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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 -
The Journal of Experimental Biology Jul 2020The epigenome determines heritable patterns of gene expression in the absence of changes in DNA sequence. The result is programming of different cellular-, tissue- and... (Review)
Review
The epigenome determines heritable patterns of gene expression in the absence of changes in DNA sequence. The result is programming of different cellular-, tissue- and organ-specific phenotypes from a single organismic genome. Epigenetic marks that comprise the epigenome (e.g. methylation) are placed upon or removed from chromatin (histones and DNA) to direct the activity of effectors that regulate gene expression and chromatin structure. Recently, the cytoskeleton has been identified as a second target for the cell's epigenetic machinery. Several epigenetic 'readers, writers and erasers' that remodel chromatin have been discovered to also remodel the cytoskeleton, regulating structure and function of microtubules and actin filaments. This points to an emerging paradigm for dual-function remodelers with 'chromatocytoskeletal' activity that can integrate cytoplasmic and nuclear functions. For example, the SET domain-containing 2 methyltransferase (SETD2) has chromatocytoskeletal activity, methylating both histones and microtubules. The SETD2 methyl mark on chromatin is required for efficient DNA repair, and its microtubule methyl mark is required for proper chromosome segregation during mitosis. This unexpected convergence of SETD2 activity on histones and microtubules to maintain genomic stability suggests the intriguing possibility of an expanded role in the cell for chromatocytoskeletal proteins that read, write and erase methyl marks on the cytoskeleton as well as chromatin. Coordinated use of methyl marks to remodel both the epigenome and the (epi)cytoskeleton opens the possibility for integrated regulation (which we refer to as 'epiregulation') of other higher-level functions, such as muscle contraction or learning and memory, and could even have evolutionary implications.
Topics: Chromatin; Cytoskeleton; DNA Methylation; Epigenesis, Genetic; Epigenome; Histones; Methylation; Microtubules
PubMed: 32620673
DOI: 10.1242/jeb.220632 -
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 -
Trends in Plant Science Mar 2012Arsenic (As) is a ubiquitous element that is widespread in the environment and causes numerous health problems. Biomethylation of As has implications for its mobility... (Review)
Review
Arsenic (As) is a ubiquitous element that is widespread in the environment and causes numerous health problems. Biomethylation of As has implications for its mobility and toxicity. Photosynthetic organisms may play a significant role in As geochemical cycling by methylating it to different As species, but little is known about the mechanisms of methylation. Methylated As species have been found in many photosynthetic organisms, and several arsenite S-adenosylmethionine (SAM) methyltransferases have been characterized in cyanobacteria and algae. However, higher plants may not have the ability to methylate As. Instead, methylated arsenicals in plants probably originate from microorganisms in soils and the rhizosphere. Here, we propose possible approaches for developing 'smart' photosynthetic organisms with an enhanced and sensitive biomethylation capacity for bioremediation and safer food.
Topics: Animals; Arsenic; Gene Expression Regulation, Enzymologic; Humans; Methylation; Methyltransferases; Photosynthesis; Phylogeny
PubMed: 22257759
DOI: 10.1016/j.tplants.2011.12.003 -
Clinical Epigenetics Jul 2021Non-coding RNA 886 (nc886) is coded from a maternally inherited metastable epiallele. We set out to investigate the determinants and dynamics of the methylation pattern...
BACKGROUND
Non-coding RNA 886 (nc886) is coded from a maternally inherited metastable epiallele. We set out to investigate the determinants and dynamics of the methylation pattern at the nc886 epiallele and how this methylation status associates with nc886 RNA expression. Furthermore, we investigated the associations between the nc886 methylation status or the levels of nc886 RNAs and metabolic traits in the YFS and KORA cohorts. The association between nc886 epiallele methylation and RNA expression was also validated in induced pluripotent stem cell (iPSC) lines.
RESULTS
We confirm that the methylation status of the nc886 epiallele is mostly binomial, with individuals displaying either a non- or hemi-methylated status, but we also describe intermediately and close to fully methylated individuals. We show that an individual's methylation status is associated with the mother's age and socioeconomic status, but not with the individual's own genetics. Once established, the methylation status of the nc886 epiallele remains stable for at least 25 years. This methylation status is strongly associated with the levels of nc886 non-coding RNAs in serum, blood, and iPSC lines. In addition, nc886 methylation status associates with glucose and insulin levels during adolescence but not with the indicators of glucose metabolism or the incidence of type 2 diabetes in adulthood. However, the nc886-3p RNA levels also associate with glucose metabolism in adulthood.
