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Archives of Pharmacal Research Feb 2019Cancer can be identified as a chaotic cell state, which breaks the rules that govern growth and reproduction, with main characteristics such as uncontrolled division,... (Review)
Review
Cancer can be identified as a chaotic cell state, which breaks the rules that govern growth and reproduction, with main characteristics such as uncontrolled division, invading other tissues, usurping resources, and eventually killing its host. It was once believed that cancer is caused by a progressive series of genetic aberrations, and certain mutations of genes, including oncogenes and tumor suppressor genes, have been identified as the cause of cancer. However, piling evidence suggests that epigenetic modifications working in concert with genetic mechanisms to regulate transcriptional activity are dysregulated in many diseases, including cancer. Cancer epigenetics explain a wide range of heritable changes in gene expression, which do not come from any alteration in DNA sequences. Aberrant DNA methylation, histone modifications, and expression of long non-coding RNAs (lncRNAs) are key epigenetic mechanisms associated with tumor initiation, cancer progression, and metastasis. Within the past decade, cancer epigenetics have enabled us to develop novel biomarkers and therapeutic target for many types of cancers. In this review, we will summarize the major epigenetic changes involved in cancer biology along with clinical and preclinical results developed as novel cancer therapeutics.
Topics: Animals; DNA Methylation; Epigenesis, Genetic; Genetic Therapy; Histones; Humans; Neoplasms
PubMed: 30806885
DOI: 10.1007/s12272-019-01126-z -
Redox Report : Communications in Free... Dec 2022Psychostimulant use induces oxidative stress and alters redox imbalance, influencing epigenetic signatures in the central nervous system (CNS). Among the various... (Review)
Review
Psychostimulant use induces oxidative stress and alters redox imbalance, influencing epigenetic signatures in the central nervous system (CNS). Among the various epigenetic changes, DNA methylation is directly linked to oxidative stress metabolism via critical redox intermediates such as NAD+, S-adenosylmethionine (SAM), and 2-oxoglutarate. Fluctuations in these intermediates directly influence epigenetic signatures, which leads to detectable alterations in gene expression and protein modification. This review focuses on recent advances in the impact of psychostimulant use on redox-imbalance-induced DNA methylation to develop novel epigenetics-based early interventions. This review is based on collective research data obtained from the PubMed, Science Direct, and Medline databases. The keywords used in the electronic search in these databases were redox, substance use disorder, psychostimulants, DNA methylation, and neurological diseases. Instability in DNA methylation levels and redox expression effects are reported in various behavioral models stimulated by psychostimulants and opioids, indicating the widespread involvement of epigenetic changes in DNA methylation signatures in neurological disorders. This review summarizes the need for more studies and experimental evaluations of DNA-methylation-based strategies that may help to understand the association between psychostimulant use and oxidative stress or redox-linked metabolic recalibration influencing neuronal impairments.
Topics: Central Nervous System Stimulants; DNA Methylation; Epigenesis, Genetic; Oxidation-Reduction; Oxidative Stress
PubMed: 35227168
DOI: 10.1080/13510002.2022.2043224 -
Discovery Medicine 2021Cardiovascular disease (CVD) is a top public health problem especially for the elderly. Atherosclerosis is the pathological basis of CVD. Many studies have shown that...
Cardiovascular disease (CVD) is a top public health problem especially for the elderly. Atherosclerosis is the pathological basis of CVD. Many studies have shown that epigenetics plays a key role in regulating the development of atherosclerotic disease. Epigenetics includes DNA methylation, histone modification, RNA methylation, and non-coding RNA. More and more epigenetic regulations are confirmed to take part in heart development, response to stress, and endothelial injury, it is even suggested that atherosclerosis is the result of abnormal epigenetic regulation. Researchers have performed studies on novel drugs through epigenetic modification, yielding varied results. It is necessary to explore a range of epigenetic mechanisms to explain the causes and progression of atherosclerosis and uncover new targets for treatment. This article summarizes the latest development of epigenetic modification and its effect on the occurrence and progression of atherosclerosis and the possible prevention and treatment modalities of atherosclerosis that these research findings would engender.
Topics: Aged; Atherosclerosis; Cardiovascular Diseases; DNA Methylation; Epigenesis, Genetic; Humans
PubMed: 34965371
DOI: No ID Found -
International Journal of Molecular... Apr 2021DNA methylation is one of the most studied epigenetic mechanisms that play a pivotal role in regulating gene expression. The epigenetic component is strongly involved in... (Review)
Review
DNA methylation is one of the most studied epigenetic mechanisms that play a pivotal role in regulating gene expression. The epigenetic component is strongly involved in aging-bone diseases, such as osteoporosis and osteoarthritis. Both are complex multi-factorial late-onset disorders that represent a globally widespread health problem, highlighting a crucial point of investigations in many scientific studies. In recent years, new findings on the role of DNA methylation in the pathogenesis of aging-bone diseases have emerged. The aim of this systematic review is to update knowledge in the field of DNA methylation associated with osteoporosis and osteoarthritis, focusing on the specific tissues involved in both pathological conditions.
