1 3604 121 IMPROVEMENT OF PHYSICAL DECLINE THROUGH COMBINED EFFECTS OF MUSCLE ENHANCEMENT AND MITOCHONDRIAL ACTIVATION BY A GASTRIC HORMONE GHRELIN IN MALE 5/6NX CKD MODEL MICE. BECAUSE A PHYSICAL DECLINE CORRELATES WITH AN INCREASED RISK OF A WIDE RANGE OF DISEASE AND MORBIDITY, AN IMPROVEMENT OF PHYSICAL PERFORMANCE IS EXPECTED TO BRING SIGNIFICANT CLINICAL BENEFITS. THE PRIMARY CAUSE OF PHYSICAL DECLINE IN 5/6 NEPHRECTOMIZED (5/6NX) CHRONIC KIDNEY DISEASE MODEL MICE HAS BEEN REGARDED AS A DECREASE IN MUSCLE MASS; HOWEVER, OUR RECENT STUDY SHOWED THAT A DECREASE IN MUSCLE MITOCHONDRIA PLAYS A CRITICAL ROLE. IN THE PRESENT STUDY, WE EXAMINED THE EFFECTS OF A GASTRIC HORMONE GHRELIN, WHICH HAS BEEN REPORTED TO PROMOTE MUSCLE MITOCHONDRIAL OXIDATION, ON THE PHYSICAL DECLINE IN THE CHRONIC KIDNEY DISEASE MODEL MICE, FOCUSING ON THE EPIGENETIC MODULATIONS OF A MITOCHONDRIAL ACTIVATOR GENE, PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA COACTIVATOR-1ALPHA (PGC-1ALPHA). GHRELIN TREATMENT IMPROVED A DECLINE IN EXERCISE ENDURANCE OF 5/6NX MICE, ASSOCIATED WITH AN INCREASE IN BOTH OF THE MUSCLE MASS AND MITOCHONDRIAL AMOUNT. THE EXPRESSION LEVEL OF PGC-1ALPHA WAS DECREASED IN THE SKELETAL MUSCLE OF 5/6NX MICE, WHICH WAS ASSOCIATED WITH AN INCREASE IN THE METHYLATION RATIO OF THE CYTOSINE RESIDUE AT 260 BASE PAIRS UPSTREAM OF THE INITIATION POINT. CONVERSELY, GHRELIN TREATMENT DE-METHYLATED THE CYTOSINE RESIDUE AND INCREASED THE EXPRESSION OF PGC-1ALPHA. A REPRESENTATIVE MUSCLE ANABOLIC FACTOR, IGF-1, DID NOT AFFECT THE EXPRESSION OF PGC-1ALPHA AND MUSCLE MITOCHONDRIAL AMOUNT, ALTHOUGH IT INCREASED MUSCLE MASS. AS A RESULT, IGF-1 TREATMENT IN 5/6NX MICE DID NOT INCREASE THE DECREASED EXERCISE ENDURANCE AS EFFECTIVELY AS GHRELIN TREATMENT DID. THESE FINDINGS INDICATE AN ADVANTAGE OF GHRELIN TREATMENT FOR A RECOVERY OF PHYSICAL DECLINE. 2015 2 3124 74 GHRELIN TREATMENT IMPROVES PHYSICAL DECLINE IN SARCOPENIA MODEL MICE THROUGH MUSCULAR ENHANCEMENT AND MITOCHONDRIAL ACTIVATION. CHRONIC KIDNEY DISEASE (CKD) IMPAIRS PHYSICAL PERFORMANCE IN HUMANS, WHICH LEADS TO A RISK OF ALL-CAUSE MORTALITY. IN OUR PREVIOUS STUDY, WE DEMONSTRATED THAT A REDUCTION IN MUSCLE MITOCHONDRIA RATHER THAN MUSCLE MASS WAS A MAJOR CAUSE OF PHYSICAL DECLINE IN 5/6 NEPHRECTOMIZED CKD MODEL MICE. BECAUSE GHRELIN ADMINISTRATION HAS BEEN REPORTED TO ENHANCE OXYGEN UTILIZATION IN SKELETAL MUSCLE, WE EXAMINED THE USEFULNESS OF GHRELIN FOR A RECOVERY OF PHYSICAL DECLINE IN 5/6 NEPHRECTOMIZED C57BL/6 MICE, FOCUSING ON THE EPIGENETIC MODIFICATION OF PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA COACTIVATOR-1ALPHA (PGC-1ALPHA), A MASTER REGULATOR OF MITOCHONDRIAL