Redox modulation of chromatin remodeling: impact on histone acetylation and deacetylation, NF-kappaB and pro-inflammatory gene expression.
ABSTRACT Reactive oxygen species (ROS), either directly or via the formation of lipid peroxidation products, such as 4-hydroxy-2-nonenal, acrolein and F2-isoprostanes, may play a role in enhancing inflammation through the activation and phosphorylation of stress kinases (JNK, ERK, p38) and redox-sensitive transcription factors such as NF-kappaB and AP-1. This increases the expression of genes regulating a battery of distinct pro-inflammatory mediators. Acetylation by histone acetyltransferase (HAT) of specific lysine residues on the N-terminal tail of core histones, results in uncoiling of the DNA and increased accessibility to transcription factor binding. In contrast, histone deacetylation by histone deacetylase (HDAC) represses gene transcription by promoting DNA winding thereby limiting access to transcription factors. Oxidative stress activates NF-kappaB resulting in expression of pro-inflammatory mediators through the activation of intrinsic HAT activity on co-activator molecules. In addition, oxidative stress also inhibits HDAC activity and in doing so enhances inflammatory gene expression which leads to a chronic inflammatory response. Oxidative stress can also increase complex formation between the co-activator CBP/p300 and the p65 subunit of NF-kappaB suggesting a further role of oxidative stress in chromatin remodeling. The antioxidant and/or anti-inflammatory effects of thiol molecules (glutathione, N-acetyl-L-cysteine and N-acystelyn), dietary polyphenols (curcumin-diferuloylmethane and resveratrol), the bronchodilator theophylline and glucocorticoids have all been shown to play a role in either controlling NF-kappaB activation or chromatin remodeling through modulation of HDAC activity and subsequently inflammatory gene expression in lung epithelial cells. Thus, oxidative stress regulates both signal transduction and chromatin remodeling which in turn impacts on pro-inflammatory responses in the lungs.
- SourceAvailable from: Sergio Adrián Morado[Show abstract] [Hide abstract]
ABSTRACT: and mature oocytes was detected, while in humans the regulation of glutathione peroxidase and SOD transcripts has been documented . As regards catalase, mRNA has been found in fertilized oocytes in the mouse and bovine , but not in humans . Catalase activity has also been detected in immature and in vitro matured bovine oocytes . It has been shown that several transcription factors involved in developmental processes are regulated by the intracellular red ox potential [21-26]. These factors are sensitive to oxidation or S-glutathionylation by ROS and require NAD (P) H o NAD (P) + . In somatic cells, it has been observed that red ox state and ROS levels are negatively related. A high intracellular oxidative activity (for example, due to the increase in the mitochondrial oxygen consumption rate) is usually associated with a decrease in ROS production . In the mouse, it has been demonstrated that redox state and ROS production regulation have a fundamental importance in early embryo development . In the bovine, we found clear and distinctive metabolic patterns as regards redox activity and fluctuations in ROS production between non-activated oocytes, in vitro fertilized and parthenogenetically activated oocytes; sperm-activated oocytes presented an increase in oxidative activity corresponding with the initiation of pronuclear formation and first mitotic division, suggesting increased demands of energy for these events . This increase can be related with results obtained by other groups who described that one and two cell bovine embryos are dependent on mitochondrial oxidative phosphorylation for energy supply, consuming oxidative substrates to produce ATP [30,31]. Coincidently, a higher oxygen consumption rate was detected prior to cleavage in bovine zygotes . It remains to be studied if these metabolic patterns are shared by other species, including humans.Austin Journal of In vitro Fertilization. 02/2015;
- [Show abstract] [Hide abstract]
ABSTRACT: Metabolite profiles of ten batches of male and female Drosophila melanogaster were com-pared using three different chromatographic methods interfaced to an Orbitrap Exactive mass spec-trometer. Several thousand features were observed and were reduced after data extraction and careful checking of around 390 metabolites excluding lipids. Chromatographic traces for these metabolites are presented as supplementary information. There were many significant differences between male and female flies. Female flies contained much higher levels of methylated lysines and methylated arginine suggesting differ-ences in histone metabolism. In addition, there were differences in the methylation of nucleosides, and S-adenosylmethionine metabolism. Differences in the methylome may relate to the requirement of compensation for the single X chromosome present in males since methylated histones inhibit gene transcription. Nucleoside phosphate levels were elevated in female flies which may relate to increased requirement for DNA biosynthesis for egg production. A se-ries of acylated amino acids previously observed in Drosophila was further characterised and these metabolites were pre-sent to a much greater extent in female flies and may be associated with the microbiome.Current Metabolomics. 01/2014; 2:174-183.
- [Show abstract] [Hide abstract]
ABSTRACT: Immature equine oocytes may be held overnight in an Earle's/Hanks' M199-based medium in the absence of meiotic inhibitors (EH medium) to schedule the onset of in vitro maturation. Holding in EH has been shown not to affect meiotic or developmental competence of equine oocytes (Choi et al. 2006 Theriogenology 66, 955-963). However, no studies have been performed to identify the mode by which this medium suppresses meiosis. We hypothesised that holding temperature may affect oocyte meiotic arrest. The effect of 3 holding temperatures (25, 30, 38°C) on chromatin status was investigated after Hoechst 33258 staining (Hinrichs et al. 2005 Biol. Reprod. 72, 1142-1150). Oocytes were recovered by scraping of follicles from slaughterhouse-derived ovaries. Data were analysed by Chi-squared test and one-way ANOVA followed by Dunn's or Holm-Sidak Multiple Comparison methods. A level of P<0.05 was considered significant. There were no significant differences in chromatin configuration between oocytes held overnight at 25°C (25°C-held) and controls (immediately-fixed oocytes); the proportion of oocytes showing meiotic resumption was 1/27, 4% and 0/26, 0%, respectively (not significant, NS). In contrast, holding at higher temperature significantly increased meiosis resumption (14/38, 37% and 14/28, 50%, at 30 and 38°C, respectively; P<0.01) and reduced the proportion of oocytes showing the most meiotically-competent germinal-vesicle (GV) configuration (condensed chromatin, CC; 24 to 29% v. 65 to 70% for control and 25°C-held, respectively; P<0.05). Based on these results, a subsequent experiment was performed in which oocyte meiotic stage and mitochondrial (mt) potential of 25°C-held (n=29) and control (n=36) oocytes was evaluated. Nuclear chromatin, mt activity (MitoTracker orange), intracellular reactive oxygen species (ROS) levels (2',7'-dichlorodihydrofluorescein diacetate, DCDHFDA), and mt/ROS colocalization (Pearson's coefficient) were analysed by epifluoscence and confocal microscopy (Martino et al. 2012 Fertil. Steril. 97, 720-728). Meiotic arrest after EH treatment at 25°C was confirmed (0/29, 0% v. 5/36, 14% for meiotic resumption in 25°C-held and controls, respectively; NS). At any GV stage, 25°C-held treatment had no effect on mt activity, ROS levels, or mt/ROS colocalization. For example, in CC oocytes, values for control and 25°C-held, respectively, were: MitoTracker, 547.8±499.5 v. 722.9±390.3; DCF fluorescence intensity, 278.5±179.3 v. 378±185, and mt/ROS colocalization, 0.5±0.1 v. 0.5±0.2; these were not significantly different (NS). In conclusion, EH holding at 25°C maintains meiotic arrest, viability, and mt potential of equine oocytes.Reproduction Fertility and Development 12/2014; 27(1):244. · 2.58 Impact Factor