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Current Opinion in Virology Apr 2023Viral RNAs (vRNAs) are decorated by post-transcriptional modifications, including methylation of nucleotides. Methylations regulate biological functions linked to the... (Review)
Review
Viral RNAs (vRNAs) are decorated by post-transcriptional modifications, including methylation of nucleotides. Methylations regulate biological functions linked to the sequence, structure, and protein interactome of RNA. Several RNA viruses were found to harbor 2'-O-methylations, affecting the ribose moiety of RNA. This mark was initially shown to target the first and second nucleotides of the 5'-end cap structure of mRNA. More recently, nucleotides within vRNA were also reported to carry 2'-O-methylations. The consequences of such methylations are still puzzling since they were associated with both proviral and antiviral effects. Here, we focus on the mechanisms governing vRNA 2'-O-methylation and we explore the possible roles of this epitranscriptomic modification for viral replication.
Topics: Methylation; RNA Caps; RNA, Messenger; Virus Replication; RNA, Viral
PubMed: 36764118
DOI: 10.1016/j.coviro.2023.101302 -
Current Opinion in Plant Biology Aug 2022Cytosine is methylated in both CpG and non-CpG contexts (mCG and mCH, respectively) in plant genomes. Although mCG and mCH are almost independent in regard to their... (Review)
Review
Cytosine is methylated in both CpG and non-CpG contexts (mCG and mCH, respectively) in plant genomes. Although mCG and mCH are almost independent in regard to their "maintenance," recent studies uncovered crosstalk between them during their "establishment," which unexpectedly functions in both RNAi-dependent and -independent pathways. In addition, the importance of linker histone H1 and variants of histone H2A to DNA methylation dynamics is starting to be understood. We summarize these new aspects of mechanisms to generate DNA methylomes and discuss future prospects.
Topics: DNA Methylation; Epigenome
PubMed: 35724481
DOI: 10.1016/j.pbi.2022.102248 -
Current Opinion in Structural Biology Dec 2020The amide bond with its planarity and lack of chemical reactivity is at the heart of protein structure. Chemical methylation of amides is known but was considered too... (Review)
Review
The amide bond with its planarity and lack of chemical reactivity is at the heart of protein structure. Chemical methylation of amides is known but was considered too harsh to be accessible to biology. Until last year there was no protein structure in the data bank with an enzymatically methylated amide. The discovery that the natural macrocyclic product, omphalotin is ribosomally synthesized, was not as had been assumed by non-ribosomal peptide synthesis. This was the first definitive evidence that an enzyme could methylate the amide bond. The enzyme, OphMA, iteratively self-hypermethylates its own C-terminus using SAM as cofactor. A second enzyme OphP, a prolyl oligopeptidase cleaves the core peptide from OphMA and cyclizes it into omphalotin. The molecular mechanism for OphMA was elucidated by mutagenesis, structural, biochemical and theoretical studies. This review highlights current progress in peptide N-methylating enzymes.
Topics: Amides; Cyclosporine; Methylation; Peptides, Cyclic; Protein Processing, Post-Translational; Proteins
PubMed: 32653730
DOI: 10.1016/j.sbi.2020.06.004 -
Biophysical Journal Jun 2021Cytosine methylated at the five-carbon position is the most widely studied reversible DNA modification. Prior findings indicate that methylation can alter mechanical...
Cytosine methylated at the five-carbon position is the most widely studied reversible DNA modification. Prior findings indicate that methylation can alter mechanical properties. However, those findings were qualitative and sometimes contradictory, leaving many aspects unclear. By applying single-molecule magnetic force spectroscopy techniques allowing for direct manipulation and dynamic observation of DNA mechanics and mechanically driven strand separation, we investigated how CpG and non-CpG cytosine methylation affects DNA micromechanical properties. We quantitatively characterized DNA stiffness using persistence length measurements from force-extension curves in the nanoscale length regime and demonstrated that cytosine methylation results in longer contour length and increased DNA flexibility (i.e., decreased persistence length). In addition, we observed the preferential formation of plectonemes over unwound single-stranded "bubbles" of DNA under physiologically relevant stretching forces and supercoiling densities. The flexibility and high structural stability of methylated DNA is likely to have significant consequences on the recruitment of proteins recognizing cytosine methylation and DNA packaging.
