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Essays in Biochemistry Dec 2019DNA methylation involves the addition of a methyl group to the fifth carbon of the pyrimidine cytosine ring (5-methylcytosine, 5mC). 5mC is widespread in vertebrate... (Review)
Review
DNA methylation involves the addition of a methyl group to the fifth carbon of the pyrimidine cytosine ring (5-methylcytosine, 5mC). 5mC is widespread in vertebrate genomes where it is predominantly found within CpG dinucleotides. In mammals, 5mC participates in long-term silencing processes such as X-chromosome inactivation, genomic imprinting, somatic silencing of germline genes, and silencing of repetitive DNA elements. The evidence for 5mC as a dynamic gene-regulatory mechanism is mostly limited to specific examples, and is far from being completely understood. Recent work from diverse model systems suggests that 5mC might not always act as a dominant repressive mechanism and that hypermethylated promoters and enhancers can be permissive to transcription in vivo and in vitro. In this review, we discuss the links between 5mC and enhancer activity, and evaluate the role of this biochemical mechanism in various biological contexts.
Topics: Animals; DNA; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation; Humans
PubMed: 31551326
DOI: 10.1042/EBC20190030 -
International Journal of Molecular... Apr 2021DNA methylation, i.e., addition of methyl group to 5'-carbon of cytosine residues in CpG dinucleotides, is an important epigenetic modification regulating gene... (Review)
Review
DNA methylation, i.e., addition of methyl group to 5'-carbon of cytosine residues in CpG dinucleotides, is an important epigenetic modification regulating gene expression, and thus implied in many cellular processes. Deregulation of DNA methylation is strongly associated with onset of various diseases, including cancer. Here, we review how DNA methylation affects carcinogenesis process and give examples of solid tumors where aberrant DNA methylation is often present. We explain principles of methods developed for DNA methylation analysis at both single gene and whole genome level, based on (i) sodium bisulfite conversion, (ii) methylation-sensitive restriction enzymes, and (iii) interactions of 5-methylcytosine (5mC) with methyl-binding proteins or antibodies against 5mC. In addition to standard methods, we describe recent advances in next generation sequencing technologies applied to DNA methylation analysis, as well as in development of biosensors that represent their cheaper and faster alternatives. Most importantly, we highlight not only advantages, but also disadvantages and challenges of each method.
Topics: 5-Methylcytosine; Animals; Biosensing Techniques; DNA Methylation; Epigenesis, Genetic; Humans
PubMed: 33921911
DOI: 10.3390/ijms22084247 -
Critical Reviews in Clinical Laboratory... May 2022Autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic vasculitis are caused by the body's immune response to... (Review)
Review
Autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic vasculitis are caused by the body's immune response to autoantigens. The pathogenesis of autoimmune diseases is complex. RNA methylation is known to play a key role in disease progression as it regulates almost all aspects of RNA processing, including RNA nuclear export, translation, splicing, and noncoding RNA processing. This review summarizes the mechanisms, molecular structures of RNA methylations and their roles in biological functions. Similar to the roles of RNA methylation in cancers, RNA methylation in RA and SLE involves "writers" that deposit methyl groups to form N6-methyladenosine (m6A) and 5-methylcytosine (m5C), "erasers" that remove these modifications, and "readers" that further affect mRNA splicing, export, translation, and degradation. Recent advances in detection methods have identified N1-methyladenosine (m1A), N6,2-O-dimethyladenosine (m6Am), and 7-methylguanosine (m7G) RNA modifications, and their roles in RA and SLE need to be further studied. The relationship between RNA methylation and other autoimmune diseases has not been reported, and the roles and mechanisms of RNA modifications in these diseases need to be explored in the future.