BIOGENESIS. THE MICE WERE INTRAPERITONEALLY ADMINISTERED ACYLATED GHRELIN (0.1 NMOL/GBW; THREE TIMES PER WEEK) FOR A MONTH. MUSCLE STRENGTH AND EXERCISE ENDURANCE WERE MEASURED BY USING A DYNAMOMETER AND TREADMILL, RESPECTIVELY. MITOCHONDRIAL DNA COPY NUMBER WAS DETERMINED BY QUANTITATIVE PCR. THE METHYLATION LEVELS OF THE CYTOSINE RESIDUE AT 260 BASE PAIRS UPSTREAM OF THE TRANSLATION INITIATION POINT (C-260) OF PGC-1ALPHA, WHICH HAS BEEN DEMONSTRATED TO DECREASE THE EXPRESSION, WAS EVALUATED BY METHYLATION-SPECIFIC PCR AND BISULFITE GENOMIC SEQUENCING METHODS AFTER THE GHRELIN ADMINISTRATION. GHRELIN ADMINISTRATION IMPROVED BOTH MUSCLE STRENGTH AND EXERCISE ENDURANCE IN THE MICE AND WAS ASSOCIATED WITH AN INCREASE IN MUSCLE MASS AND MUSCLE MITOCHONDRIAL CONTENT. GHRELIN ADMINISTRATION DECREASED THE METHYLATION RATIO OF C-260 OF PGC-1ALPHA IN THE SKELETAL MUSCLE AND INCREASED THE EXPRESSION. THEREFORE, GHRELIN ADMINISTRATION EFFECTIVELY REDUCED THE PHYSICAL DECLINE IN 5/6 NEPHRECTOMIZED MICE AND WAS ACCOMPANIED WITH AN INCREASED MITOCHONDRIAL CONTENT THROUGH DE-METHYLATION OF THE PROMOTER REGION OF PGC-1ALPHA IN THE MUSCLE. 2017 3 5189 42 PRENATAL ARSENIC EXPOSURE INDUCES IMMUNOMETABOLIC ALTERATION AND RENAL INJURY IN RATS. ARSENIC (AS) EXPOSURE IS PROGRESSIVELY ASSOCIATED WITH CHRONIC KIDNEY DISEASE (CKD), A LEADING PUBLIC HEALTH CONCERN PRESENT WORLDWIDE. THE ADVERSE EFFECT OF AS EXPOSURE ON THE KIDNEYS OF PEOPLE LIVING IN AS ENDEMIC AREAS HAVE NOT BEEN EXTENSIVELY STUDIED. FURTHERMORE, THE IMPACT OF ONLY PRENATAL EXPOSURE TO AS ON THE PROGRESSION OF CKD ALSO HAS NOT BEEN FULLY CHARACTERIZED. IN THE PRESENT STUDY, WE EXAMINED THE EFFECT OF PRENATAL EXPOSURE TO LOW DOSES OF AS 0.04 AND 0.4 MG/KG BODY WEIGHT (0.04 AND 0.4 PPM, RESPECTIVELY) ON THE PROGRESSION OF CKD IN MALE OFFSPRING USING A WISTAR RAT MODEL. INTERESTINGLY, ONLY PRENATAL AS EXPOSURE WAS SUFFICIENT TO ELEVATE THE EXPRESSION OF PROFIBROTIC (TGF-BETA1) AND PROINFLAMMATORY (IL-1ALPHA, MIP-2ALPHA, RANTES, AND TNF-ALPHA) CYTOKINES AT 2-DAY, 12- AND 38-WEEK TIME POINTS IN THE EXPOSED PROGENY. FURTHER, ALTERATION IN ADIPOGENIC FACTORS (GHRELIN, LEPTIN, AND GLUCAGON) WAS ALSO OBSERVED IN 12- AND 38-WEEK OLD MALE OFFSPRING PRENATALLY EXPOSED TO AS. AN ALTERED LEVEL OF THESE FACTORS COINCIDES WITH IMPAIRED GLUCOSE METABOLISM AND HOMEOSTASIS ACCOMPANIED BY PROGRESSIVE KIDNEY DAMAGE. WE OBSERVED A SIGNIFICANT INCREASE IN THE DEPOSITION OF EXTRACELLULAR MATRIX COMPONENTS AND GLOMERULAR AND TUBULAR DAMAGE IN THE KIDNEYS OF 38-WEEK-OLD MALE OFFSPRING PRENATALLY EXPOSED TO AS. FURTHERMORE, THE OVEREXPRESSION OF TGF-BETA1 IN KIDNEYS CORRESPONDS WITH HYPERMETHYLATION OF THE TGF-BETA1 