To date, RA is not a curable disease, and the mechanisms responsible for RA development have not yet been well understood. The development of more effective treatments and improvements in the early diagnosis of RA is direly needed to increase patients' functional capacity and their quality of life. As opposed to genetic mutation, epigenetic changes, such as DNA methylation, are reversible, making them good therapeutic candidates, modulating the immune response or aggressive synovial fibroblasts (FLS-fibroblast-like synoviocytes) activity when it is necessary. It has been suggested that DNA methylation might contribute to RA development, however, with insufficient and conflicting results. Besides, recent studies have shown that circulating cell-free methylated DNA (ccfDNA) in blood offers a very convenient, non-invasive, and repeatable "liquid biopsy", thus providing a reliable template for assessing molecular markers of various diseases, including RA. Thus, epigenetic therapies controlling autoimmunity and systemic inflammation may find wider implications for the diagnosis and management of RA. In this review, we highlight current challenges associated with the treatment of RA and other autoimmune diseases and discuss how targeting DNA methylation may improve diagnostic, prognostic, and therapeutic approaches.
Topics: Animals; Arthritis, Rheumatoid; DNA Methylation; Humans
PubMed: 31443448
DOI: 10.3390/cells8090953 -
Methods in Molecular Biology (Clifton,... 2023Arrays provide a cost-effective platform for the analysis of human DNA methylation. ShinyÉPICo is an interactive, web-based, and graphical tool that allows the user to...
Arrays provide a cost-effective platform for the analysis of human DNA methylation. ShinyÉPICo is an interactive, web-based, and graphical tool that allows the user to analyze Illumina DNA methylation arrays (450 k and EPIC), from the user's own computer or from a server. This tool covers the analysis entirely, from the raw data input to the final list of differentially methylated positions or regions. Here, we describe the steps of the analysis, the different parameters available, and useful information to understand and select the best options in each step.
Topics: Humans; Software; DNA Methylation; Data Interpretation, Statistical; CpG Islands
PubMed: 36723806
DOI: 10.1007/978-1-0716-2962-8_2