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Environmental Pollution (Barking, Essex... Jul 2022Lead (Pb) exposure can induce DNA damage and alter DNA methylation but their inter-relationships have not been adequately determined. Our overall aims were to explore...
Lead (Pb) exposure can induce DNA damage and alter DNA methylation but their inter-relationships have not been adequately determined. Our overall aims were to explore such relationships and to evaluate underlying epigenetic mechanisms of Pb-induced genotoxicity in Chinese workers. Blood Pb levels (BLLs) were determined and used as individual's Pb-exposure dose and the Comet assay (i.e., % tail DNA) was conducted to evaluate DNA damage. In the screening assay, 850 K BeadChip sequencing was performed on peripheral blood from 10 controls (BLLs ≤100 μg/L) and 20 exposed workers (i.e., 10 DNA-damaged and 10 DNA-undamaged workers). Using the technique, differentially methylated positions (DMPs) between the controls and the exposed workers were identified. In addition, DMPs were identified between the DNA-undamaged and DNA-damaged workers (% tail DNA >2.14%). In our validation assay, methylation levels of four candidate genes were measured by pyrosequencing in an independent sample set (n = 305), including RRAGC (Ras related GTP binding C), USP1 (Ubiquitin specific protease 1), COPS7B (COP9 signalosome subunit 7 B) and CHEK1 (Checkpoint kinase 1). The result of comparisons between the controls and the Pb-exposed workers show that DMPs were significantly enriched in genes related to nerve conduction and cell cycle. Between DNA-damaged group and DNA-undamaged group, differentially methylated genes were enriched in the pathways related to cell cycle and DNA integrity checkpoints. Additionally, methylation levels of RRAGC and USP1 were negatively associated with BLLs (P < 0.05), and the former mediated 19.40% of the effect of Pb on the % tail DNA. These findings collectively indicated that Pb-induced DNA damage was closely related to methylation of genes in cell cycle regulation, and methylation levels of RRAGC were involved in Pb-induced genotoxicity.
Topics: DNA; DNA Damage; DNA Methylation; Humans; Lead; Occupational Exposure
PubMed: 35385786
DOI: 10.1016/j.envpol.2022.119252 -
Clinical Epigenetics Oct 2021
Topics: DNA Methylation; Disease Susceptibility; Ethnicity; Humans
PubMed: 34635160
DOI: 10.1186/s13148-021-01180-9 -
Bioorganic Chemistry Dec 2023Peptide-based drugs have garnered considerable attention in recent years owing to their increasingly crucial role in the treatment of diverse diseases. However, the... (Review)
Review
Peptide-based drugs have garnered considerable attention in recent years owing to their increasingly crucial role in the treatment of diverse diseases. However, the limited pharmacokinetic properties of peptides have hindered their full potential. One prominent strategy for enhancing the druggability of peptides is N-methylation, which involves the addition of a methyl group to the nitrogen atom of the peptide backbone. This modification significantly improves the stability, bioavailability, receptor binding affinity and selectivity of peptide drug candidates. In this review, we provide a comprehensive overview of the advancements in synthetic methods for N-methylated peptide synthesis, as well as the associated limitations. Moreover, we explore the versatile effects of N-methylation on various aspects of peptide properties. Furthermore, we emphasize the efforts dedicated to N-methylated peptide pharmaceuticals that have successfully obtained marketing approval.
Topics: Methylation; Peptides; Drug Development; Nitrogen; Pharmaceutical Preparations
PubMed: 37776681
DOI: 10.1016/j.bioorg.2023.106892 -
Chemical Society Reviews May 2021The selective and efficient C-H methylation of sp and sp carbon centres has become a powerful transformation in the synthetic toolbox. Due to the potential for profound... (Review)
Review
The selective and efficient C-H methylation of sp and sp carbon centres has become a powerful transformation in the synthetic toolbox. Due to the potential for profound changes to physicochemical properties attributed to the installation of a "Magic Methyl" group at a strategic site in a lead compound, such techniques have become highly desirable in modern drug discovery and synthesis programmes. This review will cover the diverse techniques that have been employed to enable the selective installation of the C-Me bond in a wide range of chemical structures, from simple building blocks to complex drug-like architectures.
Topics: Chemistry Techniques, Synthetic; Methylation; Molecular Structure; Organic Chemicals
PubMed: 33690769
DOI: 10.1039/d0cs00973c -
International Journal For Equity in... Sep 2023Historical trauma experienced by Indigenous peoples of North America is correlated with health disparities and is hypothesized to be associated with DNA methylation....
BACKGROUND
Historical trauma experienced by Indigenous peoples of North America is correlated with health disparities and is hypothesized to be associated with DNA methylation. Massive group traumas such as genocide, loss of land and foodways, and forced conversion to Western lifeways may be embodied and affect individuals, families, communities, cultures, and health. This study approaches research with Alaska Native people using a community-engaged approach designed to create mutually-beneficial partnerships, including intentional relationship development, capacity building, and sample and data care.