GENE-BODY, INDICATING A POSSIBLE INVOLVEMENT OF PRENATAL AS EXPOSURE-DRIVEN EPIGENETIC MODULATIONS OF TGF-BETA1 EXPRESSION. OUR STUDY PROVIDES EVIDENCE THAT PRENATAL AS EXPOSURE TO MALES CAN ADVERSELY AFFECT THE IMMUNOMETABOLISM OF OFFSPRING WHICH CAN PROMOTE KIDNEY DAMAGE LATER IN LIFE. 2022 4 2002 24 EPIGENETIC AND POST-TRANSCRIPTIONAL REPRESSION SUPPORT METABOLIC SUPPRESSION IN CHRONICALLY HYPOXIC GOLDFISH. GOLDFISH ENTER A HYPOMETABOLIC STATE TO SURVIVE CHRONIC HYPOXIA. WE RECENTLY DESCRIBED TISSUE-SPECIFIC CONTRIBUTIONS OF MEMBRANE LIPID COMPOSITION REMODELING AND MITOCHONDRIAL FUNCTION TO METABOLIC SUPPRESSION ACROSS DIFFERENT GOLDFISH TISSUES. HOWEVER, THE MOLECULAR AND ESPECIALLY EPIGENETIC FOUNDATIONS OF HYPOXIA TOLERANCE IN GOLDFISH UNDER METABOLIC SUPPRESSION ARE NOT WELL UNDERSTOOD. HERE WE SHOW THAT COMPONENTS OF THE MOLECULAR OXYGEN-SENSING MACHINERY ARE ROBUSTLY ACTIVATED ACROSS TISSUES IRRESPECTIVE OF HYPOXIA DURATION. INDUCTION OF GENE EXPRESSION OF ENZYMES INVOLVED IN DNA METHYLATION TURNOVER AND MICRORNA BIOGENESIS SUGGEST A ROLE FOR EPIGENETIC TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL SUPPRESSION OF GENE EXPRESSION IN THE HYPOXIA-ACCLIMATED BRAIN. CONVERSELY, MECHANISTIC TARGET OF RAPAMYCIN-DEPENDENT TRANSLATIONAL MACHINERY ACTIVITY IS NOT REDUCED IN LIVER AND WHITE MUSCLE, SUGGESTING THIS PATHWAY DOES NOT CONTRIBUTE TO LOWERING CELLULAR ENERGY EXPENDITURE. FINALLY, MOLECULAR EVIDENCE SUPPORTS PREVIOUSLY REPORTED CHRONIC HYPOXIA-DEPENDENT CHANGES IN MEMBRANE CHOLESTEROL, LIPID METABOLISM AND MITOCHONDRIAL FUNCTION VIA CHANGES IN TRANSCRIPTS INVOLVED IN CHOLESTEROL BIOSYNTHESIS, BETA-OXIDATION, AND MITOCHONDRIAL FUSION IN MULTIPLE TISSUES. OVERALL, THIS STUDY SHOWS THAT CHRONIC HYPOXIA ROBUSTLY INDUCES EXPRESSION OF OXYGEN-SENSING MACHINERY ACROSS TISSUES, INDUCES REPRESSIVE TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL EPIGENETIC MARKS ESPECIALLY IN THE CHRONIC HYPOXIA-ACCLIMATED BRAIN AND SUPPORTS A ROLE FOR MEMBRANE REMODELING AND MITOCHONDRIAL FUNCTION AND DYNAMICS IN PROMOTING METABOLIC SUPPRESSION. 2022 5 1567 35 DNA METHYLATION OF THE KLF14 GENE REGION IN WHOLE BLOOD CELLS PROVIDES PREDICTION FOR THE CHRONIC INFLAMMATION IN THE ADIPOSE TISSUE. KRUPPEL-LIKE FACTOR 14 (KLF14) GENE, WHICH APPEARS TO BE A MASTER REGULATOR OF GENE EXPRESSION IN THE ADIPOSE TISSUE AND HAVE PREVIOUSLY BEEN ASSOCIATED WITH BMI AND TYPE 2 DIABETES (T2D) BY LARGE GENOME-WIDE ASSOCIATION STUDIES. IN ORDER TO FIND PREDICTIVE BIOMARKERS FOR THE DEVELOPMENT OF T2D, IT IS NECESSARY TO TAKE EPIGENOMIC CHANGES AFFECTED BY ENVIRONMENTAL FACTORS INTO ACCOUNT. THIS STUDY FOCUSES ON AGEING AND OBESITY, WHICH ARE T2D RISK