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Physical exercise is established as an important factor of health and generally is recommended for its positive effects on several tissues, organs, and systems. These positive effects come from metabolic adaptations that also include oxidative eustress, in which physical activity increases ROS production and antioxidant mechanisms, although this depends on the intensity of the exercise. Muscle metabolism through mechanisms such as aerobic and anaerobic glycolysis, tricarboxylic acid cycle, and oxidative lipid metabolism can produce metabolites and co-factors which directly impact the epigenetic machinery. In this review, we clearly reinforce the evidence that exercise regulates several epigenetic mechanisms and explain how these mechanisms can be regulated by metabolic products and co-factors produced during exercise. In fact, recent evidence has demonstrated the importance of epigenetics in the gene expression changes implicated in metabolic adaptation after exercise. Importantly, intermediates of the metabolism generated by continuous, acute, moderate, or strenuous exercise control the activity of epigenetic enzymes, therefore turning on or turning off the gene expression of specific programs which can lead to physiological adaptations after exercise. [Display omitted] • Epigenetic mechanisms depend on changes in the levels of metabolites, which are modified during physical exercise. • Exercise produces free radical species which impact epigenetic regulation. • Physical exercise modulates the epigenetic machinery, and this control is influenced by the intensity and duration of the exercise. [ABSTRACT FROM AUTHOR]

Epigenetic regulation of gene expression provides a finely tuned response capacity for cells when undergoing environmental changes. However, in the context of human physiology or disease, any cellular imbalance that modulates homeostasis has the potential to trigger molecular changes that result either in physiological adaptation to a new situation or pathological conditions. These effects are partly due to alterations in the functionality of epigenetic regulators, which cause long-term and often heritable changes in cell lineages. As such, free radicals resulting from unbalanced/extended oxidative stress have been proved to act as modulators of epigenetic agents, resulting in alterations of the epigenetic landscape. In the present review we will focus on the particular effect that oxidative stress and free radicals produce in histone post-translational modifications that contribute to altering the histone code and, consequently, gene expression. The pathological consequences of the changes in this epigenetic layer of regulation of gene expression are thoroughly evidenced by data gathered in many physiological adaptive processes and in human diseases that range from age-related neurodegenerative pathologies to cancer, and that include respiratory syndromes, infertility, and systemic inflammatory conditions like sepsis. [Display omitted] • Oxidative stress and free radicals produce direct and indirect changes in histone post-translational modifications. • Histone H3 is the one more severely affected by oxidative stress-related processes. • H3 the only histone with cysteine residues, which can be glutathionylated and are redox-sensitive. • Redox-PTMs are involved in the physiopathology of age-associated diseases and the regulation of the cell cycle. [ABSTRACT FROM AUTHOR]

Epigenetics is a rapidly growing field that studies gene expression modifications not involving changes in the DNA sequence. Histone H3, one of the basic proteins in the nucleosomes that make up chromatin, is S-glutathionylated in mammalian cells and tissues, making Gamma-L-glutamyl-L-cysteinylglycine, glutathione (GSH), a physiological antioxidant and second messenger in cells, a new post-translational modifier of the histone code that alters the structure of the nucleosome. However, the role of GSH in the epigenetic mechanisms likely goes beyond a mere structural function. Evidence supports the hypothesis that there is a link between GSH metabolism and the control of epigenetic mechanisms at different levels (i.e., substrate availability, enzymatic activity for DNA methylation, changes in the expression of microRNAs, and participation in the histone code). However, little is known about the molecular pathways by which GSH can control epigenetic events. Studying mutations in enzymes involved in GSH metabolism and the alterations of the levels of cofactors affecting epigenetic mechanisms appears challenging. However, the number of diseases induced by aberrant epigenetic regulation is growing, so elucidating the intricate network between GSH metabolism, oxidative stress and epigenetics could shed light on how their deregulation contributes to the development of neurodegeneration, cancer, metabolic pathologies and many other types of diseases. [ABSTRACT FROM AUTHOR]

Abstract: Chromatin is a dynamic structure formed mainly by DNA and histones, and chemical modifications on these elements regulate its compaction. Histone posttranslational modifications (PTMs) have a direct impact on chromatin conformation, controlling important cellular events such as cell proliferation and differentiation. Redox-related posttranslational modifications may have important effects on chromatin structure and function, offering a new intriguing area of research termed “redox epigenetics.” Little is known about histone carbonylation, a PTM that may be related to modifications in the cellular redox environment. The aim of our study was to determine the carbonylation of the various histones during cell proliferation, a moment in cell life during which important redox changes take place. Here, we describe changes in histone carbonylation during cell proliferation in NIH3T3 fibroblasts. In addition, we have studied the variations of poly(ADP-ribosyl)ation and phospho-H2AX at the same time, because both modifications are related to DNA damage responses. High levels of carbonylation on specific histones (H1, H10, and H3.1 dimers) were found when cells were in an active phase of DNA synthesis. The modification decreased when nuclear proteasome activity was activated. However, these results did not correlate completely with poly(ADP-ribosyl)ation and phospho-H2AX levels. Therefore, histone carbonylation may represent a specific event during cell proliferation. We describe a new methodology named oxy-2D-TAU Western blot that allowed us to separate and analyze the carbonylation patterns of the histone variants. In addition we offer a new role for histone carbonylation and its implication in redox epigenetics. Our results suggest that histone carbonylation is involved in histone detoxification during DNA synthesis. [Copyright &y& Elsevier]

