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RANK/RANKL/OPG pathway is an important for the epigenetic regulation of obesity.
Kalkan, R, Becer, E
Molecular biology reports. 2019;(5):5425-5432
Abstract
Obesity is a complex disorder that is influenced by genetic and environmental factors. DNA methylation is an epigenetic mechanism that is involved in development of obesity and its metabolic complications. The aim of this study was to investigate the association between the RANKL and c-Fos gene methylation on obesity with body mass index (BMI), lipid parameters, homeostasis model assessment of insulin resistance (HOMA-IR), plasma leptin, adiponectin and resistin levels. The study included 68 obese and 46 non-obese subjects. Anthropometric parameters, including body weight, body mass index, waist circumference, and waist-hip ratio, were assessed. Serum glucose, triglycerides (TG), total cholesterol, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), plasma leptin, adiponectin and resistin levels were measured. Methylation status of RANKL and c-Fos gen were evaluated by MS-HRM. Statistically significant differences were observed between obese patients and the controls with respect to RANKL and c-Fos gene methylation status (p < 0.001). Also, statistically significant importance was observed RANKL gene methylation and increased level of leptin in obese subjects (p = 0.0081). At the same time, statistically significant association between methylation of c-Fos and increased level of adiponectin was observed in obese patients (p = 0.03) On the other hand, decreased level of resistin was observed where the c-Fos was unmetyladed in controls (p = 0.01). We conclude that methylation of RANKL and c-Fos genes have significant influences on obesity and adipokine levels. Based on literature this was the first study which shows the interactions between RANKL and c-Fos methylation and obesity.
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CpG and Non-CpG Methylation in the Diet-Epigenetics-Neurodegeneration Connection.
Fuso, A, Lucarelli, M
Current nutrition reports. 2019;(2):74-82
Abstract
PURPOSE OF REVIEW Unraveling the diet-epigenetics-neurodegeneration connection may disclose associated mechanisms and novel approaches to the neurodegenerative diseases. This review summarizes the basic concepts and the innovative results in this field focusing on the relevance of non-CpG methylation. RECENT FINDINGS Many multifactorial neurodegenerative diseases are associated with epigenetic changes, and the brain seems more prone to epigenetic changes than other tissues. Several environmental factors induce epigenetic modulation in the organisms: diet and nutrition retain a high capacity to modulate the epigenetic traits. Finally, unexpected, specific, and functional non-CpG methylation in the brain was identified. Non-CpG methylation modulates brain expression of genes especially in promoters characterized by low-density CpGs distribution. These genes appear more prone to the epigenetic effect of environmental factors, i.e., diet, possibly inducing neurodegenerative processes. Understanding these processes could help in setting nutritional intervention aimed at contrasting neurodegenerative diseases.
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Estrogen down regulates COMT transcription via promoter DNA methylation in human breast cancer cells.
Wu, Q, Odwin-Dacosta, S, Cao, S, Yager, JD, Tang, WY
Toxicology and applied pharmacology. 2019;:12-22
Abstract
Catechol-O-methyltransferase (COMT) acts as a 'gate-keeper' to prevent DNA damage during estrogen metabolism. Both experimental and epidemiological studies suggest the role of COMT in pathogenesis of human breast cancer (BCa). It was previously reported that inhibition of COMT enzyme activity in estradiol-treated human breast epithelial carcinoma-derived MCF-7 cells caused increased oxidative DNA damage and formation of mutagenic depurinating adducts. To improve our understanding of factors influencing estrogen metabolism in BCa, it requires a mechanistic study illustrating the regulation of this 'gate-keeper'. We investigated the epigenetic mechanisms underlying decreased COMT transcription in MCF-7 cells exposed to 17ß-estradiol (E2) and the phytoestrogen, genistein (GEN). CpG site-specific methylation at promoters for both soluble (S) and membrane-bound (MB) COMT transcripts were assessed. Both E2 and GEN induced CpG site-specific methylation within the distal promoter of MB-COMT. In addition, ChIP analysis showed that there was increased binding of DNMT3B, MBD2 and HDAC1 within this promoter. These epigenetic changes were associated with decreased COMT transcript levels. Interestingly, sulforaphane, an antioxidant commonly found in cruciferous vegetables, was able to reverse the estrogen-induced epigenetic changes and gene silencing of COMT. Our data provide a new insight in epigenetically targeting COMT transcription. Since reactive estrogen metabolites may contribute to breast cancer, our findings may help in developing prevention and/or intervention strategies for human BCa.
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Evidence of epigenetic alterations in thrombosis and coagulation: A systematic review.