FACTORS, AND EXAMINES EPIGENETIC CHANGES AND INFLAMMATORY CHANGES. WE INVESTIGATED DNA METHYLATION CHANGES IN THE KLF14 PROMOTER REGION IN DIFFERENT ORGANS OF MICE FOR COMPARING AGING AND WEIGHT. WE FOUND THAT METHYLATION LEVELS OF THESE SITES WERE INCREASED WITH AGING AND WEIGHT IN THE SPLEEN, THE ADIPOSE TISSUE, THE KIDNEY, THE LUNG, THE COLON AND THE WHOLE BLOOD CELLS. IN ADDITION, IN THE SPLEEN, THE ADIPOSE TISSUE AND THE WHOLE BLOOD, THESE EPIGENETIC CHANGES WERE ALSO SIGNIFICANTLY ASSOCIATED WITH INFLAMMATORY LEVELS. MOREOVER, NOT ONLY KLF14, BUT ALSO EXPRESSION LEVELS OF SOME DOWNSTREAM GENES WERE DECREASED WITH METHYLATION IN THE SPLEEN, THE ADIPOSE TISSUE AND THE WHOLE BLOOD CELLS. TAKEN TOGETHER, OUR RESULTS SUGGEST THAT METHYLATION CHANGES OF KLF14 IN THOSE TISSUES MAY BE ASSOCIATED WITH CHANGES IN GENE EXPRESSION AND INFLAMMATION ON THE ADIPOSE TISSUE OF OBESITY AND T2D. IN ADDITION, THE METHYLATION CHANGES IN THE WHOLE BLOOD CELLS MAY SERVE AS A PREDICTIVE EPIGENETIC BIOMARKER FOR THE DEVELOPMENT OF T2D. 2018 6 2926 30 GENERATION OF AN EPIGENETIC SIGNATURE BY CHRONIC HYPOXIA IN PROSTATE CELLS. INCREASING LEVELS OF TISSUE HYPOXIA HAVE BEEN REPORTED AS A NATURAL FEATURE OF THE AGING PROSTATE GLAND AND MAY BE A RISK FACTOR FOR THE DEVELOPMENT OF PROSTATE CANCER. IN THIS STUDY, WE HAVE USED PWR-1E BENIGN PROSTATE EPITHELIAL CELLS AND AN EQUIVALENTLY AGED HYPOXIA-ADAPTED PWR-1E SUB-LINE TO IDENTIFY PHENOTYPIC AND EPIGENETIC CONSEQUENCES OF CHRONIC HYPOXIA IN PROSTATE CELLS. WE HAVE IDENTIFIED A SIGNIFICANTLY ALTERED CELLULAR PHENOTYPE IN RESPONSE TO CHRONIC HYPOXIA AS CHARACTERIZED BY INCREASED RECEPTOR-MEDIATED APOPTOTIC RESISTANCE, THE INDUCTION OF CELLULAR SENESCENCE, INCREASED INVASION AND THE INCREASED SECRETION OF IL-1 BETA, IL6, IL8 AND TNFALPHA CYTOKINES. IN ASSOCIATION WITH THESE PHENOTYPIC CHANGES AND THE ABSENCE OF HIF-1 ALPHA PROTEIN EXPRESSION, WE HAVE DEMONSTRATED SIGNIFICANT INCREASES IN GLOBAL LEVELS OF DNA METHYLATION AND H3K9 HISTONE ACETYLATION IN THESE CELLS, CONCOMITANT WITH THE INCREASED EXPRESSION OF DNA METHYLTRANSFERASE DMNT3B AND GENE-SPECIFIC CHANGES IN DNA METHYLATION AT KEY IMPRINTING LOCI. IN CONCLUSION, WE HAVE DEMONSTRATED A GENOME-WIDE ADJUSTMENT OF DNA METHYLATION AND HISTONE ACETYLATION UNDER CHRONIC HYPOXIC CONDITIONS IN THE PROSTATE. THESE EPIGENETIC SIGNATURES MAY REPRESENT AN ADDITIONAL MECHANISM TO PROMOTE AND MAINTAIN A HYPOXIC-ADAPTED CELLULAR PHENOTYPE WITH A POTENTIAL ROLE IN TUMOUR DEVELOPMENT. 