Topics: Humans; Lupus Erythematosus, Systemic; Methylation; Molecular Structure; RNA; RNA Processing, Post-Transcriptional
PubMed: 34775884
DOI: 10.1080/10408363.2021.2002256 -
BMC Medicine Sep 2023Epigenetic age is an estimator of biological age based on DNA methylation; its discrepancy from chronologic age warrants further investigation. We recently reported that... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Epigenetic age is an estimator of biological age based on DNA methylation; its discrepancy from chronologic age warrants further investigation. We recently reported that greater polyphenol intake benefitted ectopic fats, brain function, and gut microbiota profile, corresponding with elevated urine polyphenols. The effect of polyphenol-rich dietary interventions on biological aging is yet to be determined.
METHODS
We calculated different biological aging epigenetic clocks of different generations (Horvath2013, Hannum2013, Li2018, Horvath skin and blood2018, PhenoAge2018, PCGrimAge2022), their corresponding age and intrinsic age accelerations, and DunedinPACE, all based on DNA methylation (Illumina EPIC array; pre-specified secondary outcome) for 256 participants with abdominal obesity or dyslipidemia, before and after the 18-month DIRECT PLUS randomized controlled trial. Three interventions were assigned: healthy dietary guidelines, a Mediterranean (MED) diet, and a polyphenol-rich, low-red/processed meat Green-MED diet. Both MED groups consumed 28 g walnuts/day (+ 440 mg/day polyphenols). The Green-MED group consumed green tea (3-4 cups/day) and Mankai (Wolffia globosa strain) 500-ml green shake (+ 800 mg/day polyphenols). Adherence to the Green-MED diet was assessed by questionnaire and urine polyphenols metabolomics (high-performance liquid chromatography quadrupole time of flight).
RESULTS
Baseline chronological age (51.3 ± 10.6 years) was significantly correlated with all methylation age (mAge) clocks with correlations ranging from 0.83 to 0.95; p < 2.2e - 16 for all. While all interventions did not differ in terms of changes between mAge clocks, greater Green-Med diet adherence was associated with a lower 18-month relative change (i.e., greater mAge attenuation) in Li and Hannum mAge (beta = - 0.41, p = 0.004 and beta = - 0.38, p = 0.03, respectively; multivariate models). Greater Li mAge attenuation (multivariate models adjusted for age, sex, baseline mAge, and weight loss) was mostly affected by higher intake of Mankai (beta = - 1.8; p = 0.061) and green tea (beta = - 1.57; p = 0.0016) and corresponded with elevated urine polyphenols: hydroxytyrosol, tyrosol, and urolithin C (p < 0.05 for all) and urolithin A (p = 0.08), highly common in green plants. Overall, participants undergoing either MED-style diet had ~ 8.9 months favorable difference between the observed and expected Li mAge at the end of the intervention (p = 0.02).
CONCLUSIONS
This study showed that MED and green-MED diets with increased polyphenols intake, such as green tea and Mankai, are inversely associated with biological aging. To the best of our knowledge, this is the first clinical trial to indicate a potential link between polyphenol intake, urine polyphenols, and biological aging.
TRIAL REGISTRATION
ClinicalTrials.gov, NCT03020186.
Topics: Humans; Adult; Middle Aged; DNA Methylation; Aging; Diet, Mediterranean; Ethnicity; Gastrointestinal Microbiome
PubMed: 37743489
DOI: 10.1186/s12916-023-03067-3 -
International Journal of Molecular... Jul 2022Methyl group metabolism belongs to a relatively understudied field of research. Its importance lies in the fact that methyl group metabolic pathways are crucial for the... (Review)
Review
Methyl group metabolism belongs to a relatively understudied field of research. Its importance lies in the fact that methyl group metabolic pathways are crucial for the successful conversion of dietary nutrients into the basic building blocks to carry out any cellular methylation reaction. Methyl groups play essential roles in numerous cellular functions such as DNA methylation, nucleotide- and protein biosynthesis. Especially, DNA methylation is responsible for organizing the genome into transcriptionally silent and active regions. Ultimately, it is this proper annotation that determines the quality of expression patterns required to ensure and shape the phenotypic integrity and function of a highly specialized cell type. Life is characterized by constantly changing environmental conditions, which are addressed by changes in DNA methylation. This relationship is increasingly coming into focus as it is of fundamental importance for differentiation, aging, and cancer. The stability and permanence of these metabolic processes, fueling the supplementation of methyl groups, seem to be important criteria to prevent deficiencies and erosion of the methylome. Alterations in the metabolic processes can lead to epigenetic and genetic perturbations, causative for diverse disorders, accelerated aging, and various age-related diseases. In recent decades, the intake of methyl group compounds has changed significantly due to, e.g., environmental pollution and food additives. Based on the current knowledge, this review provides a brief overview of the highly interconnected relationship between nutrition, metabolism, changes in epigenetic modifications, cancer, and aging. One goal is to provide an impetus to additionally investigate changes in DNA methylation as a possible consequence of an impaired methyl group metabolism.
