scholarly journals Programmed suppression of oxidative phosphorylation and mitochondrial function by gestational alcohol exposure correlate with widespread increases in H3K9me2 that do not suppress transcription

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Richard C. Chang ◽  
Kara N. Thomas ◽  
Nicole A. Mehta ◽  
Kylee J. Veazey ◽  
Scott E. Parnell ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stress Response ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Function ◽  
Chromatin Structure ◽  
Alcohol Exposure ◽  
Structural Defects ◽  
Congenital Defects ◽  
Sequencing Analysis ◽  
Oxidative Homeostasis

Abstract Background A critical question emerging in the field of developmental toxicology is whether alterations in chromatin structure induced by toxicant exposure control patterns of gene expression or, instead, are structural changes that are part of a nuclear stress response. Previously, we used a mouse model to conduct a three-way comparison between control offspring, alcohol-exposed but phenotypically normal animals, and alcohol-exposed offspring exhibiting craniofacial and central nervous system structural defects. In the cerebral cortex of animals exhibiting alcohol-induced dysgenesis, we identified a dramatic increase in the enrichment of dimethylated histone H3, lysine 9 (H3K9me2) within the regulatory regions of key developmental factors driving histogenesis in the brain. However, whether this change in chromatin structure is causally involved in the development of structural defects remains unknown. Results Deep-sequencing analysis of the cortex transcriptome reveals that the emergence of alcohol-induced structural defects correlates with disruptions in the genetic pathways controlling oxidative phosphorylation and mitochondrial function. The majority of the affected pathways are downstream targets of the mammalian target of rapamycin complex 2 (mTORC2), indicating that this stress-responsive complex plays a role in propagating the epigenetic memory of alcohol exposure through gestation. Importantly, transcriptional disruptions of the pathways regulating oxidative homeostasis correlate with the emergence of increased H3K9me2 across genic, repetitive, and non-transcribed regions of the genome. However, although associated with gene silencing, none of the candidate genes displaying increased H3K9me2 become transcriptionally repressed, nor do they exhibit increased markers of canonical heterochromatin. Similar to studies in C. elegans, disruptions in oxidative homeostasis induce the chromatin looping factor SATB2, but in mammals, this protein does not appear to drive increased H3K9me2 or altered patterns of gene expression. Conclusions Our studies demonstrate that changes in H3K9me2 associate with alcohol-induced congenital defects, but that this epigenetic change does not correlate with transcriptional suppression. We speculate that the mobilization of SATB2 and increased enrichment of H3K9me2 may be components of a nuclear stress response that preserve chromatin integrity and interactions under prolonged oxidative stress. Further, we postulate that while this response may stabilize chromatin structure, it compromises the nuclear plasticity required for normal differentiation.

scholarly journals Almond Skin Extracts and Chlorogenic Acid Delay Chronological Aging and Enhanced Oxidative Stress Response in Yeast

Life ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 80 ◽  
Author(s):  
Duangjai Tungmunnithum ◽  
Malika Abid ◽  
Ahmed Elamrani ◽  
Samantha Drouet ◽  
Mohamed Addi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Stress Response ◽  
Life Span ◽  
Chlorogenic Acid ◽  
Mitochondrial Function ◽  
Oxidative Stress Response ◽  
Skin Extract ◽  
Protein Carbonyl Content ◽  
Chronological Life Span