2009 7 2119 30 EPIGENETIC HISTONE MODIFICATION REGULATES DEVELOPMENTAL LEAD EXPOSURE INDUCED HYPERACTIVITY IN RATS. LEAD (PB) EXPOSURE WAS COMMONLY CONSIDERED AS A HIGH ENVIRONMENTAL RISK FACTOR FOR THE DEVELOPMENT OF ATTENTION-DEFICIT/HYPERACTIVITY DISORDER (ADHD). HOWEVER, THE MOLECULAR BASIS OF THIS PATHOLOGICAL PROCESS STILL REMAINS ELUSIVE. IN LIGHT OF THE ROLE OF EPIGENETICS IN MODULATING THE NEUROLOGICAL DISEASE AND THE CAUSATIVE ENVIRONMENT, THE ALTERATIONS OF HISTONE MODIFICATIONS IN THE HIPPOCAMPUS OF RATS EXPOSED BY VARIOUS DOSES OF LEAD, ALONG WITH CONCOMITANT BEHAVIORAL DEFICITS, WERE INVESTIGATED IN THIS STUDY. ACCORDING TO THE FREE AND FORCED OPEN FIELD TEST, THERE SHOWED THAT IN A DOSAGE-DEPENDENT MANNER, LEAD EXPOSURE COULD RESULT IN THE INCREASED LOCOMOTOR ACTIVITY OF RATS, THAT IS, HYPERACTIVITY: A SUBTYPE OF ADHD. WESTERN BLOTTING ASSAYS REVEALED THAT THE LEVELS OF HISTONE ACETYLATION INCREASED SIGNIFICANTLY IN THE HIPPOCAMPUS BY CHRONIC LEAD EXPOSURE, WHILE NO DRAMATIC CHANGES WERE DETECTED IN TERMS OF EXPRESSION YIELDS OF ADHD-RELATED DOPAMINERGIC PROTEINS, INDICATING THAT HISTONE ACETYLATION PLAYS ESSENTIAL ROLES IN THIS TOXICANT-INVOLVED PATHOGENESIS. IN ADDITION, THE INCREASED LEVEL OF HISTONE ACETYLATION MIGHT BE ATTRIBUTED TO THE ENZYMATIC ACTIVITY OF P300, A TYPICAL HISTONE ACETYLTRANSFERASE, AS THE TRANSCRIPTIONAL LEVEL OF P300 WAS SIGNIFICANTLY INCREASED UPON HIGHER-DOSE PB EXPOSURE. IN SUMMARY, THIS STUDY FIRST DISCOVERED THE EPIGENETIC MECHANISM BRIDGING THE ENVIRONMENTAL INFLUENCE (PB) AND THE DISEASE ITSELF (ADHD) IN THE HISTONE MODIFICATION LEVEL, PAVING THE WAY FOR THE COMPREHENSIVE UNDERSTANDING OF ADHD'S ETIOLOGY AND IN FURTHER STEPS, ESTABLISHING THE THERAPY STRATEGY OF THIS WIDESPREAD NEUROLOGICAL DISORDER. 2014 8 3403 23 HOW EPIGENETIC MODIFICATIONS DRIVE THE EXPRESSION AND MEDIATE THE ACTION OF PGC-1ALPHA IN THE REGULATION OF METABOLISM. EPIGENETIC CHANGES ARE A HALLMARK OF SHORT- AND LONG-TERM TRANSCRIPTIONAL REGULATION, AND HENCE INSTRUMENTAL IN THE CONTROL OF CELLULAR IDENTITY AND PLASTICITY. EPIGENETIC MECHANISMS LEADING TO CHANGES IN CHROMATIN STRUCTURE, ACCESSIBILITY FOR RECRUITMENT OF TRANSCRIPTIONAL COMPLEXES, AND INTERACTION OF ENHANCERS AND PROMOTERS ALL CONTRIBUTE TO ACUTE AND CHRONIC ADAPTATIONS OF CELLS, TISSUES AND ORGANS TO INTERNAL AND EXTERNAL PERTURBATIONS. SIMILARLY, THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA COACTIVATOR 1ALPHA (PGC-1ALPHA) IS ACTIVATED BY STIMULI THAT ALTER THE CELLULAR ENERGETIC DEMAND, AND SUBSEQUENTLY CONTROLS COMPLEX TRANSCRIPTIONAL NETWORKS RESPONSIBLE FOR CELLULAR PLASTICITY. IT THUS IS OF NO SURPRISE THAT PGC-1ALPHA IS UNDER THE CONTROL OF EPIGENETIC MECHANISMS, AND CONSTITUTES A MEDIATOR OF EPIGENETIC CHANGES IN VARIOUS TISSUES AND CONTEXTS. IN THIS REVIEW, WE SUMMARIZE THE CURRENT KNOWLEDGE OF THE LINK BETWEEN EPIGENETICS AND PGC-1ALPHA IN HEALTH AND DISEASE. 