CONCLUSIONS
These results indicate that nc886 metastable epiallele methylation is tuned by the periconceptional conditions and it associates with glucose metabolism through the expression of the ncRNAs coded in the epiallele region.
Topics: Adult; DNA Methylation; Epigenesis, Genetic; Glucose Metabolism Disorders; Humans; RNA, Untranslated
PubMed: 34294131
DOI: 10.1186/s13148-021-01132-3 -
Cancer Science Apr 2005Cancer epigenetics is rapidly moving into a translational phase, and knowledge on how aberrant DNA methylation is induced is becoming important. Aging, chronic... (Review)
Review
Cancer epigenetics is rapidly moving into a translational phase, and knowledge on how aberrant DNA methylation is induced is becoming important. Aging, chronic inflammation, and viral infections are known to promote methylation of non-core regions of promoter CpG islands (CGI). The non-core methylation and 'seeds of methylation', scattered methylation in a CGI, are considered to serve as triggers for dense methylation of a promoter CGI, which permanently represses expression of its downstream gene. Decreased gene transcription is an important factor that promotes induction of dense methylation. The presence of the CGI methylator phenotype (CIMP), in which methylation of multiple CGI was observed, is under dispute. Some gastric cancer cell lines have increased rates of de novo methylation, and neuroblastoma cases with CIMP show qualitatively different prognosis from those without. This strongly supports the presence of CIMP, but it seems to contain multiple entities. Limited knowledge is available for epimutagens, the chemicals that induce DNA demethylation or methylation. We have developed an assay system to detect demethylating agents, and an assay system for methylating agents is necessary. Efforts in the field on how aberrant methylation is induced will lead to new cancer prevention, diagnostics, and therapeutics.
Topics: Animals; CpG Islands; DNA Methylation; Epigenesis, Genetic; Humans; Neoplasms
PubMed: 15819717
DOI: 10.1111/j.1349-7006.2005.00035.x -
Cancer Science Jan 2011A subgroup of colorectal cancer (CRC) shows non-random accumulation of aberrant DNA methylation, so-called CpG island methylator phenotype (CIMP), which was associated... (Review)
Review
A subgroup of colorectal cancer (CRC) shows non-random accumulation of aberrant DNA methylation, so-called CpG island methylator phenotype (CIMP), which was associated with microsatellite instability and BRAF mutation. As just one group of methylation markers was suitable to extract CIMP+/CIMP-high, and had been commonly used in the "one-panel method", it had been unclear whether another cluster of CRC with DNA methylation accumulation exists in microsatellite-stable CRC. We therefore epigenotyped CRC by a comprehensive approach, that is, the two-way unsupervised hierarchical clustering method using highly quantitative methylation data by a single detection method, MALDI-TOF mass spectrometry, on novel regions selected genome-widely through methylated DNA immunoprecipitation on array analysis. CRC was clearly clustered into three DNA methylation epigenotypes, high-, intermediate- and low-methylation epigenotypes (HME, IME, and LME, respectively). Methylation markers are clustered into two distinct groups: Group-1 methylated specifically in HME and including most reported CIMP-related markers; and Group-2 methylated both in HME and IME. While suitable markers to detect a subgroup of CRC with intermediate methylation and correlation to KRAS mutation have been expected to be developed, our data indicated that a "two-panel method" is necessary to properly classify CRC into three epigenotypes, the first panel to extract HME using Group-1 markers, and the second panel to divide the remaining into IME and LME using Group-2 markers. Here we review and compare our recent study and reported CRC classification methods by DNA methylation information, and propose the use of two panels of methylation markers as CRC classifiers.
Topics: Biomarkers; Colorectal Neoplasms; CpG Islands; DNA Methylation; Epigenesis, Genetic; Genotype; Humans; Oncogenes
PubMed: 21159060
DOI: 10.1111/j.1349-7006.2010.01712.x -
Journal of Dental Research Nov 2020The packaging of DNA around nucleosomes exerts dynamic control over eukaryotic gene expression either by granting access to the transcriptional machinery in an open...
