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RNA Biology Sep 2017Chemical modification of nucleobases plays an important role for the control of gene expression on different levels. That includes the modulation of translation by... (Review)
Review
Chemical modification of nucleobases plays an important role for the control of gene expression on different levels. That includes the modulation of translation by modified tRNA-bases or silencing and reactivation of genes by methylation and demethylation of cytosine in promoter regions. Especially dynamic methylation of adenine and cytosine is essential for cells to adapt to their environment or for the development of complex organisms from a single cell. Errors in the cytosine methylation pattern are associated with most types of cancer and bacteria use methylated nucleobases to resist antibiotics. This Point of View wants to shed light on the known and potential chemistry of DNA and RNA methylation and demethylation. Understanding the chemistry of these processes on a molecular level is the first step towards a deeper knowledge about their regulation and function and will help us to find ways how nucleobase methylation can be manipulated to treat diseases.
Topics: Animals; DNA; DNA Methylation; Demethylation; Epigenesis, Genetic; Humans; Methylation; RNA
PubMed: 28440690
DOI: 10.1080/15476286.2017.1318241 -
International Journal of Biological... 2023Protein arginine methyltransferase (PRMT)-mediated arginine methylation is an important post-transcriptional modification that regulates various cellular processes... (Review)
Review
Protein arginine methyltransferase (PRMT)-mediated arginine methylation is an important post-transcriptional modification that regulates various cellular processes including epigenetic gene regulation, genome stability maintenance, RNA metabolism, and stress-responsive signal transduction. The varying substrates and biological functions of arginine methylation in cancer and neurological diseases have been extensively discussed, providing a rationale for targeting PRMTs in clinical applications. An increasing number of studies have demonstrated an interplay between arginine methylation and viral infections. PRMTs have been found to methylate and regulate several host cell proteins and different functional types of viral proteins, such as viral capsids, mRNA exporters, transcription factors, and latency regulators. This modulation affects their activity, subcellular localization, protein-nucleic acid and protein-protein interactions, ultimately impacting their roles in various virus-associated processes. In this review, we discuss the classification, structure, and regulation of PRMTs and their pleiotropic biological functions through the methylation of histones and non-histones. Additionally, we summarize the broad spectrum of PRMT substrates and explore their intricate effects on various viral infection processes and antiviral innate immunity. Thus, comprehending the regulation of arginine methylation provides a critical foundation for understanding the pathogenesis of viral diseases and uncovering opportunities for antiviral therapy.
Topics: Humans; Arginine; Methylation; Histones; Gene Expression Regulation; Virus Diseases
PubMed: 37928266
DOI: 10.7150/ijbs.89498 -
Seminars in Cancer Biology Aug 2022Methylation is a major post-translational modification (PTM) generated by methyltransferase on target proteins; it is recognized by the epigenetic reader to expand the... (Review)
Review
Methylation is a major post-translational modification (PTM) generated by methyltransferase on target proteins; it is recognized by the epigenetic reader to expand the functional diversity of proteins. Methylation can occur on specific lysine or arginine residues localized within regulatory domains in both histone and nonhistone proteins, thereby allowing distinguished properties of the targeted protein. Methylated residues are recognized by chromodomain, malignant brain tumor (MBT), Tudor, plant homeodomain (PHD), PWWP, WD-40, ADD, and ankyrin repeats by an induced-fit mechanism. Methylation-dependent activities regulate distinct aspects of target protein function and are largely reliant on methyl readers of histone and nonhistone proteins in various diseases. Methylation of nonhistone proteins that are recognized by methyl readers facilitates the degradation of unwanted proteins, as well as the stabilization of necessary proteins. Unlike nonhistone substrates, which are mainly monomethylated by methyltransferase, histones are di- or trimethylated by the same methyltransferases and then connected to other critical regulators by methyl readers. These fine-tuned controls by methyl readers are significant for the progression or inhibition of diseases, including cancers. Here, current knowledge and our perspectives about regulating protein function by methyl readers are summarized. We also propose that expanded research on the strong crosstalk mechanisms between methylation and other PTMs via methyl readers would augment therapeutic research in cancer.
Topics: Histones; Humans; Lysine; Methylation; Methyltransferases; Neoplasms
PubMed: 33753223
DOI: 10.1016/j.semcancer.2021.03.015 -
Epigenetics Dec 2023Abnormal DNA methylation is a fundamental characterization of epigenetics in cancer. Here we demonstrate that aberrant DNA methylating can modulate the tumour immune...
Abnormal DNA methylation is a fundamental characterization of epigenetics in cancer. Here we demonstrate that aberrant DNA methylating can modulate the tumour immune microenvironment in 16 cancer types. Differential DNA methylation in promoter region can regulate the transcriptomic pattern of immune-related genes and DNA hypomethylation mainly participated in the processes of immunity, carcinogenesis and immune infiltration. Moreover, many cancer types shared immune-related functions, like activation of innate immune response, interferon gamma response and NOD-like receptor signalling pathway. DNA methylation can further help identify molecular subtypes of kidney renal clear cell carcinoma. These subtypes are characterized by DNA methylation pattern, major histocompatibility complex, cytolytic activity and cytotoxic t lymphocyte and tumour mutation burden, and subtype with hypomethylation pattern shows unstable immune status. Then, we investigate the DNA methylation pattern of exhaustion-related marker genes and further demonstrate the role of hypomethylation in tumour immune microenvironment. In summary, our findings support the use of hypomethylation as a biomarker to understand the mechanism of tumour immune environment.