Almond (Prunus dulcis (Mill.) D.A.Webb) is one of the largest nut crops in the world. Recently, phenolic compounds, mostly stored in almond skin, have been associated with much of the health-promoting behavior associated with their intake. The almond skin enriched fraction obtained from cold-pressed oil residues of the endemic Moroccan Beldi ecotypes is particularly rich in chlorogenic acid. In this study, both almond skin extract (AE) and chlorogenic acid (CHL) supplements, similar to traditional positive control resveratrol, significantly increased the chronological life-span of yeast compared to the untreated group. Our results showed that AE and CHL significantly reduced the production of reactive oxygen and nitrogen species (ROS/RNS), most likely due to their ability to maintain mitochondrial function during aging, as indicated by the maintenance of normal mitochondrial membrane potential in treated groups. This may be associated with the observed activation of the anti-oxidative stress response in treated yeast, which results in activation at both gene expression and enzymatic activity levels for SOD2 and SIR2, the latter being an upstream inducer of SOD2 expression. Interestingly, the differential gene expression induction of mitochondrial SOD2 gene at the expense of the cytosolic SOD1 gene confirms the key role of mitochondrial function in this regulation. Furthermore, AE and CHL have contributed to the survival of yeast under UV-C-induced oxidative stress, by reducing the development of ROS/RNS, resulting in a significant reduction in cellular oxidative damage, as evidenced by decreased membrane lipid peroxidation, protein carbonyl content and 8-oxo-guanine formation in DNA. Together, these results demonstrate the interest of AE and CHL as new regulators in the chronological life-span and control of the oxidative stress response of yeast.

scholarly journals Almond Skin Extracts and Chlorogenic Acid Delay Replicative Aging by Enhanced Oxidative Stress Response Involving SIR2 and SOD2 in Yeast

2020 ◽  
Author(s):  
Duangjai Tungmunnithum ◽  
Malika Abid ◽  
Ahmed Elamrani ◽  
Samantha Drouet ◽  
Mohamed Addi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Stress Response ◽  
Life Span ◽  
Chlorogenic Acid ◽  
Mitochondrial Function ◽  
Oxidative Stress Response ◽  
Skin Extract ◽  
Protein Carbonyl Content ◽  
Replicative Life Span

Almond (Prunus dulcis (Mill.) D.A.Webb) is one of the largest nut crops in the world. Recently, phenolic compounds, mostly stored in almond skin, have been associated with much of the health-promoting behavior associated with their intake. The almond skin enriched fraction obtained from cold-pressed oil residues of the endemic Moroccan Beldi ecotypes is particularly rich in chlorogenic acid. In this study, both almond skin extract (AE) and chlorogenic acid (CHL) supplements, similar to traditional positive control resveratrol, significantly increased the replicative life-span of yeast compared to the untreated group. Our results showed that AE and CHL significantly reduced the production of reactive oxygen and nitrogen species (ROS/RNS), most likely due to their ability to maintain mitochondrial function during aging, as indicated by the maintenance of normal mitochondrial membrane potential in treated groups. This may be associated with the observed activation of the anti-oxidative stress response in treated yeast, which results in activation at both gene expression and enzymatic activity levels for SOD2 and SIR2, the latter being an upstream inducer of SOD2 expression. Interestingly, the differential gene expression induction of mitochondrial SOD2 gene at the expense of the cytosolic SOD1 gene confirms the key role of mitochondrial function in this regulation. Furthermore, AE and CHL have contributed to the survival of yeast under UV-C-induced oxidative stress, by reducing the development of ROS / RNS, resulting in a significant reduction in cellular oxidative damage as evidenced by decreased membrane lipid peroxidation, protein carbonyl content and 8-oxo-guanine formation in DNA. Together, these results demonstrate the interest of AE and CHL as new regulators in the replicative life-span and control of the oxidative stress response of yeast.

Abstract 16641: The SGLT2 Inhibitor Ertugliflozin Induces Oxidative Phosphorylation Gene Expression and Improves Systolic Function Independent of Diabetes in Mice

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Dominique Croteau ◽  
Ivan Luptak ◽  
Fuzhong Qin ◽  
Jordan M Chambers ◽  
Ion A Hobai ◽  
...  
Keyword(s):  
Gene Expression ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Function ◽  
Systolic Function ◽  
High Energy ◽  
Enrichment Score ◽  
High Energy Phosphates ◽  
Gene Set ◽  
Work Demand ◽  
Myocardial Gene Expression

