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The Journal of Biological Chemistry Dec 2023One-carbon metabolism is a central metabolic pathway critical for the biosynthesis of several amino acids, methyl group donors, and nucleotides. The pathway mostly... (Review)
Review
One-carbon metabolism is a central metabolic pathway critical for the biosynthesis of several amino acids, methyl group donors, and nucleotides. The pathway mostly relies on the transfer of a carbon unit from the amino acid serine, through the cofactor folate (in its several forms), and to the ultimate carbon acceptors that include nucleotides and methyl groups used for methylation of proteins, RNA, and DNA. Nucleotides are required for DNA replication, DNA repair, gene expression, and protein translation, through ribosomal RNA. Therefore, the one-carbon metabolism pathway is essential for cell growth and function in all cells, but is specifically important for rapidly proliferating cells. The regulation of one-carbon metabolism is a critical aspect of the normal and pathological function of the pathway, such as in cancer, where hijacking these regulatory mechanisms feeds an increased need for nucleotides. One-carbon metabolism is regulated at several levels: via gene expression, posttranslational modification, subcellular compartmentalization, allosteric inhibition, and feedback regulation. In this review, we aim to inform the readers of relevant one-carbon metabolism regulation mechanisms and to bring forward the need to further study this aspect of one-carbon metabolism. The review aims to integrate two major aspects of cancer metabolism-signaling downstream of nutrient sensing and one-carbon metabolism, because while each of these is critical for the proliferation of cancerous cells, their integration is critical for comprehensive understating of cellular metabolism in transformed cells and can lead to clinically relevant insights.
Topics: Humans; Amino Acids; Carbon; Cell Proliferation; Enzyme Activation; Enzymes; Folic Acid; Methylation; Neoplasms; Nucleotides; Serine
PubMed: 37949226
DOI: 10.1016/j.jbc.2023.105457 -
British Journal of Cancer Oct 2023Tobacco smoking is suggested as a risk factor for colorectal cancer (CRC), but the complex relationship and the potential pathway are not fully understood.
BACKGROUND
Tobacco smoking is suggested as a risk factor for colorectal cancer (CRC), but the complex relationship and the potential pathway are not fully understood.
METHODS
We performed two-sample Mendelian randomisation (MR) analyses with genetic instruments for smoking behaviours and related DNA methylation in blood and summary-level GWAS data of colorectal cancer to disentangle the relationship. Colocalization analyses and prospective gene-environment interaction analyses were also conducted as replication.
RESULTS
Convincing evidence was identified for the pathogenic effect of smoking initiation on CRC risk and suggestive evidence was observed for the protective effect of smoking cessation in the univariable MR analyses. Multivariable MR analysis revealed that these associations were independent of other smoking phenotypes and alcohol drinking. Genetically predicted methylation at CpG site cg17823346 [ZMIZ1] were identified to decrease CRC risk; while genetically predicted methylation at cg02149899 would increase CRC risk. Colocalization and gene-environment interaction analyses added further evidence to the relationship between epigenetic modification at cg17823346 [ZMIZ1] as well as cg02149899 and CRC risk.
DISCUSSION
Our study confirms the significant association between tobacco smoking, DNA methylation and CRC risk and yields a novel insight into the pathogenic effect of tobacco smoking on CRC risk.
Topics: Humans; Smoking; DNA Methylation; Prospective Studies; Colorectal Neoplasms; Tobacco Smoking; Genome-Wide Association Study; Polymorphism, Single Nucleotide
PubMed: 37608097
DOI: 10.1038/s41416-023-02397-6 -
Cancer Research Jun 2024Tobacco use is a major modifiable risk factor for adverse health outcomes, including cancer, and elicits profound epigenetic changes thought to be associated with...
UNLABELLED
Tobacco use is a major modifiable risk factor for adverse health outcomes, including cancer, and elicits profound epigenetic changes thought to be associated with long-term cancer risk. While electronic cigarettes (e-cigarettes) have been advocated as harm reduction alternatives to tobacco products, recent studies have revealed potential detrimental effects, highlighting the urgent need for further research into the molecular and health impacts of e-cigarettes. Here, we applied computational deconvolution methods to dissect the cell- and tissue-specific epigenetic effects of tobacco or e-cigarette use on DNA methylation (DNAme) in over 3,500 buccal/saliva, cervical, or blood samples, spanning epithelial and immune cells at directly and indirectly exposed sites. The 535 identified smoking-related DNAme loci [cytosine-phosphate-guanine sites (CpG)] clustered into four functional groups, including detoxification or growth signaling, based on cell type and anatomic site. Loci hypermethylated in buccal epithelial cells of smokers associated with NOTCH1/RUNX3/growth factor receptor signaling also exhibited elevated methylation in cancer tissue and progressing lung carcinoma in situ lesions, and hypermethylation of these sites predicted lung cancer development in buccal samples collected from smokers up to 22 years prior to diagnosis, suggesting a potential role in driving carcinogenesis. Alarmingly, these CpGs were also hypermethylated in e-cigarette users with a limited smoking history. This study sheds light on the cell type-specific changes to the epigenetic landscape induced by smoking-related products.