Patsouras, MD, Vlachoyiannopoulos, PG
Journal of autoimmunity. 2019;:102347
Abstract
Thrombosis in the context of Cardiovascular disease (CVD) affects mainly the blood vessels supplying the heart, brain and peripheries and it is the leading cause of death worldwide. The pathophysiological thrombotic mechanisms are largely unknown. Heritability contributes to a 30% of the incidence of CVD. The remaining variation can be explained by life style factors such as smoking, dietary and exercise habits, environmental exposure to toxins, and drug usage and other comorbidities. Epigenetic variation can be acquired or inherited and constitutes an interaction between genes and the environment. Epigenetics have been implicated in atherosclerosis, ischemia/reperfusion damage and the cardiovascular response to hypoxia. Epigenetic regulators of gene expression are mainly the methylation of CpG islands, histone post translational modifications (PTMs) and microRNAs (miRNAs). These epigenetic regulators control gene expression either through activation or silencing. Epigenetic control is mostly dynamic and can potentially be manipulated to prevent or reverse the uncontrolled expression of genes, a trait that renders them putative therapeutic targets. In the current review, we systematically studied and present available data on epigenetic alterations implicated in thrombosis derived from human studies. Evidence of epigenetic alterations is observed in several thrombotic diseases such as Coronary Artery Disease and Cerebrovascular Disease, Preeclampsia and Antiphospholipid Syndrome. Differential CpG methylation and specific histone PTMs that control transcription of prothrombotic and proinflammatory genes have also been associated with predisposing factors of thrombosis and CVD, such us smoking, air pollution, hypertriglyceridemia, occupational exposure to particulate matter and comorbidities including cancer, Chronic Obstructive Pulmonary Disease and Chronic Kidney Disease. These clinical observations are further supported by in vitro experiments and indicate that epigenetic regulation affects the pathophysiology of thrombotic disorders with potential diagnostic or therapeutic utility.
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An Evolutionary Perspective on Why Food Overconsumption Impairs Cognition.
Mattson, MP
Trends in cognitive sciences. 2019;(3):200-212
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Abstract
Brain structures and neuronal networks that mediate spatial navigation, decision-making, sociality, and creativity evolved, in part, to enable success in food acquisition. Here, I discuss evidence suggesting that the reason that overconsumption of energy-rich foods negatively impacts cognition is that signaling pathways that evolved to respond adaptively to food scarcity are relatively disengaged in the setting of continuous food availability. Obesity impairs cognition and increases the risk for some psychiatric disorders and dementias. Moreover, maternal and paternal obesity predispose offspring to poor cognitive outcomes by epigenetic molecular mechanisms. Neural signaling pathways that evolved to bolster cognition in settings of food insecurity can be stimulated by intermittent fasting and exercise to support the cognitive health of current and future generations.
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Epigenetic Modifications as Outcomes of Exercise Interventions Related to Specific Metabolic Alterations: A Systematic Review.
Barrón-Cabrera, E, Ramos-Lopez, O, González-Becerra, K, Riezu-Boj, JI, Milagro, FI, Martínez-López, E, Martínez, JA
Lifestyle genomics. 2019;(1-6):25-44
Abstract
BACKGROUND Chronic diseases arise as a consequence of an unhealthy lifestyle primarily characterized by physical inactivity and unbalanced diets. Regular physical activity can improve health, and there is consistent evidence that these improvements may be the result of epigenetic modifications. OBJECTIVE To identify epigenetic modificationsas outcomes of exercise interventions related to specific metabolic alterations. METHODS The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) methodology for manuscript research and preparation was followed using PubMed and EBSCO databases for literature review. Out of 2,638 articles identified, only 34 articles met the inclusion criteria. RESULTS The sections of the review were organized by metabolic alterations in which studies were grouped according to healthy, diseased, and trained individuals. Resistance exercise in humans induced epigenetic changes in pathways associated with energy metabolism and insulin sensitivity, contributing to healthy skeletal muscle. Endurance exercise also caused modifications in biomarkers associated to metabolic alterations through changes in DNA methylation and the expression of specific miRNAs. However, both resistance and endurance exercise are necessary to obtain a better physiological adaptation and a combination of both seems to be needed to properly tackle the increasing prevalence of non-communicable pathologies. CONCLUSION Given the heterogeneity and complexity of the existing literature, it is currently not possible to propose a specific recommendation about the type, intensity, or duration of exercise that could be beneficial for different subsets of the population (healthy, diseased, and/or trained). Nevertheless, this review highlights the importance of exercise for health and shows the need to perform more research in this emerging area to identify epigenetic biomarkers that could serve as indicators of exercise adaptations.
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Epigenetics in eating disorders: a systematic review.
Hübel, C, Marzi, SJ, Breen, G, Bulik, CM
Molecular psychiatry. 2019;(6):901-915
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Abstract
Eating disorders are complex heritable conditions influenced by both genetic and environmental factors. Given the progress of genomic discovery in anorexia nervosa, with the identification of the first genome-wide significant locus, as well as animated discussion of epigenetic mechanisms in linking environmental factors with disease onset, our goal was to conduct a systematic review of the current body of evidence on epigenetic factors in eating disorders to inform future directions in this area. Following PRISMA guidelines, two independent authors conducted a search within PubMed and Web of Science and identified 18 journal articles and conference abstracts addressing anorexia nervosa (n = 13), bulimia nervosa (n = 6), and binge-eating disorder (n = 1), published between January 2003 and October 2017. We reviewed all articles and included a critical discussion of field-specific methodological considerations. The majority of epigenetic analyses of eating disorders investigated methylation at candidate genes (n = 13), focusing on anorexia and bulimia nervosa in very small samples with considerable sample overlap across published studies. Three studies used microarray-based technologies to examine DNA methylation across the genome of anorexia nervosa and binge-eating disorder patients. Overall, results were inconclusive and were primarily exploratory in nature. The field of epigenetics in eating disorders remains in its infancy. We encourage the scientific community to apply methodologically sound approaches using genome-wide designs including epigenome-wide association studies (EWAS), to increase sample sizes, and to broaden the focus to include all eating disorder types.