Topics: DNA Methylation; Epigenomics; Humans; Osteoarthritis; Osteoporosis
PubMed: 33921902
DOI: 10.3390/ijms22084244 -
Clinical Epigenetics Jul 2021The dilation of the aorta that occurs as a consequence of a congenitally bicuspid aortic valve (BAV) is associated with a risk of dissection, aneurysm or rupture. With...
BACKGROUND
The dilation of the aorta that occurs as a consequence of a congenitally bicuspid aortic valve (BAV) is associated with a risk of dissection, aneurysm or rupture. With progressive aortopathy, surgery is often recommended, but current patient selection strategies have limitations. A blood-based assay to identify those who would most benefit from prophylactic surgery would be an important medical advance. In a proof-of-concept study, we sought to identify aorta-specific differentially methylated regions (DMRs) detectable in plasma cell-free DNA (cfDNA) obtained from patients undergoing surgery for BAV-associated aortopathy.
METHODS
We used bioinformatics and publicly available human methylomes to identify aorta-specific DMRs. We used data from 4D-flow cardiac magnetic resonance imaging to identify regions of elevated aortic wall shear stress (WSS) in patients with BAV-associated aortopathy undergoing surgery and correlated WSS regions with aortic tissue cell death assessed using TUNEL staining. Cell-free DNA was isolated from patient plasma, and levels of candidate DMRs were correlated with aortic diameter and aortic wall cell death.
RESULTS
Aortic wall cell death was not associated with maximal aortic diameter but was significantly associated with elevated WSS. We identified 24 candidate aorta-specific DMRs and selected 4 for further study. A DMR on chromosome 11 was specific for the aorta and correlated significantly with aortic wall cell death. Plasma levels of total and aorta-specific cfDNA did not correlate with aortic diameter.
CONCLUSIONS
In a cohort of patients undergoing surgery for BAV-associated aortopathy, elevated WSS created by abnormal flow hemodynamics was associated with increased aortic wall cell death which supports the use of aorta-specific cfDNA as a potential tool to identify aortopathy and stratify patient risk.
Topics: Aorta; Bicuspid Aortic Valve Disease; Cell-Free Nucleic Acids; DNA Methylation; Humans
PubMed: 34321094
DOI: 10.1186/s13148-021-01137-y -
Heredity Jul 2010Epigenetics investigates heritable changes in gene expression that occur without changes in DNA sequence. Several epigenetic mechanisms, including DNA methylation and... (Review)
Review
Epigenetics investigates heritable changes in gene expression that occur without changes in DNA sequence. Several epigenetic mechanisms, including DNA methylation and histone modifications, can change genome function under exogenous influence. We review current evidence indicating that epigenetic alterations mediate effects caused by exposure to environmental toxicants. Results obtained from animal models indicate that in utero or early-life environmental exposures produce effects that can be inherited transgenerationally and are accompanied by epigenetic alterations. The search for human equivalents of the epigenetic mechanisms identified in animal models is under way. Recent investigations have identified a number of environmental toxicants that cause altered methylation of human repetitive elements or genes. Some exposures can alter epigenetic states and the same and/or similar epigenetic alterations can be found in patients with the disease of concern. On the basis of current evidence, we propose possible models for the interplay between environmental exposures and the human epigenome. Several investigations have examined the relationship between exposure to environmental chemicals and epigenetics, and have identified toxicants that modify epigenetic states. Whether environmental exposures have transgenerational epigenetic effects in humans remains to be elucidated. In spite of the current limitations, available evidence supports the concept that epigenetics holds substantial potential for furthering our understanding of the molecular mechanisms of environmental toxicants, as well as for predicting health-related risks due to conditions of environmental exposure and individual susceptibility.
Topics: Animals; DNA Methylation; Disease Models, Animal; Disease Susceptibility; Environmental Exposure; Environmental Pollutants; Epigenesis, Genetic; Humans
PubMed: 20179736
DOI: 10.1038/hdy.2010.2 -
Clinical Epigenetics Jul 2019Peptides originating from different sources (endogenous, food derived, environmental, and synthetic) are able to influence different aspects of epigenetic regulation.... (Review)
Review
Peptides originating from different sources (endogenous, food derived, environmental, and synthetic) are able to influence different aspects of epigenetic regulation. Endogenous short peptides, resulting from proteolytic cleavage of proteins or upon translation of non-annotated out of frame transcripts, can block DNA methylation and hereby regulate gene expression. Peptides entering the body by digestion of food-related proteins can modulate DNA methylation and/or histone acetylation while environmental peptides, synthesized by bacteria, fungi, and marine sponges, mainly inhibit histone deacetylation. In addition, synthetic peptides that reverse or inhibit different epigenetic modifications of both histones and the DNA can be developed as well. Next to these DNA and histone modifications, peptides can also influence the expression of non-coding RNAs such as lncRNAs and the maturation of miRNAs.Seen the advantages over small molecules, the development of peptide therapeutics is an interesting approach to treat diseases with a strong epigenetic basis like cancer and Alzheimer's disease. To date, only a limited number of drugs with a proven epigenetic mechanism of action have been approved by the FDA of which two (romidepsin and nesiritide) are peptides. A large knowledge gap concerning epigenetic effects of peptides is present, and this class of molecules deserves more attention in the development as epigenetic modulators. In addition, none of the currently approved peptide drugs are under investigation for their potential effects on epigenetics, hampering drug repositioning of these peptides to other indications with an epigenetic etiology.