Topics: Cytosine; DNA; DNA Methylation; Micromanipulation; Nanotechnology
PubMed: 33838135
DOI: 10.1016/j.bpj.2021.03.039 -
Environment International Jan 2022Residential greenness has been associated with health benefits, but its biological mechanism is largely unknown. Investigation of greenness-related DNA methylation...
BACKGROUND
Residential greenness has been associated with health benefits, but its biological mechanism is largely unknown. Investigation of greenness-related DNA methylation profiles can contribute to mechanistic understanding of the health benefits of residential greenness.
OBJECTIVE
To identify DNA methylation profiles associated with greenness in the immediate surroundings of the residence.
METHODS
We analyzed genome-wide DNA methylation in 1938 blood samples (982 participants) from the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA). We estimated residential greenness based on normalized difference vegetation index at 30 × 30 m cell (green30) and 500 m buffer (green500) around the residential address. We conducted epigenome-wide association study (EWAS) to identify differentially methylated CpGs and regions, and enrichment tests by comparing to the CpGs that previous EWAS identified as associated with allergy, physical activity, and allostatic load-relevant biomarkers.
RESULTS
We identified no genome-wide significant CpGs, but 163 and 56 differentially methylated regions for green30 and green500, respectively. Green30-related DNA methylation profiles showed enrichments in allergy, physical activity, and allostatic load, while green500-related methylation was enriched in allergy and allostatic load.
CONCLUSIONS
Residential greenness may have health impacts through allergic sensitization, stress coping, or behavioral changes. Exposure to more proximal greenness may be more health-relevant.
Topics: Air Pollution; Cohort Studies; DNA; DNA Methylation; Epigenome; Humans
PubMed: 34689037
DOI: 10.1016/j.envint.2021.106945 -
Biomolecules Sep 2020Arsenic occurs naturally in the environment, and exists predominantly as inorganic arsenite (As (III) and arsenate As (V)). Arsenic contamination of drinking water has... (Review)
Review
Arsenic occurs naturally in the environment, and exists predominantly as inorganic arsenite (As (III) and arsenate As (V)). Arsenic contamination of drinking water has long been recognized as a major global health concern. Arsenic exposure causes changes in skin color and lesions, and more severe health conditions such as black foot disease as well as various cancers originating in the lungs, skin, and bladder. In order to efficiently metabolize and excrete arsenic, it is methylated to monomethylarsonic and dimethylarsinic acid. One single enzyme, arsenic methyltransferase (AS3MT) is responsible for generating both metabolites. AS3MT has been purified from several mammalian and nonmammalian species, and its mRNA sequences were determined from amino acid sequences. With the advent of genome technology, mRNA sequences of have been predicted from many species throughout the animal kingdom. Horizontal gene transfer had been postulated for this gene through phylogenetic studies, which suggests the importance of this gene in appropriately handling arsenic exposures in various organisms. An altered ability to methylate arsenic is dependent on specific single nucleotide polymorphisms (SNPs) in AS3MT. Reduced AS3MT activity resulting in poor metabolism of iAs has been shown to reduce expression of the tumor suppressor gene, , which is a potential pathway in arsenic carcinogenesis. Arsenic is also known to induce oxidative stress in cells. However, the presence of antioxidant response elements (AREs) in the promoter sequences of in several species does not correlate with the ability to methylate arsenic. ARE elements are known to bind NRF2 and induce antioxidant enzymes to combat oxidative stress. NRF2 may be partly responsible for the biotransformation of iAs and the generation of methylated arsenic species via AS3MT. In this article, arsenic metabolism, excretion, and toxicity, a discussion of the gene and its evolutionary history, and DNA methylation resulting from arsenic exposure have been reviewed.
Topics: Animals; Arsenic; Cysteine; Humans; Methylation; Methyltransferases; Phylogeny; Polymorphism, Single Nucleotide; Water Pollutants, Chemical
PubMed: 32971865
DOI: 10.3390/biom10091351 -
The Journal of Organic Chemistry Jun 2021The convenient and scalable preparative approach for the two-step α-methylation of ketones is described. The optimized protocols for regioselective preparation of...