SIGNIFICANCE
The use of both cigarettes and e-cigarettes elicits cell- and exposure-specific epigenetic effects that are predictive of carcinogenesis, suggesting caution when broadly recommending e-cigarettes as aids for smoking cessation.
Topics: Humans; DNA Methylation; Cigarette Smoking; Electronic Nicotine Delivery Systems; Carcinogenesis; Epigenesis, Genetic; Female; Lung Neoplasms; Vaping; Male; Receptor, Notch1; Adult
PubMed: 38503267
DOI: 10.1158/0008-5472.CAN-23-2957 -
Cancer Communications (London, England) Nov 2023
Topics: Humans; Stomach Neoplasms; DNA Methylation; Promoter Regions, Genetic; Cytoskeletal Proteins; Ubiquitin-Protein Ligases
PubMed: 37584087
DOI: 10.1002/cac2.12478 -
FEBS Open Bio Jul 2023Myasthenia gravis (MG) is a common neuromuscular junction disorder and autoimmune disease mediated by several antibodies. Several studies have shown that genetic factors...
Myasthenia gravis (MG) is a common neuromuscular junction disorder and autoimmune disease mediated by several antibodies. Several studies have shown that genetic factors play an important role in MG pathogenesis. To gain insight into the epigenetic factors affecting MG, we report here genome-scale DNA methylation profiles of MG. DNA was extracted from eight MG patients and four healthy controls for genome-wide DNA methylation analysis using the Illumina HumanMethylation 850K BeadChip. Verification of pyrosequencing was conducted based on differential methylation positions. Subsequently, C2C12 and HT22 cell lines (derived from mouse) were treated with demethylation drugs. Transcribed mRNA of the screened differential genes was detected using quantitative real-time PCR. The control and MG group were compared, and two key probe positions were selected. The corresponding genes were CAMK1D and CREB5 (P < 0.05). Similarly, the myasthenic crisis (MC) and non-MC group were compared and four key probe positions were selected. The corresponding genes were SAV1, STK3, YAP1, and WWTR1 (P < 0.05). Subsequently, pyrosequencing was performed for verification, revealing that hypomethylation of CAMK1D was significantly different between the MG and control group (P < 0.001). Moreover, transcription of CREB5, PKD, YAP1, and STK3 genes in the C2C12 cells was downregulated (P < 0.05) after drug treatment, but only YAP1 mRNA was downregulated in HT22 cells (P < 0.05). This is the first study to investigate genome-scale DNA methylation profiles of MG using 850 K BeadChip. The identified molecular markers of methylation may aid in the prevention, diagnosis, treatment, and prognosis of MG.
Topics: Animals; Mice; DNA Methylation; Epigenome; Myasthenia Gravis; Biomarkers; RNA, Messenger
PubMed: 37254650
DOI: 10.1002/2211-5463.13656 -
Plant Signaling & Behavior Dec 2023Methyltransferase (MTase) enzymes catalyze the addition of a methyl group to a variety of biological substrates. MTase-like (METTL) proteins are Class I MTases whose...
Methyltransferase (MTase) enzymes catalyze the addition of a methyl group to a variety of biological substrates. MTase-like (METTL) proteins are Class I MTases whose enzymatic activities contribute to the epigenetic and epitranscriptomic regulation of multiple cellular processes. N-adenosine methylation (mA) is a common chemical modification of eukaryotic and viral RNA whose abundance is jointly regulated by MTases and METTLs, demethylases, and mA binding proteins. mA affects various cellular processes including RNA degradation, post-transcriptional processing, and antiviral immunity. Here, we used and plum pox virus (PPV), an RNA virus of the family, to investigated the roles of MTases in plant-virus interaction. RNA sequencing analysis identified MTase transcripts that are differentially expressed during PPV infection; among these, accumulation of a METTL gene was significantly downregulated. Two METTL transcripts (NbMETTL1 and NbMETTL2) were cloned and further characterized. Sequence and structural analyses of the two encoded proteins identified a conserved S-adenosyl methionine (SAM) binding domain, showing they are SAM-dependent MTases phylogenetically related to human METTL16 and FIONA1. Overexpression of NbMETTL1 and NbMETTL2 caused a decrease of PPV accumulation. In sum, our results indicate that METTL homologues participate in plant antiviral responses.
Topics: Humans; Methyltransferases; Nicotiana; Methylation; S-Adenosylmethionine; Antiviral Agents
PubMed: 37210738
DOI: 10.1080/15592324.2023.2214760 -
Genes & Development Aug 2023Specialized enzymes add methyl groups to the nitrogens of the amino acid histidine, altering the chemical properties of its imidazole ring and, in turn, the function of... (Review)
Review
Specialized enzymes add methyl groups to the nitrogens of the amino acid histidine, altering the chemical properties of its imidazole ring and, in turn, the function of the modified (poly)peptide. In this issue of , Shimazu and colleagues (pp. 724-742) make the remarkable discovery that CARNMT1 acts as a dual-specificity histidine methyltransferase, modifying both the small-molecule dipeptide carnosine and a set of proteins, predominantly within RNA-binding C3H zinc finger (C3H ZF) motifs. As a result, CARNMT1 modulates the activity of its protein targets to affect RNA processing and metabolism, ultimately contributing an essential function during mammalian development.