2019 9 1117 26 COMPARATIVE AND EXPERIMENTAL STUDIES ON THE GENES ALTERED BY CHRONIC HYPOXIA IN HUMAN BRAIN MICROENDOTHELIAL CELLS. BACKGROUND : HYPOXIA INDUCIBLE FACTOR 1 ALPHA (HIF1A) IS A MASTER REGULATOR OF ACUTE HYPOXIA; HOWEVER, WITH CHRONIC HYPOXIA, HIF1A LEVELS RETURN TO THE NORMOXIC LEVELS. IMPORTANTLY, THE GENES THAT ARE INVOLVED IN THE CELL SURVIVAL AND VIABILITY UNDER CHRONIC HYPOXIA ARE NOT KNOWN. THEREFORE, WE TESTED THE HYPOTHESIS THAT CHRONIC HYPOXIA LEADS TO THE UPREGULATION OF A CORE GROUP OF GENES WITH ASSOCIATED CHANGES IN THE PROMOTER DNA METHYLATION THAT MEDIATES THE CELL SURVIVAL UNDER HYPOXIA. RESULTS : WE EXAMINED THE EFFECT OF CHRONIC HYPOXIA (3 DAYS; 0.5% OXYGEN) ON HUMAN BRAIN MICRO ENDOTHELIAL CELLS (HBMEC) VIABILITY AND APOPTOSIS. HYPOXIA CAUSED A SIGNIFICANT REDUCTION IN CELL VIABILITY AND AN INCREASE IN APOPTOSIS. NEXT, WE EXAMINED CHRONIC HYPOXIA ASSOCIATED CHANGES IN TRANSCRIPTOME AND GENOME-WIDE PROMOTER METHYLATION. THE DATA OBTAINED WAS COMPARED WITH 16 OTHER MICROARRAY STUDIES ON CHRONIC HYPOXIA. NINE GENES WERE ALTERED IN RESPONSE TO CHRONIC HYPOXIA IN ALL 17 STUDIES. INTERESTINGLY, HIF1A WAS NOT ALTERED WITH CHRONIC HYPOXIA IN ANY OF THE STUDIES. FURTHERMORE, WE COMPARED OUR DATA TO THREE OTHER STUDIES THAT IDENTIFIED HIF-RESPONSIVE GENES BY VARIOUS APPROACHES. ONLY TWO GENES WERE FOUND TO BE HIF DEPENDENT. WE SILENCED EACH OF THESE 9 GENES USING CRISPR/CAS9 SYSTEM. DOWNREGULATION OF EGLN3 SIGNIFICANTLY INCREASED THE CELL DEATH UNDER CHRONIC HYPOXIA, WHEREAS DOWNREGULATION OF ERO1L, ENO2, ADRENOMEDULLIN, AND SPAG4 REDUCED THE CELL DEATH UNDER HYPOXIA. CONCLUSIONS : WE PROVIDE A CORE GROUP OF GENES THAT REGULATES CELLULAR ACCLIMATIZATION UNDER CHRONIC HYPOXIC STRESS, AND MOST OF THEM ARE HIF INDEPENDENT. 2017 10 2408 28 EPIGENETIC REWIRING OF SKELETAL MUSCLE ENHANCERS AFTER EXERCISE TRAINING SUPPORTS A ROLE IN WHOLE-BODY FUNCTION AND HUMAN HEALTH. OBJECTIVES: REGULAR PHYSICAL EXERCISE IMPROVES HEALTH BY REDUCING THE RISK OF A PLETHORA OF CHRONIC DISORDERS. WE HYPOTHESIZED THAT ENDURANCE EXERCISE TRAINING REMODELS THE ACTIVITY OF GENE ENHANCERS IN SKELETAL MUSCLE AND THAT THIS REMODELING CONTRIBUTES TO THE BENEFICIAL EFFECTS OF EXERCISE ON HUMAN HEALTH. METHODS AND RESULTS: BY STUDYING CHANGES IN HISTONE MODIFICATIONS, WE MAPPED THE GENOME-WIDE POSITIONS AND ACTIVITIES OF ENHANCERS IN SKELETAL MUSCLE BIOPSIES COLLECTED FROM YOUNG SEDENTARY MEN BEFORE AND AFTER 6 WEEKS OF ENDURANCE EXERCISE. WE IDENTIFIED EXTENSIVE REMODELING OF ENHANCER ACTIVITIES AFTER EXERCISE TRAINING, WITH A LARGE SUBSET OF THE REMODELED ENHANCERS LOCATED IN THE PROXIMITY OF GENES