Background: Inhibitors of sodium glucose linked transporter 2 (SGLT2i) improve heart failure (HF) outcomes in patients independent of diabetes. While animal studies suggest SGLT2i improve cardiac metabolism, the effect of SGLT2i on mitochondrial function in the heart is not known. Our goal was to assess the effects of SGLT2i on mitochondrial function, high energy phosphates and genes encoding mitochondrial proteins in hearts of mice with and without diet-induced diabetes. Methods & Results: Ertugliflozin (Ertu; 0.5 mg/g) was given for 4 months to mice fed a high fat, high sucrose (HFHS) diet that causes diabetic cardiomyopathy or control diet (CD). Mitochondrial function was measured in isolated cardiac mitochondria. Myocardial energetics were assessed by NMR spectroscopy simultaneously with systolic function in isolated beating hearts. Myocardial gene expression was assessed by RNA seq using gene set analysis. HFHS diet caused myocardial hypertrophy and diastolic dysfunction, mitochondrial dysfunction (decreased ATP production, increased reactive oxygen species release) and an impaired energetic response to increased work demand - all of which were prevented by Ertu. Systolic function, as reflected by the rate x pressure product (RPP), was super-normalized to a value 124% of CD hearts at high work demand. In control mice, Ertu had no effect on isolated mitochondria function or high energy phosphates, but similar to HFHS hearts, caused super-normalization of RPP to 125% of CD hearts. Myocardial gene expression analysis revealed oxidative phosphorylation (OXPHOS) as the top scoring gene set that was both down-regulated by HFHS with a normalized enrichment score (NES) of -2.08, and up-regulated by Ertu in HFHS (NES, +3.32 vs HFHS). OXPHOS was the top scoring gene set up-regulated by Ertu a) across all groups while controlling for diet (NES, +3.71) and b) in CD-fed mice only (NES, +3.34). Conclusion: The super-normalization of systolic function and induction of the OXPHOS gene set by Ertu is independent of diabetic status. Pro-metabolic remodeling of the myocardium by Ertu may support increased systolic function and contribute to the beneficial actions of Ertu in states such as HF that are associated with impaired cardiac mitochondrial function.

A New Approach for Predicting the Value of Gene Expression: Two-way Collaborative Filtering

2019 ◽  
Vol 14 (6) ◽  
pp. 480-490 ◽  
Author(s):  
Tuncay Bayrak ◽  
Hasan Oğul
Keyword(s):  
Gene Expression ◽  
Regression Model ◽  
Collaborative Filtering ◽  
High Throughput Sequencing ◽  
Mean Squared Error ◽  
Experimental Studies ◽  
Kernel Functions ◽  
Feature Representation ◽  
Sequencing Analysis ◽  
Computational Systems Biology

Background: Predicting the value of gene expression in a given condition is a challenging topic in computational systems biology. Only a limited number of studies in this area have provided solutions to predict the expression in a particular pattern, whether or not it can be done effectively. However, the value of expression for the measurement is usually needed for further meta-data analysis. Methods: Because the problem is considered as a regression task where a feature representation of the gene under consideration is fed into a trained model to predict a continuous variable that refers to its exact expression level, we introduced a novel feature representation scheme to support work on such a task based on two-way collaborative filtering. At this point, our main argument is that the expressions of other genes in the current condition are as important as the expression of the current gene in other conditions. For regression analysis, linear regression and a recently popularized method, called Relevance Vector Machine (RVM), are used. Pearson and Spearman correlation coefficients and Root Mean Squared Error are used for evaluation. The effects of regression model type, RVM kernel functions, and parameters have been analysed in our study in a gene expression profiling data comprising a set of prostate cancer samples. Results: According to the findings of this study, in addition to promising results from the experimental studies, integrating data from another disease type, such as colon cancer in our case, can significantly improve the prediction performance of the regression model. Conclusion: The results also showed that the performed new feature representation approach and RVM regression model are promising for many machine learning problems in microarray and high throughput sequencing analysis.

scholarly journals Mapping chromatin accessibility and active regulatory elements reveals pathological mechanisms in human gliomas

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Karolina Stępniak ◽  
Magdalena A. Machnicka ◽  
Jakub Mieczkowski ◽  
Anna Macioszek ◽  
Bartosz Wojtaś ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chromatin Structure ◽  
Molecular Mechanisms ◽  
Genome Mapping ◽  
Malignant Gliomas ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Multiple Tumor ◽  
Genes Encoding ◽  
Methylation Patterns