Topics: Aging; DNA Methylation; Epigenesis, Genetic; Epigenomics; Humans; Neoplasms
PubMed: 35955511
DOI: 10.3390/ijms23158378 -
Proceedings of the National Academy of... Apr 2023The analysis of cell-free DNA (cfDNA) from plasma offers great promise for the earlier detection of cancer. At present, changes in DNA sequence, methylation, or copy...
The analysis of cell-free DNA (cfDNA) from plasma offers great promise for the earlier detection of cancer. At present, changes in DNA sequence, methylation, or copy number are the most sensitive ways to detect the presence of cancer. To further increase the sensitivity of such assays with limited amounts of sample, it would be useful to be able to evaluate the same template molecules for all these changes. Here, we report an approach, called MethylSaferSeqS, that achieves this goal, and can be applied to any standard library preparation method suitable for massively parallel sequencing. The innovative step was to copy both strands of each DNA-barcoded molecule with a primer that allows the subsequent separation of the original strands (retaining their 5-methylcytosine residues) from the copied strands (in which the 5-methylcytosine residues are replaced with unmodified cytosine residues). The epigenetic and genetic alterations present in the DNA molecules can then be obtained from the original and copied strands, respectively. We applied this approach to plasma from 265 individuals, including 198 with cancers of the pancreas, ovary, lung, and colon, and found the expected patterns of mutations, copy number alterations, and methylation. Furthermore, we could determine which original template DNA molecules were methylated and/or mutated. MethylSaferSeqS should be useful for addressing a variety of questions relating genetics and epigenetics.
Topics: Female; Humans; Methylation; DNA Copy Number Variations; 5-Methylcytosine; DNA; Mutation; Neoplasms; DNA Methylation
PubMed: 37014860
DOI: 10.1073/pnas.2220704120 -
Advances in Experimental Medicine and... 2022Covalent modification of DNA via deposition of a methyl group at the 5' position on cytosine residues alters the chemical groups available for interaction in the major...
Covalent modification of DNA via deposition of a methyl group at the 5' position on cytosine residues alters the chemical groups available for interaction in the major groove of DNA. This modification, thereby, alters the affinity and specificity of DNA-binding proteins; some of them favor interaction with methylated DNA, and others disfavor it. Molecular recognition of cytosine methylation by proteins often initiates sequential regulatory events that impact gene expression and chromatin structure. The known methyl-DNA-binding proteins have unique domains responsible for DNA methylation recognition: (1) the methyl-CpG-binding domain (MBD), (2) the SET- and RING finger-associated domain (SRA), and (3) some of TF families, such as the C2H2 zinc finger domain, basic helix-loop-helix (bHLH), basic leucine-zipper (bZIP), and homeodomain proteins. Structural analyses have revealed that each domain has a characteristic methylated DNA-binding pattern, and the difference in the recognition mechanisms renders the DNA methylation mark able to transmit complicated biological information. Recent genetic and genomic studies have revealed novel functions of methyl-DNA-binding proteins. These emerging data have also provided glimpses into how methyl-DNA-binding proteins possess unique features and, presumably, functions. In this chapter, we summarize structural and biochemical analyses elucidating the mechanisms for recognition of DNA methylation and correlate this information with emerging genomic and functional data.