The convenient and scalable preparative approach for the two-step α-methylation of ketones is described. The optimized protocols for regioselective preparation of enaminones with further diastereoselective and functional groups tolerant hydrogenation to α-methylketones are developed. The scope and limitations of the proposed methodology are discussed. The advantages compared to known procedures are demonstrated. The unexpected role of acetone in the hydrogenation is suggested. The evaluation of the method for both early building block synthesis and late-stage CH-functionalization is shown. The elaborate procedures' preparability and scalability are demonstrated by the synthesis of several α-methyl ketones up to 100 g amount.
Topics: Catalysis; Hydrogenation; Ketones; Methylation
PubMed: 34042433
DOI: 10.1021/acs.joc.1c00148 -
Epigenetics Dec 2019Increasing numbers of studies implicate abnormal DNA methylation in cancer and many non-malignant diseases. This is consistent with numerous findings about... (Review)
Review
Increasing numbers of studies implicate abnormal DNA methylation in cancer and many non-malignant diseases. This is consistent with numerous findings about differentiation-associated changes in DNA methylation at promoters, enhancers, gene bodies, and sites that control higher-order chromatin structure. Abnormal increases or decreases in DNA methylation contribute to or are markers for cancer formation and tumour progression. Aberrant DNA methylation is also associated with neurological diseases, immunological diseases, atherosclerosis, and osteoporosis. In this review, I discuss DNA hypermethylation in disease and its interrelationships with normal development as well as proposed mechanisms for the origin of and pathogenic consequences of disease-associated hypermethylation. Disease-linked DNA hypermethylation can help drive oncogenesis partly by its effects on cancer stem cells and by the CpG island methylator phenotype (CIMP); atherosclerosis by disease-related cell transdifferentiation; autoimmune and neurological diseases through abnormal perturbations of cell memory; and diverse age-associated diseases by age-related accumulation of epigenetic alterations.
Topics: DNA Methylation; Epigenesis, Genetic; Humans; Immune System Diseases; Neoplasms; Nervous System Diseases
PubMed: 31284823
DOI: 10.1080/15592294.2019.1638701 -
Topics in Current Chemistry (Cham) May 2022Direct reductive N-methylation of inexpensive and readily available nitro compounds as raw material feedstocks is more attractive and straightforward compared with... (Review)
Review
Direct reductive N-methylation of inexpensive and readily available nitro compounds as raw material feedstocks is more attractive and straightforward compared with conventional N-methylation of amines to prepare biologically and pharmaceutically important N-methylated amine derivatives. This strategy for synthesis of N-methylamines avoids prepreparation of NH-free amines and therefore significantly shortens the separation and purification steps. In recent years, numerous methylating agents and catalytic systems have been reported for this appealing transformation. Thus, it is an appropriate time to summarize such advances. This review elaborates on the most important discoveries and advances in this research arena, with special emphasis on the mechanistic aspect of reactions that may provide new insights into catalyst improvement.
Topics: Amines; Catalysis; Methylation; Nitro Compounds
PubMed: 35606628
DOI: 10.1007/s41061-022-00382-w -
Nature Communications Sep 2023DNA methylation at the CpG dinucleotide is considered a stable epigenetic mark due to its presumed long-term inheritance through clonal expansion. Here, we perform...
DNA methylation at the CpG dinucleotide is considered a stable epigenetic mark due to its presumed long-term inheritance through clonal expansion. Here, we perform high-throughput bisulfite sequencing on clonally derived somatic cell lines to quantitatively measure methylation inheritance at the nucleotide level. We find that although DNA methylation is generally faithfully maintained at hypo- and hypermethylated sites, this is not the case at intermediately methylated CpGs. Low fidelity intermediate methylation is interspersed throughout the genome and within genes with no or low transcriptional activity, and is not coordinately maintained between neighbouring sites. We determine that the probabilistic changes that occur at intermediately methylated sites are likely due to DNMT1 rather than DNMT3A/3B activity. The observed lack of clonal inheritance at intermediately methylated sites challenges the current epigenetic inheritance model and has direct implications for both the functional relevance and general interpretability of DNA methylation as a stable epigenetic mark.
Topics: Base Sequence; Nucleotides; DNA Methylation; Cell Line; Epigenesis, Genetic
PubMed: 37660134
DOI: 10.1038/s41467-023-40845-2