AbstractChromatin structure and accessibility, and combinatorial binding of transcription factors to regulatory elements in genomic DNA control transcription. Genetic variations in genes encoding histones, epigenetics-related enzymes or modifiers affect chromatin structure/dynamics and result in alterations in gene expression contributing to cancer development or progression. Gliomas are brain tumors frequently associated with epigenetics-related gene deregulation. We perform whole-genome mapping of chromatin accessibility, histone modifications, DNA methylation patterns and transcriptome analysis simultaneously in multiple tumor samples to unravel epigenetic dysfunctions driving gliomagenesis. Based on the results of the integrative analysis of the acquired profiles, we create an atlas of active enhancers and promoters in benign and malignant gliomas. We explore these elements and intersect with Hi-C data to uncover molecular mechanisms instructing gene expression in gliomas.

scholarly journals Stress-induced differential gene expression in cardiac tissue

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ana Elisa T. S. de Carvalho ◽  
Marco A. Cordeiro ◽  
Luana S. Rodrigues ◽  
Daniela Ortolani ◽  
Regina C. Spadari
Keyword(s):  
Gene Expression ◽  
Stress Response ◽  
Left Ventricle ◽  
Differential Gene Expression ◽  
Cardiac Tissue ◽  
Stressful Situation ◽  
Adaptive Mechanism ◽  
Number Of Genes ◽  
Differential Gene ◽  
Shock Stress

AbstractThe stress response is adaptive and aims to guarantee survival. However, the persistence of a stressor can culminate in pathology. Catecholamines released as part of the stress response over activate beta adrenoceptors (β-AR) in the heart. Whether and how stress affects the expression of components of the intracellular environment in the heart is still, however, unknown. This paper used microarray to analyze the gene expression in the left ventricle wall of rats submitted to foot shock stress, treated or not treated with the selective β2-AR antagonist ICI118,551 (ICI), compared to those of non-stressed rats also treated or not with ICI, respectively. The main findings were that stress induces changes in gene expression in the heart and that β2-AR plays a role in this process. The vast majority of genes disregulated by stress were exclusive for only one of the comparisons, indicating that, in the same stressful situation, the profile of gene expression in the heart is substantially different when the β2-AR is active or when it is blocked. Stress induced alterations in the expression of such a large number of genes seems to be part of stress-induced adaptive mechanism.

scholarly journals Deuterium Oxide (D2O) Induces Early Stress Response Gene Expression and Impairs Growth and Metastasis of Experimental Malignant Melanoma

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 605
Author(s):  
Jana Jandova ◽  
Anh B. Hua ◽  
Jocelyn Fimbres ◽  
Georg T. Wondrak
Keyword(s):  
Gene Expression ◽  
Stress Response ◽  
Malignant Melanoma ◽  
Tumor Growth ◽  
Deuterium Oxide ◽  
Human Melanoma ◽  
Pharmacological Intervention ◽  
Melanoma Metastasis ◽  
Response Gene ◽  
Stress Response Gene

There are two stable isotopes of hydrogen, protium (1H) and deuterium (2H; D). Cellular stress response dysregulation in cancer represents both a major pathological driving force and a promising therapeutic target, but the molecular consequences and potential therapeutic impact of deuterium (2H)-stress on cancer cells remain largely unexplored. We have examined the anti-proliferative and apoptogenic effects of deuterium oxide (D2O; ‘heavy water’) together with stress response gene expression profiling in panels of malignant melanoma (A375V600E, A375NRAS, G361, LOX-IMVI), and pancreatic ductal adenocarcinoma (PANC-1, Capan-2, or MIA PaCa-2) cells with inclusion of human diploid Hs27 skin fibroblasts. Moreover, we have examined the efficacy of D2O-based pharmacological intervention in murine models of human melanoma tumor growth and metastasis. D2O-induction of apoptosis was substantiated by AV-PI flow cytometry, immunodetection of PARP-1, and pro-caspase 3 cleavage, and rescue by pan-caspase inhibition. Differential array analysis revealed early modulation of stress response gene expression in both A375 melanoma and PANC-1 adenocarcinoma cells elicited by D2O (90%; ≤6 h) (upregulated: CDKN1A, DDIT3, EGR1, GADD45A, HMOX1, NFKBIA, or SOD2 (up to 9-fold; p < 0.01)) confirmed by independent RT-qPCR analysis. Immunoblot analysis revealed rapid onset of D2O-induced stress response phospho-protein activation (p-ERK, p-JNK, p-eIF2α, or p-H2AX) or attenuation (p-AKT). Feasibility of D2O-based chemotherapeutic intervention (drinking water (30% w/w)) was demonstrated in a severe combined immunodeficiency (SCID) mouse melanoma metastasis model using luciferase-expressing A375-Luc2 cells. Lung tumor burden (visualized by bioluminescence imaging) was attenuated by D2O, and inhibition of invasiveness was also confirmed in an in vitro Matrigel transwell invasion assay. D2O supplementation also suppressed tumor growth in a murine xenograft model of human melanoma, and median survival was significantly increased without causing adverse effects. These data demonstrate for the first time that systemic D2O administration impairs growth and metastasis of malignant melanoma through the pharmacological induction of deuterium (2H)-stress.