Topics: Humans; DNA Methylation; Cytosine; DNA-Binding Proteins; DNA; Protein Domains; CpG Islands
PubMed: 36350514
DOI: 10.1007/978-3-031-11454-0_11 -
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 -
Free Radical Biology & Medicine Jul 2021One-carbon metabolism provides the methyl groups for both DNA and histone tail methylation reactions, two of the main epigenetic processes that tightly regulate the... (Review)
Review
One-carbon metabolism provides the methyl groups for both DNA and histone tail methylation reactions, two of the main epigenetic processes that tightly regulate the chromatin structure and gene expression levels. Several enzymes involved in one-carbon metabolism, as well as several epigenetic enzymes, are regulated by intracellular metabolites and redox cofactors, but their expression levels are in turn regulated by epigenetic modifications, in such a way that metabolism and gene expression reciprocally regulate each other to maintain homeostasis and regulate cell growth, survival, differentiation and response to environmental stimuli. Increasing evidence highlights the contribution of impaired one-carbon metabolism and epigenetic modifications in neurodegeneration. This article provides an overview of DNA and histone tail methylation changes in major neurodegenerative disorders, namely Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, discussing the contribution of oxidative stress and impaired one-carbon and redox metabolism to their onset and progression.
Topics: Biology; Carbon; DNA Methylation; Epigenesis, Genetic; Humans; Neurodegenerative Diseases; Oxidation-Reduction
PubMed: 33307166
DOI: 10.1016/j.freeradbiomed.2020.12.002 -
Nature Apr 2020Frequently referred to as the 'magic methyl effect', the installation of methyl groups-especially adjacent (α) to heteroatoms-has been shown to dramatically increase...
Frequently referred to as the 'magic methyl effect', the installation of methyl groups-especially adjacent (α) to heteroatoms-has been shown to dramatically increase the potency of biologically active molecules. However, existing methylation methods show limited scope and have not been demonstrated in complex settings. Here we report a regioselective and chemoselective oxidative C(sp)-H methylation method that is compatible with late-stage functionalization of drug scaffolds and natural products. This combines a highly site-selective and chemoselective C-H hydroxylation with a mild, functional-group-tolerant methylation. Using a small-molecule manganese catalyst, Mn(CFPDP), at low loading (at a substrate/catalyst ratio of 200) affords targeted C-H hydroxylation on heterocyclic cores, while preserving electron-neutral and electron-rich aryls. Fluorine- or Lewis-acid-assisted formation of reactive iminium or oxonium intermediates enables the use of a mildly nucleophilic organoaluminium methylating reagent that preserves other electrophilic functionalities on the substrate. We show this late-stage C(sp)-H methylation on 41 substrates housing 16 different medicinally important cores that include electron-rich aryls, heterocycles, carbonyls and amines. Eighteen pharmacologically relevant molecules with competing sites-including drugs (for example, tedizolid) and natural products-are methylated site-selectively at the most electron rich, least sterically hindered position. We demonstrate the syntheses of two magic methyl substrates-an inverse agonist for the nuclear receptor RORc and an antagonist of the sphingosine-1-phosphate receptor-1-via late-stage methylation from the drug or its advanced precursor. We also show a remote methylation of the B-ring carbocycle of an abiraterone analogue. The ability to methylate such complex molecules at late stages will reduce synthetic effort and thereby expedite broader exploration of the magic methyl effect in pursuit of new small-molecule therapeutics and chemical probes.
Topics: Androstenes; Biological Products; Carbon; Catalysis; Chemistry Techniques, Synthetic; Drug Inverse Agonism; Electrons; Fluorine; Hydrogen; Hydroxylation; Lewis Acids; Manganese; Methylation; Nuclear Receptor Subfamily 1, Group F, Member 3; Oxazolidinones; Oxidation-Reduction; Pharmaceutical Preparations; Sphingosine-1-Phosphate Receptors; Tetrazoles
PubMed: 32179876
DOI: 10.1038/s41586-020-2137-8