The packaging of DNA around nucleosomes exerts dynamic control over eukaryotic gene expression either by granting access to the transcriptional machinery in an open chromatin state or by silencing transcription via chromatin compaction. Histone methylation modification affects chromatin through the addition of methyl groups to lysine or arginine residues of histones H3 and H4 by means of histone methyl transferases or histone demethylases. Changes in histone methylation state modulate periodontal gene expression and have profound effects on periodontal development, health, and therapy. At the onset of periodontal development, progenitor cell populations such as dental follicle cells are characterized by an open H3K4me3 chromatin mark on RUNX2, MSX2, and DLX5 gene promoters. During further development, periodontal progenitor differentiation undergoes a global switch from the H3K4me3 active methyl mark to the H3K27me3 repressive mark. When compared with dental pulp cells, periodontal neural crest lineage differentiation is characterized by repressive H3K9me3 and H3K27me3 marks on typical dentinogenesis-related genes. Inflammatory conditions as they occur during periodontal disease result in unique histone methylation signatures in affected cell populations, including repressive H3K9me3 and H3K27me3 histone marks on extracellular matrix gene promoters and active H3K4me3 marks on interleukin, defensin, and chemokine gene promoters, facilitating a rapid inflammatory response to microbial pathogens. The inflammation-induced repression of chromatin on extracellular matrix gene promoters presents a therapeutic opportunity for the application of histone methylation inhibitors capable of inhibiting suppressive trimethylation marks. Furthermore, inhibition of chromatin coregulators through interference with key inflammatory mediators such as NF-kB by means of methyltransferase inhibitors provides another avenue to halt the exacerbation of the inflammatory response in periodontal tissues. In conclusion, histone methylation dynamics play an intricate role in the fine-tuning of chromatin states during periodontal development and harbor yet-to-be-realized potential for the treatment of periodontal disease.
Topics: DNA Methylation; Epigenesis, Genetic; Histones; Homeostasis; Lysine; Methylation; Protein Processing, Post-Translational
PubMed: 32762486
DOI: 10.1177/0022034520932491 -
Research in Microbiology 2020Mercury methylation converts inorganic mercury into the toxic methylmercury, and the consequences of this transformation are worrisome for human health and the...
Mercury methylation converts inorganic mercury into the toxic methylmercury, and the consequences of this transformation are worrisome for human health and the environment. This process is performed by anaerobic microorganisms, such as several strains related to Pseudodesulfovibrio and Desulfovibrio genera. In order to provide new insights into the molecular mechanisms of mercury methylation, we performed a comparative genomic analysis on mercury methylators and non-methylators from (Pseudo)Desulfovibrio strains. Our results showed that (Pseudo)Desulfovibrio species are phylogenetically and metabolically distant and consequently, these genera should be divided into various genera. Strains able to perform methylation are affiliated with one branch of the phylogenetic tree, but, except for hgcA and hgcB genes, no other specific genetic markers were found among methylating strains. hgcA and hgcB genes can be found adjacent or separated, but proximity between those genes does not promote higher mercury methylation. In addition, close examination of the non-methylator Pseudodesulfovibrio piezophilus C1TLV30 strain, showed a syntenic structure that suggests a recombination event and may have led to hgcB depletion. The genomic analyses identify also arsR gene coding for a putative regulator upstream hgcA. Both genes are cotranscribed suggesting a role of ArsR in hgcA expression and probably a role in mercury methylation.
Topics: Bacterial Proteins; Desulfovibrio; Desulfovibrionaceae; Gene Expression Regulation, Bacterial; Genome, Bacterial; Mercury; Methylation; Phylogeny
PubMed: 31655199
DOI: 10.1016/j.resmic.2019.10.003 -
The International Journal of... 2009Genes constitute only a small proportion of the mammalian genome, the majority of which is composed of non-genic repetitive elements including interspersed repeats and... (Review)
Review
Genes constitute only a small proportion of the mammalian genome, the majority of which is composed of non-genic repetitive elements including interspersed repeats and satellites. A unique feature of the mammalian genome is that there are numerous tissue-dependent, differentially methylated regions (T-DMRs) in the non-repetitive sequences, which include genes and their regulatory elements. The epigenetic status of T-DMRs varies from that of repetitive elements and constitutes the DNA methylation profile genome-wide. Since the DNA methylation profile is specific to each cell and tissue type, much like a fingerprint, it can be used as a means of identification. The formation of DNA methylation profiles is the basis for cell differentiation and development in mammals. The epigenetic status of each T-DMR is regulated by the interplay between DNA methyltransferases, histone modification enzymes, histone subtypes, non-histone nuclear proteins and non-coding RNAs. In this review, we will discuss how these epigenetic factors cooperate to establish cell- and tissue-specific DNA methylation profiles.
Topics: Amino Acid Sequence; Animals; Chromatin Assembly and Disassembly; DNA Methylation; Epigenesis, Genetic; Histones; Methylation; Models, Biological; Molecular Sequence Data; Stem Cells
PubMed: 19412882
DOI: 10.1387/ijdb.082741ki