METHODS
A total of 117 Alaska Native individuals from two regions of Alaska joined the research study. Participants completed surveys on cultural identification, historical trauma (historical loss scale and historical loss associated symptoms scale), and general wellbeing. Participants provided a blood sample which was used to assess DNA methylation with the Illumina Infinium MethylationEPIC array.
RESULTS
We report an association between historical loss associated symptoms and DNA methylation at five CpG sites, evidencing the embodiment of historical trauma. We further report an association between cultural identification and general wellbeing, complementing evidence from oral narratives and additional studies that multiple aspects of cultural connection may buffer the effects of and/or aid in the healing process from historical trauma.
CONCLUSION
A community-engaged approach emphasizes balanced partnerships between communities and researchers. Here, this approach helps better understand embodiment of historical trauma in Alaska Native peoples. This analysis reveals links between the historical trauma response and DNA methylation. Indigenous communities have been stigmatized for public health issues instead caused by systemic inequalities, social disparities, and discrimination, and we argue that the social determinants of health model in Alaska Native peoples must include the vast impact of historical trauma and ongoing colonial violence.
Topics: Humans; Methylation; Alaska; Community Participation; Historical Trauma; Stakeholder Participation; Indigenous Peoples
PubMed: 37679827
DOI: 10.1186/s12939-023-01967-7 -
PloS One 2022Low socioeconomic status neighborhood exposure to stress and violence may be sources of negative stimuli that poses significant health risks for children, adolescents...
BACKGROUND
Low socioeconomic status neighborhood exposure to stress and violence may be sources of negative stimuli that poses significant health risks for children, adolescents and throughout the life course of an individual. The study aims to investigate if aberrant epigenetic DNA methylation changes may be a potential mechanism for regulating neighborhood exposures and health outcomes.
METHODS
Exposure to environmental stressors identified in 98 young African American (AA) adults aged 18-25 years old from the Washington D.C., area were used in the study. We correlated the association between stress markers; cortisol, CRP, IgG, IGA, IgM, and self-reported exposure to violence and stress, with quantitative DNA methylation changes in a panel of gene-specific loci using saliva DNA.
RESULTS
In all participants studied, the exposure to violence was significant and negatively correlated with DNA methylation of MST1R loci (p = 0.032; r = -0.971) and nominally significant with NR3C1 loci (p = 0.053; r = -0.948). In addition, we observed significant and negative correlation of DNA methylation changes of LINE1 (p = 0.044; r = -0.248); NR3C1 (p = 0.017; r = -0.186); MSTR1 (p = 0.022; r = -0.192); and DRD2 (p = 0.056; r = -0.184; albeit nominal significant correlation) with IgA expression. On the other hand, we observed a significant and position correlation of DNA methylation changes in DRD2 (p = 0.037; r = 0.184) with IgG expression. When participants were stratified by sex, we observed in AA young male adults, significant DNA methylation changes of MST1R (p< 0.05) and association with exposure to violence and IgG level. We also observed significant DNA methylation levels of DRD2 (p< 0.05) and association with IgA, IgG, and cortisol level. Furthermore, we observed significant DNA methylation changes of NR3C1 (p< 0.05) with stress, IgA, and IgG in the male participants only. On the other hand, we only observed significant and a positive association of IgG with DNA methylation levels of ESR1 (p = 0.041) in the young AA female participants.
CONCLUSION
Our preliminary observation of significant DNA methylation changes in neuronal and immune genes in saliva samples supports our recently published genome-wide DNA methylations changes in blood samples from young AA male adults indicating that saliva offers a non-invasive means for DNA methylation prediction of exposure to environmental stressors in a gender-specific manner.
Topics: Adolescent; Adult; Black or African American; Child; DNA; DNA Methylation; Female; Humans; Hydrocortisone; Immunoglobulin A; Immunoglobulin G; Male; Saliva; Sex Characteristics; Young Adult
PubMed: 36067197
DOI: 10.1371/journal.pone.0273717 -
Biology Direct May 2024The enzymes performing protein post-translational modifications (PTMs) form a critical post-translational regulatory circuitry that orchestrates literally all cellular... (Review)
Review
The enzymes performing protein post-translational modifications (PTMs) form a critical post-translational regulatory circuitry that orchestrates literally all cellular processes in the organism. In particular, the balance between cellular stemness and differentiation is crucial for the development of multicellular organisms. Importantly, the fine-tuning of this balance on the genetic level is largely mediated by specific PTMs of histones including lysine methylation. Lysine methylation is carried out by special enzymes (lysine methyltransferases) that transfer the methyl group from S-adenosyl-L-methionine to the lysine residues of protein substrates. Set7/9 is one of the exemplary protein methyltransferases that however, has not been fully studied yet. It was originally discovered as histone H3 lysine 4-specific methyltransferase, which later was shown to methylate a number of non-histone proteins that are crucial regulators of stemness and differentiation, including p53, pRb, YAP, DNMT1, SOX2, FOXO3, and others. In this review we summarize the information available to date on the role of Set7/9 in cellular differentiation and tissue development during embryogenesis and in adult organisms. Finally, we highlight and discuss the role of Set7/9 in pathological processes associated with aberrant cellular differentiation and self-renewal, including the formation of cancer stem cells.