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Anticancer potential of naturally occurring immunoepigenetic modulators: A promising avenue?
Schnekenburger, M, Dicato, M, Diederich, MF
Cancer. 2019;(10):1612-1628
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Abstract
The immune system represents the major primary defense line against carcinogenesis and acts by identifying and eradicating nascent transformed cells. A growing body of evidence is indicating that aberrant epigenetic reprogramming plays a key role in tumor immune escape through: 1) impaired efficient recognition of neoplastic cells by the immune system, resulting from a downregulation or loss of the expression of tumor-associated antigens, human leukocyte antigens, antigen processing and presenting machinery, and costimulatory molecule genes; 2) aberrant expression of immune checkpoint proteins and their ligands; and 3) modification of cytokine profiles and tumor-associated immune cell populations toward an immunosuppressive state in the tumor microenvironment. Consistent with the inherent reversibility of epigenetic alterations, epigenetic drugs, including DNA methyltransferase and histone deacetylase inhibitors, have the unique potential to favorably modify the tumor microenvironment, restore tumor recognition and stimulate an antitumor immune response. The objective of this review is to highlight selected, naturally occurring epigenetic modulators, namely, butyrate, curcumin, (-)-epigallocatechin-3-gallate, resveratrol, romidepsin, and trichostatin A, with a special focus on their antitumor immune properties.
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DNA phosphorothioate modification-a new multi-functional epigenetic system in bacteria.
Wang, L, Jiang, S, Deng, Z, Dedon, PC, Chen, S
FEMS microbiology reviews. 2019;(2):109-122
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Abstract
Synthetic phosphorothioate (PT) internucleotide linkages, in which a nonbridging oxygen is replaced by a sulphur atom, share similar physical and chemical properties with phosphodiesters but confer enhanced nuclease tolerance on DNA/RNA, making PTs a valuable biochemical and pharmacological tool. Interestingly, PT modification was recently found to occur naturally in bacteria in a sequence-selective and RP configuration-specific manner. This oxygen-sulphur swap is catalysed by the gene products of dndABCDE, which constitute a defence barrier with DndFGH in some bacterial strains that can distinguish and attack non-PT-modified foreign DNA, resembling DNA methylation-based restriction-modification (R-M) systems. Despite their similar defensive mechanisms, PT- and methylation-based R-M systems have evolved to target different consensus contexts in the host cell because when they share the same recognition sequences, the protective function of each can be impeded. The redox and nucleophilic properties of PT sulphur render PT modification a versatile player in the maintenance of cellular redox homeostasis, epigenetic regulation and environmental fitness. The widespread presence of dnd systems is considered a consequence of extensive horizontal gene transfer, whereas the lability of PT during oxidative stress and the susceptibility of PT to PT-dependent endonucleases provide possible explanations for the ubiquitous but sporadic distribution of PT modification in the bacterial world.
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DNA Methylation Status in Cancer Disease: Modulations by Plant-Derived Natural Compounds and Dietary Interventions.
Jasek, K, Kubatka, P, Samec, M, Liskova, A, Smejkal, K, Vybohova, D, Bugos, O, Biskupska-Bodova, K, Bielik, T, Zubor, P, et al
Biomolecules. 2019;(7)
Abstract
The modulation of the activity of DNA methyltransferases (DNMTs) represents a crucial epigenetic mechanism affecting gene expressions or DNA repair mechanisms in the cells. Aberrant modifications in the function of DNMTs are a fundamental event and part of the pathogenesis of human cancer. Phytochemicals, which are biosynthesized in plants in the form of secondary metabolites, represent an important source of biomolecules with pleiotropic effects and thus provide a wide range of possible clinical applications. It is well documented that phytochemicals demonstrate significant anticancer properties, and in this regard, rapid development within preclinical research is encouraging. Phytochemicals affect several epigenetic molecular mechanisms, including DNA methylation patterns such as the hypermethylation of tumor-suppressor genes and the global hypomethylation of oncogenes, that are specific cellular signs of cancer development and progression. This review will focus on the latest achievements in using plant-derived compounds and plant-based diets targeting epigenetic regulators and modulators of gene transcription in preclinical and clinical research in order to generate novel anticancer drugs as sensitizers for conventional therapy or compounds suitable for the chemoprevention clinical setting in at-risk individuals. In conclusion, indisputable anticancer activities of dietary phytochemicals linked with proper regulation of DNA methylation status have been described. However, precisely designed and well-controlled clinical studies are needed to confirm their beneficial epigenetic effects after long-term consumption in humans.