Epigenetics is defined as the mitotically/meiotically heritable changes in gene expression that are not due to changes in the primary DNA sequence. Over recent years, growing evidence has suggested a link between redox metabolism and the control of epigenetic mechanisms. The effect of the redox control, oxidative stress, and glutathione (GSH) on the epigenetic mechanisms occur at different levels affecting DNA methylation, miRNAs expression, and histone post-translational modifications (PTMs). Furthermore, a number of redox PTMs are being described, so enriching the histone code. Pioneer works showed how oxidized GSH inhibits the activity of S-adenosyl methionine synthetase, MAT1A , a key enzyme involved in the synthesis of S-adenosyl methionine (SAM), which is used by DNA methyltransferases (DNMTs) and histone methyltransferases (HMTs). Alteration in NAD /NADH ratio affects the activity of class III histone deacetylases (HDACs) and poly-ADP ribosyltransferases (PARPs). Furthermore, the iron redox state of the catalytic center of key enzymes influences the activity of HDACs and the activity of Tet methylcytosine dioxygenases (DNA demetylases) and JmjC histone demethylases. In this communication, we will show the intricate mechanisms that participate in the redox control of the epigenetic mechanisms. We specially focus our work in the characterization of new PTMs in histones, such as histone carbonylation and glutathionylation. Demonstrating how GSH influences the epigenetic mechanisms beyond a mere regulation of SAM levels. The mechanisms described in this communication place GSH and redox control in the landscape of the epigenetic regulation. The results shown underscore the relevant role that oxidative stress and GSH play as key factors in epigenetics, opening a new window for understating the underlying mechanisms that control cell differentiation, proliferation, development, and disease. [ABSTRACT FROM AUTHOR]

Lafora disease (LD; OMIM 254780, ORPHA501) is a devastating neurodegenerative disorder characterized by the presence of glycogen-like intracellular inclusions called Lafora bodies and caused, in most cases, by mutations in either the EPM2A or the EPM2B gene, encoding respectively laforin, a phosphatase with dual specificity that is involved in the dephosphorylation of glycogen, and malin, an E3-ubiquitin ligase involved in the polyubiquitination of proteins related to glycogen metabolism. Thus, it has been reported that laforin and malin form a functional complex that acts as a key regulator of glycogen metabolism and that also plays a crucial role in protein homeostasis (proteostasis). Regarding this last function, it has been shown that cells are more sensitive to ER stress and show defects in proteasome and autophagy activities in the absence of a functional laforin–malin complex. More recently, we have demonstrated that oxidative stress accompanies these proteostasis defects and that various LD models show an increase in reactive oxygen species and oxidative stress products together with a dysregulated antioxidant enzyme expression and activity. In this review we discuss possible connections between the multiple defects in protein homeostasis present in LD and oxidative stress. [ABSTRACT FROM AUTHOR]

Lafora Disease (LD, OMIM 254780, ORPHA501) is a fatal neurodegenerative disorder characterized by the presence of glycogen-like intracellular inclusions called Lafora bodies and caused, in the vast majority of cases, by mutations in either EPM2A or EPM2B genes, encoding respectively laforin and malin. In the last years, several reports have revealed molecular details of these two proteins and have identified several processes affected in LD, but the pathophysiology of the disease still remains largely unknown. Since autophagy impairment has been reported as a characteristic treat in both Lafora disease cell and animal models, and as there is a link between autophagy and mitochondrial performance, we sought to determine if mitochondrial function could be altered in those models. Using fibroblasts from LD patients, deficient in laforin or malin, we found mitochondrial alterations, oxidative stress and a deficiency in antioxidant enzymes involved in the detoxification of reactive oxygen species (ROS). Similar results were obtained in brain tissue samples from transgenic mice deficient in either the EPM2A or EPM2B genes. Furthermore, in a proteomic analysis of brain tissue obtained from Epm2b-/- mice, we observed an increase in a modified form of peroxirredoxin-6, an antioxidant enzyme involved in other neurological pathologies, thus corroborating an alteration of the redox condition. These data support that oxidative stress produced by an increase in ROS production and an impairment of the antioxidant enzyme response to this stress play an important role in development of LD. [ABSTRACT FROM AUTHOR]