Topics: Acetylation; DNA Methylation; Epigenesis, Genetic; Histones; Humans; Peptides
PubMed: 31300053
DOI: 10.1186/s13148-019-0700-7 -
FEBS Letters Jul 2011Methylation of cytosines is a pervasive feature of eukaryotic genomes and an important epigenetic layer that is fundamental for cellular differentiation processes and... (Review)
Review
Methylation of cytosines is a pervasive feature of eukaryotic genomes and an important epigenetic layer that is fundamental for cellular differentiation processes and control of transcriptional potential. DNA methylation patterns can be inherited and influenced by the environment, diet and aging, and disrupted in diseases. Complete DNA methylomes for several organisms are now available, helping clarify the evolutionary story of this epigenetic mark and its distribution in key genomic elements. Nonetheless, a complete understanding of its role, the mechanisms responsible for its establishment and maintenance, and its cross talk with other components of cellular machinery remains elusive.
Topics: Animals; DNA Methylation; Epigenesis, Genetic; Humans
PubMed: 21056564
DOI: 10.1016/j.febslet.2010.10.061 -
Clinical Epigenetics Apr 2021In DNA methylation analyses like epigenome-wide association studies, effects in differentially methylated CpG sites are assessed. Two kinds of outcomes can be used for...
BACKGROUND
In DNA methylation analyses like epigenome-wide association studies, effects in differentially methylated CpG sites are assessed. Two kinds of outcomes can be used for statistical analysis: Beta-values and M-values. M-values follow a normal distribution and help to detect differentially methylated CpG sites. As biological effect measures, differences of M-values are more or less meaningless. Beta-values are of more interest since they can be interpreted directly as differences in percentage of DNA methylation at a given CpG site, but they have poor statistical properties. Different frameworks are proposed for reporting estimands in DNA methylation analysis, relying on Beta-values, M-values, or both.
RESULTS
We present and discuss four possible approaches of achieving estimands in DNA methylation analysis. In addition, we present the usage of M-values or Beta-values in the context of bioinformatical pipelines, which often demand a predefined outcome. We show the dependencies between the differences in M-values to differences in Beta-values in two data simulations: a analysis with and without confounder effect. Without present confounder effects, M-values can be used for the statistical analysis and Beta-values statistics for the reporting. If confounder effects exist, we demonstrate the deviations and correct the effects by the intercept method. Finally, we demonstrate the theoretical problem on two large human genome-wide DNA methylation datasets to verify the results.
CONCLUSIONS
The usage of M-values in the analysis of DNA methylation data will produce effect estimates, which cannot be biologically interpreted. The parallel usage of Beta-value statistics ignores possible confounder effects and can therefore not be recommended. Hence, if the differences in Beta-values are the focus of the study, the intercept method is recommendable. Hyper- or hypomethylated CpG sites must then be carefully evaluated. If an exploratory analysis of possible CpG sites is the aim of the study, M-values can be used for inference.
Topics: DNA Methylation; Epigenesis, Genetic; Epigenome; Genome-Wide Association Study; Humans
PubMed: 33926513
DOI: 10.1186/s13148-021-01083-9 -
Genetics Nov 2020DNA methylation, a prototypical epigenetic modification implicated in gene silencing, occurs in many eukaryotes and plays a significant role in the etiology of diseases...
DNA methylation, a prototypical epigenetic modification implicated in gene silencing, occurs in many eukaryotes and plays a significant role in the etiology of diseases such as cancer. The filamentous fungus places DNA methylation at regions of constitutive heterochromatin such as in centromeres and in other A:T-rich regions of the genome, but this modification is dispensable for normal growth and development. This and other features render an excellent model to genetically dissect elements of the DNA methylation pathway. We implemented a forward genetic selection on a massive scale, utilizing two engineered antibiotic-resistance genes silenced by DNA methylation, to isolate mutants efective n ethylation (). Hundreds of potential mutants were characterized, yielding a rich collection of informative alleles of 11 genes important for DNA methylation, most of which were already reported. In parallel, we characterized the pairwise interactions in nuclei of the DCDC, the only histone H3 lysine 9 methyltransferase complex in Neurospora, including those between the DIM-5 catalytic subunit and other complex members. We also dissected the N- and C-termini of the key protein DIM-7, required for DIM-5 histone methyltransferase localization and activation. Lastly, we identified two alleles of a novel gene, - a homolog of Clr5 in - that is not essential for DNA methylation, but is necessary for repression of the antibiotic-resistance genes used in the selection, which suggests that both DIM-10 and DNA methylation promote silencing of constitutive heterochromatin.
Topics: DNA Methylation; Fungal Proteins; Mutation; Neurospora crassa
PubMed: 32873602
DOI: 10.1534/genetics.120.303471