Topics: Animals; Histidine; Methylation; Amino Acids; Methyltransferases; Organogenesis; Mammals
PubMed: 37673460
DOI: 10.1101/gad.351097.123 -
Nature Dec 2023Cytosine DNA methylation is essential in brain development and is implicated in various neurological disorders. Understanding DNA methylation diversity across the entire...
Cytosine DNA methylation is essential in brain development and is implicated in various neurological disorders. Understanding DNA methylation diversity across the entire brain in a spatial context is fundamental for a complete molecular atlas of brain cell types and their gene regulatory landscapes. Here we used single-nucleus methylome sequencing (snmC-seq3) and multi-omic sequencing (snm3C-seq) technologies to generate 301,626 methylomes and 176,003 chromatin conformation-methylome joint profiles from 117 dissected regions throughout the adult mouse brain. Using iterative clustering and integrating with companion whole-brain transcriptome and chromatin accessibility datasets, we constructed a methylation-based cell taxonomy with 4,673 cell groups and 274 cross-modality-annotated subclasses. We identified 2.6 million differentially methylated regions across the genome that represent potential gene regulation elements. Notably, we observed spatial cytosine methylation patterns on both genes and regulatory elements in cell types within and across brain regions. Brain-wide spatial transcriptomics data validated the association of spatial epigenetic diversity with transcription and improved the anatomical mapping of our epigenetic datasets. Furthermore, chromatin conformation diversities occurred in important neuronal genes and were highly associated with DNA methylation and transcription changes. Brain-wide cell-type comparisons enabled the construction of regulatory networks that incorporate transcription factors, regulatory elements and their potential downstream gene targets. Finally, intragenic DNA methylation and chromatin conformation patterns predicted alternative gene isoform expression observed in a whole-brain SMART-seq dataset. Our study establishes a brain-wide, single-cell DNA methylome and 3D multi-omic atlas and provides a valuable resource for comprehending the cellular-spatial and regulatory genome diversity of the mouse brain.
Topics: Animals; Mice; Brain; Chromatin; Cytosine; Datasets as Topic; DNA Methylation; Epigenome; Multiomics; Single-Cell Analysis; Transcription Factors; Transcription, Genetic
PubMed: 38092913
DOI: 10.1038/s41586-023-06805-y -
The Yale Journal of Biology and Medicine Jun 2023Many chemicals and toxicants are released into our ecosystem and environment every day, which can cause harmful effects on human populations. Agricultural compounds are... (Review)
Review
Many chemicals and toxicants are released into our ecosystem and environment every day, which can cause harmful effects on human populations. Agricultural compounds are used in most crop production and have been shown to cause negative health impacts, including effects on reproduction and other pathologies. Although these chemicals can be helpful for pest and weed control, the compounds indirectly impact humans. Several compounds have been banned in the European Union but continue to be used in the United States. Recent work has shown most toxicants affect transgenerational generations more than the directly exposed generations through epigenetic inheritance. While some toxicants do not impact the directly exposed generation, the later generations that are transgenerational or ancestrally exposed suffer health impacts. Due to impacts to future generations, exposure becomes an environmental justice concern. The term "environmental justice" denotes the application of fair strategies when resolving unjust environmental contamination. Fair treatment means that no group should bear a disproportionate share of negative environmental consequences resulting from industrial, municipal, and commercial operations. This article illustrates how research on directly exposed generations is often prioritized over studies on transgenerational generations. However, research on the latter generations suggests the need to take environmental justice concerns seriously moving forward, as future generations could be unduly shouldering harms, while not enjoying benefits of production.
Topics: Humans; Epigenesis, Genetic; DNA Methylation; Ecosystem
PubMed: 37396986
DOI: 10.59249/FKWS5176 -
Clinical Epigenetics Aug 2023Peripheral T-cell lymphomas (PTCLs) are a group of highly aggressive malignancies with generally poor prognoses, and the first-line chemotherapy of PTCL has limited... (Review)
Review
Peripheral T-cell lymphomas (PTCLs) are a group of highly aggressive malignancies with generally poor prognoses, and the first-line chemotherapy of PTCL has limited efficacy. Currently, several novel targeted agents, including histone deacetylase inhibitors (HDACis), have been investigated to improve the therapeutic outcome of PTCLs. Several HDACis, such as romidepsin, belinostat, and chidamide, have demonstrated favorable clinical efficacy and safety in PTCLs. More novel HDACis and new combination therapies are undergoing preclinical or clinical trials. Mutation analysis based on next-generation sequencing may advance our understanding of the correlation between epigenetic mutation profiles and relevant targeted therapies. Multitargeted HDACis and HDACi-based prodrugs hold promising futures and offer further directions for drug design.
Topics: Humans; Lymphoma, T-Cell, Peripheral; Histone Deacetylase Inhibitors; DNA Methylation; Antineoplastic Agents; Combined Modality Therapy
PubMed: 37533111
DOI: 10.1186/s13148-023-01531-8