Topics: Histone-Lysine N-Methyltransferase; Cell Differentiation; Humans; Animals; Protein Processing, Post-Translational; Methylation; Stem Cells
PubMed: 38812048
DOI: 10.1186/s13062-024-00484-z -
Proceedings of the National Academy of... Jun 2020The development of methyl-transverse relaxation-optimized spectroscopy (methyl-TROSY)-based NMR methods, in concert with robust strategies for incorporation of...
The development of methyl-transverse relaxation-optimized spectroscopy (methyl-TROSY)-based NMR methods, in concert with robust strategies for incorporation of methyl-group probes of structure and dynamics into the protein of interest, has facilitated quantitative studies of high-molecular-weight protein complexes. Here we develop a one-pot in vitro reaction for producing NMR quantities of methyl-labeled DNA at the C5 and N6 positions of cytosine (5mC) and adenine (6mA) nucleobases, respectively, enabling the study of high-molecular-weight DNA molecules using TROSY approaches originally developed for protein applications. Our biosynthetic strategy exploits the large number of naturally available methyltransferases to specifically methylate DNA at a desired number of sites that serve as probes of structure and dynamics. We illustrate the methodology with studies of the 153-base pair Widom DNA molecule that is simultaneously methyl-labeled at five sites, showing that high-quality C-H spectra can be recorded on 100 μM samples in a few minutes. NMR spin relaxation studies of labeled methyl groups in both DNA and the H2B histone protein component of the 200-kDa nucleosome core particle (NCP) establish that methyl groups at 5mC and 6mA positions are, in general, more rigid than Ile, Leu, and Val methyl probes in protein side chains. Studies focusing on histone H2B of NCPs wrapped with either wild-type DNA or DNA methylated at all 26 CpG sites highlight the utility of NMR in investigating the structural dynamics of the NCP and how its histone core is affected through DNA methylation, an important regulator of transcription.
Topics: Adenine; Carbon Isotopes; CpG Islands; Cytosine; DNA; DNA Methylation; DNA-Binding Proteins; Molecular Dynamics Simulation; Molecular Weight; Nuclear Magnetic Resonance, Biomolecular; Nucleosomes; Spectrum Analysis
PubMed: 32457157
DOI: 10.1073/pnas.2004317117 -
Communications Biology May 2020The methyl cycle is a universal metabolic pathway providing methyl groups for the methylation of nuclei acids and proteins, regulating all aspects of cellular...
The methyl cycle is a universal metabolic pathway providing methyl groups for the methylation of nuclei acids and proteins, regulating all aspects of cellular physiology. We have previously shown that methyl cycle inhibition in mammals strongly affects circadian rhythms. Since the methyl cycle and circadian clocks have evolved early during evolution and operate in organisms across the tree of life, we sought to determine whether the link between the two is also conserved. Here, we show that methyl cycle inhibition affects biological rhythms in species ranging from unicellular algae to humans, separated by more than 1 billion years of evolution. In contrast, the cyanobacterial clock is resistant to methyl cycle inhibition, although we demonstrate that methylations themselves regulate circadian rhythms in this organism. Mammalian cells with a rewired bacteria-like methyl cycle are protected, like cyanobacteria, from methyl cycle inhibition, providing interesting new possibilities for the treatment of methylation deficiencies.
Topics: Animals; Arabidopsis; Caenorhabditis elegans; Chlamydomonas reinhardtii; Chlorophyta; Circadian Rhythm; Drosophila melanogaster; Humans; Methylation; Mice; Synechococcus; Zebrafish
PubMed: 32376902
DOI: 10.1038/s42003-020-0942-0 -
Genes Feb 2023Epigenetics is a gene-environment interaction mechanism, manifested mostly through changes in regulatory gene expression. Stress is an established environmental factor...
Epigenetics is a gene-environment interaction mechanism, manifested mostly through changes in regulatory gene expression. Stress is an established environmental factor known to induce epigenetic changes. This study aimed to assess the long-term effect of stress as juveniles, or juvenile and adult stress, on alterations in glutamic acid decarboxylase genes (, ). We assessed DNA methylation and RNA expression in four rat groups: (1) control group, (2) juvenile stress group sacrificed two days following stress exposure (JSe) (RNA only), (3) juvenile stress group sacrificed as adults (JS), and (4) juvenile and adult stress group (JS + AS). Three different areas of the brain were examined in each group: the dorsal dentate gyrus (dDG), the dorsal CA1 (dCA1), and the basolateral amygdala (BLA). A significantly low methylation level of in the BLA was observed among the JS group, followed by almost complete recovery among the JS + AS group. However, in dDG, an opposite trend was captured, and higher methylation was found in JS. In addition, RNA levels were found to be decreased in JS compared to JSe and JS + AS. These findings can point to a possible mechanism: while juvenile stress may enhance a better coping strategy with life challenges, additional stress in adulthood may trigger a contradictory response, either beneficial or harmful.
Topics: Rats; Animals; Brain; DNA Methylation; Epigenesis, Genetic; RNA
PubMed: 36980837
DOI: 10.3390/genes14030565