TRANSCRIPTIONALLY REGULATED AFTER EXERCISE. BY OVERLAPPING THE POSITION OF ENHANCERS WITH GENETIC VARIANTS, WE IDENTIFIED AN ENRICHMENT OF DISEASE-ASSOCIATED GENETIC VARIANTS WITHIN THE EXERCISE-REMODELED ENHANCERS. CONCLUSION: OUR DATA PROVIDE EVIDENCE OF A FUNCTIONAL LINK BETWEEN EPIGENETIC REWIRING OF ENHANCERS TO CONTROL THEIR ACTIVITY AFTER EXERCISE TRAINING AND THE MODULATION OF DISEASE RISK IN HUMANS. 2021 11 1326 21 DEPLETION OF NUCLEAR HISTONE H2A VARIANTS IS ASSOCIATED WITH CHRONIC DNA DAMAGE SIGNALING UPON DRUG-EVOKED SENESCENCE OF HUMAN SOMATIC CELLS. CELLULAR SENESCENCE IS ASSOCIATED WITH GLOBAL CHROMATIN CHANGES, ALTERED GENE EXPRESSION, AND ACTIVATION OF CHRONIC DNA DAMAGE SIGNALING. THESE EVENTS ULTIMATELY LEAD TO MORPHOLOGICAL AND PHYSIOLOGICAL TRANSFORMATIONS IN PRIMARY CELLS. IN THIS STUDY, WE SHOW THAT CHRONIC DNA DAMAGE SIGNALS CAUSED BY GENOTOXIC STRESS IMPACT THE EXPRESSION OF HISTONES H2A FAMILY MEMBERS AND LEAD TO THEIR DEPLETION IN THE NUCLEI OF SENESCENT HUMAN FIBROBLASTS. OUR DATA REINFORCE THE HYPOTHESIS THAT PROGRESSIVE CHROMATIN DESTABILIZATION MAY LEAD TO THE LOSS OF EPIGENETIC INFORMATION AND IMPAIRED CELLULAR FUNCTION ASSOCIATED WITH CHRONIC DNA DAMAGE UPON DRUG-EVOKED SENESCENCE. WE PROPOSE THAT CHANGES IN THE HISTONE BIOSYNTHESIS AND CHROMATIN ASSEMBLY MAY DIRECTLY CONTRIBUTE TO CELLULAR AGING. IN ADDITION, WE ALSO OUTLINE THE METHOD THAT ALLOWS FOR QUANTITATIVE AND UNBIASED MEASUREMENT OF THESE CHANGES. 2012 12 6564 28 TRANSIENT EXPOSURE TO ELEVATED GLUCOSE LEVELS CAUSES PERSISTENT CHANGES IN DERMAL MICROVASCULAR ENDOTHELIAL CELL RESPONSES TO INJURY. BACKGROUND: THE PURPOSE OF THIS STUDY WAS TO DETERMINE WHETHER ELEVATED GLUCOSE CAN INDUCE A DERMAL MICROVASCULAR ENDOTHELIAL CELL METABOLIC MEMORY, THUS AFFECTING ANGIOGENESIS IN THE REPAIR PROCESS OF MAMMALIAN CUTANEOUS WOUND. WE HYPOTHESIZED THAT TRANSIENT ELEVATED GLUCOSE LEVELS CAUSE SUSTAINED ALTERATION OF ENDOTHELIAL CELL RESPONSES TO INJURY AND PERSISTENT EPIGENETIC CHANGES IN GENE EXPRESSION. METHODS: HUMAN DERMAL MICROVASCULAR ENDOTHELIAL CELLS WERE EXPOSED TO EXPERIMENTAL CONDITIONS WITH OR WITHOUT 30 MM D-GLUCOSE. THE CONTROL GROUP WAS MAINTAINED AT 5 MM D-GLUCOSE; WHILE IN THE TRANSIENT GLUCOSE GROUP, AFTER BEING EXPOSED TO 30 MM D-GLUCOSE FOR TWO DAYS, THEN BEING PUT UNDER THE CONTROL CONDITIONS DURING THE EXPERIMENT. BESIDES, IN THE WHOLE PROCESS OF THE EXPERIMENT, THE CHRONIC GLUCOSE GROUP WAS KEPT IN THE CONDITION WITH 30 MM D-GLUCOSE. PROLIFERATION, MIGRATION, TUBE FORMATION, GENE EXPRESSION AND HISTONE METHYLATION WERE ASSESSED FOR INDIVIDUAL CONDITIONS. RESULTS: TRANSIENT ELEVATED GLUCOSE CAUSED SUSTAINED EFFECTS ON ENDOTHELIAL CELL