scholarly journals Gene Expression Profiling of Mitochondrial Oxidative Phosphorylation (OXPHOS) Complex I in Friedreich Ataxia (FRDA) Patients

PLoS ONE ◽  
2014 ◽  
Vol 9 (4) ◽  
pp. e94069 ◽  
Author(s):  
Mohammad Hossein Salehi ◽  
Behnam Kamalidehghan ◽  
Massoud Houshmand ◽  
Goh Yong Meng ◽  
Majid Sadeghizadeh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Oxidative Phosphorylation ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Complex I ◽  
Friedreich Ataxia ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Oxphos Complex

scholarly journals Fusarium head blight resistance in European winter wheat: insights from genome-wide transcriptome analysis

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Maria Buerstmayr ◽  
Christian Wagner ◽  
Tetyana Nosenko ◽  
Jimmy Omony ◽  
Barbara Steiner ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Wall ◽  
Stress Response ◽  
Secondary Cell Wall ◽  
Fungal Colonization ◽  
Head Blight ◽  
Resistance Level ◽  
Expression Of Genes ◽  
European Winter Wheat ◽  
Fhb Resistance

Abstract Background Fusarium head blight (FHB) is a devastating disease of wheat worldwide. Resistance to FHB is quantitatively controlled by the combined effects of many small to medium effect QTL. Flowering traits, especially the extent of extruded anthers, are strongly associated with FHB resistance. Results To characterize the genetic basis of FHB resistance, we generated and analyzed phenotypic and gene expression data on the response to Fusarium graminearum (Fg) infection in 96 European winter wheat genotypes, including several lines containing introgressions from the highly resistant Asian cultivar Sumai3. The 96 lines represented a broad range in FHB resistance and were assigned to sub-groups based on their phenotypic FHB severity score. Comparative analyses were conducted to connect sub-group-specific expression profiles in response to Fg infection with FHB resistance level. Collectively, over 12,300 wheat genes were Fusarium responsive. The core set of genes induced in response to Fg was common across different resistance groups, indicating that the activation of basal defense response mechanisms was largely independent of the resistance level of the wheat line. Fg-induced genes tended to have higher expression levels in more susceptible genotypes. Compared to the more susceptible non-Sumai3 lines, the Sumai3-derivatives demonstrated higher constitutive expression of genes associated with cell wall and plant-type secondary cell wall biogenesis and higher constitutive and Fg-induced expression of genes involved in terpene metabolism. Gene expression analysis of the FHB QTL Qfhs.ifa-5A identified a constitutively expressed gene encoding a stress response NST1-like protein (TraesCS5A01G211300LC) as a candidate gene for FHB resistance. NST1 genes are key regulators of secondary cell wall biosynthesis in anther endothecium cells. Whether the stress response NST1-like gene affects anther extrusion, thereby affecting FHB resistance, needs further investigation. Conclusion Induced and preexisting cell wall components and terpene metabolites contribute to resistance and limit fungal colonization early on. In contrast, excessive gene expression directs plant defense response towards programmed cell death which favors necrotrophic growth of the Fg pathogen and could thus lead to increased fungal colonization.

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