Topics: Humans; DNA Methylation; Neoplasms; Epigenesis, Genetic; Biomarkers, Tumor; Immunity; Tumor Microenvironment
PubMed: 36945884
DOI: 10.1080/15592294.2023.2192894 -
Oncotarget Jun 2015With ever-increasing elder population, the high incidence of age-related diseases such as neurodegenerative disorders has turned out to be a huge public concern.... (Review)
Review
With ever-increasing elder population, the high incidence of age-related diseases such as neurodegenerative disorders has turned out to be a huge public concern. Especially the elders and their families dreadfully suffer from the learning, behavioral and cognitive impairments. The lack of effective therapies for such a horrible symptom makes a great demanding for biological mechanism study for cognitive aging. Epigenetics is an emerging field that broadens the dimensions of mammalian genome blueprint. It is, unlike genetics, not only inheritable but also reversible. Recent studies suggest that DNA methylation, one of major epigenetic mechanisms, plays a pivotal role in the pathogenesis of age-related neurodegenerations and cognitive defects. In this review, the evolving knowledge of age-related cognitive functions and the potential DNA methylation mechanism of cognitive aging are discussed. That indicates the impairment of DNA methylation may be a crucial but reversible mechanism of behavioral and cognitive related neurodegeneration. The methods to examine the dynamics of DNA methylation patterns at tissue and single cell level and at the representative scale as well as the whole genome single base resolution are also briefly discussed. Importantly, the challenges of DNA methylation mechanism of cognitive aging research are brought up, and the possible solutions to tackle these difficulties are put forward.
Topics: Animals; Cognitive Aging; DNA Methylation; Epigenesis, Genetic; Humans
PubMed: 26015403
DOI: 10.18632/oncotarget.4215 -
Current Opinion in Plant Biology Apr 2017The type, amount, and location of DNA methylation within a gene provides pivotal information on the enzymatic pathway by which it was achieved and its functional... (Review)
Review
The type, amount, and location of DNA methylation within a gene provides pivotal information on the enzymatic pathway by which it was achieved and its functional consequences. In plants (angiosperms specifically), gene body methylation (gbM) refers to genes with an enrichment of CG DNA methylation within the transcribed regions and depletion at the transcriptional start and termination sites. GbM genes often compose the bulk of methylated genes within angiosperm genomes and are enriched for housekeeping functions. Contrary to the transcriptionally repressive effects of other chromatin modifications within gene bodies, gbM genes are constitutively expressed. GbM has intrigued researchers since its discovery, and much effort has been placed on identifying its functional role. Here, we highlight the recent findings on the evolutionary origin and molecular mechanism of gbM and synthesize studies describing the possible roles for this enigmatic epigenetic phenotype.
Topics: DNA Methylation; Evolution, Molecular; Gene Silencing; Genes, Plant; Magnoliopsida
PubMed: 28258985
DOI: 10.1016/j.pbi.2016.12.007 -
F1000Research 2019Our understanding of the expanded genetic alphabet has been growing rapidly over the last two decades, and many of these developments came more than 80 years after the... (Review)
Review
Our understanding of the expanded genetic alphabet has been growing rapidly over the last two decades, and many of these developments came more than 80 years after the original discovery of a modified guanine in tuberculosis DNA. These new understandings, leading to the field of epigenetics, have led to exciting new fundamental and applied knowledge and to the development of novel classes of drugs exploiting this new biology. The number of methyl modifications to RNA is about seven times greater than those found on DNA, and our ability to interrogate these enigmatic nucleobases has lagged significantly until recent years as an explosion in technologies and understanding has revealed the roles and regulation of RNA methylation in several fundamental and disease-associated biological processes. Here, we outline how the technology has evolved and which strategies are commonly used in the modern epitranscriptomics revolution and give a foundation in the understanding and application of the rich variety of these methods to novel biological questions.
Topics: Epigenesis, Genetic; Methylation; RNA
PubMed: 31069058
DOI: 10.12688/f1000research.17956.1 -
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 -
Methods in Molecular Biology (Clifton,... 2018MethyLight is a quantitative, fluorescence-based, real-time PCR method to sensitively detect and quantify DNA methylation of candidate regions of the genome. MethyLight...
MethyLight is a quantitative, fluorescence-based, real-time PCR method to sensitively detect and quantify DNA methylation of candidate regions of the genome. MethyLight is uniquely suited for detecting low-frequency methylated DNA regions against a high background of unmethylated DNA, as it combines methylation-specific priming with methylation-specific fluorescent probing. The quantitative accuracy of real-time PCR and the ability to design bisulfite-dependent, DNA methylation-independent control reactions together allow for a quantitative assessment of these low frequency methylation events. Here we describe the experimental steps of MethyLight analysis in detail. Furthermore, we present principles and design examples for three types of quality control reactions. QC-1 reactions are methylation-independent reactions to monitor sample quantity and integrity. QC-2 reactions are bisulfite-independent reactions to monitor recovery efficiencies of the bisulfite conversion methodology used. QC-3 reactions are bisulfite-independently primed reactions with variable bisulfite-dependent probing to monitor completeness of the sodium bisulfite treatment. We show that these control reactions perform as expected in a time course experiment interrupting sodium bisulfite conversion at various timepoints. Finally, we describe Digital MethyLight, in which MethyLight is combined with Digital PCR, for the highly sensitive detection of individual methylated molecules, with use in disease detection and screening.
Topics: CpG Islands; DNA Methylation; Epigenesis, Genetic; Fluorescent Dyes; Humans; Real-Time Polymerase Chain Reaction; Sulfites
PubMed: 29224160
DOI: 10.1007/978-1-4939-7481-8_25 -
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