MIGRATION, TUBE FORMATION AND TIMP3 GENE EXPRESSION. THE EFFECTS ON TIMP3 EXPRESSION WERE ASSOCIATED WITH PERSISTENT CHANGES IN HISTONE MODIFICATION AT THE 5' END OF THE TIMP3 GENE, SUGGESTING AN EPIGENETIC EFFECT. CONCLUSIONS: HYPERGLYCEMIA INDUCED METABOLIC MEMORY COULD PROMOTE THE REGULATION OF TIMP3, AND IT CAN BE USED AS A POSSIBLE INNOVATIVE MOLECULAR TARGET FOR THERAPEUTIC INTERVENTION IN THE TREATMENT OF CHRONIC NON-HEALING DIABETIC WOUNDS. 2021 13 4528 21 MULTIGENERATIONAL EFFECTS OF CADMIUM ON THE LIFESPAN AND FERTILITY OF DROSOPHILA MELANOGASTER. ALTHOUGH THE DAMAGE AND TOLERANCE MECHANISMS OF CD STRESS ARE KNOWN, THE DATA ON GENETIC RISK ARE LIMITED. THE AIM OF THIS STUDY WAS TO ASSESS THE CHRONIC TOXICITY OF CD, GENETIC RESPONSES, AND MULTIGENERATIONAL EFFECTS IN FIVE GENERATIONS OF DROSOPHILA MELANOGASTER. FOR EACH GENERATION, LIFESPAN AND FERTILITY WERE STATISTICALLY ANALYSED AND THE EXPRESSION OF APOPTOSIS- (P53 AND CASPASE-3) AND EPIGENESIS-RELATED (DDNMT2 AND DMBD2/3) GENES WAS EXAMINED. LIFESPAN AND FERTILITY SIGNIFICANTLY DECLINED UNDER CD STRESS AND THESE EFFECTS WERE MAINTAINED FOR TWO GENERATIONS AND ONE GENERATION, RESPECTIVELY, WHEN CD STRESS WAS REMOVED. THE EXPRESSION OF P53 AND CASPASE-3 WAS SIGNIFICANTLY UP-REGULATED AFTER EXPOSURE, SUGGESTING THAT APOPTOSIS CONTRIBUTES TO THE RESISTANCE MECHANISM. THEIR ALTERED EXPRESSION WAS RETAINED FOR TWO GENERATIONS. FURTHERMORE, HIGH EXPRESSION OF DDNMT2 AND DMBD2/3 ACCOMPANIED CD EXPOSURE, WHICH WAS PASSED ON TO THREE GENERATIONS, SUGGESTING THAT GENETIC MODIFICATIONS IN APOPTOSIS-RELATED GENES ARE CARRIED TO THE OFFSPRING THROUGH EPIGENETIC REGULATION. 2020 14 4391 36 MODERATE EXERCISE INDUCES TRAINED IMMUNITY IN MACROPHAGES. DESPITE ITS IMPORTANCE IN PROTECTING THE HOST FROM INFECTIONS AND INJURY, EXCESSIVE INFLAMMATION MAY LEAD TO SERIOUS HUMAN DISEASES INCLUDING AUTOIMMUNE DISORDERS, CARDIOVASCULAR DISEASES, DIABETES, AND CANCER. EXERCISE IS A KNOWN IMMUNOMODULATOR; HOWEVER, WHETHER EXERCISE CAUSES LONG-TERM CHANGES IN INFLAMMATORY RESPONSES AND HOW THESE CHANGES OCCUR ARE LACKING. HERE, WE SHOW THAT CHRONIC MODERATE-INTENSITY TRAINING OF MICE LEADS TO PERSISTENT METABOLIC REWIRING AND CHANGES TO CHROMATIN ACCESSIBILITY IN BONE MARROW-DERIVED MACROPHAGES (BMDMS), WHICH, IN TURN, TEMPERS THEIR INFLAMMATORY RESPONSES. WE SHOW THAT BMDMS FROM EXERCISED MICE EXHIBITED A DECREASE IN LIPOPOLYSACCHARIDE (LPS)-INDUCED NF-KAPPAB ACTIVATION AND PROINFLAMMATORY GENE EXPRESSION ALONG WITH AN INCREASE IN M2-LIKE-ASSOCIATED GENES WHEN COMPARED WITH BMDMS FROM SEDENTARY MICE. THIS WAS ASSOCIATED WITH IMPROVED MITOCHONDRIAL QUALITY AND INCREASED RELIANCE ON OXIDATIVE PHOSPHORYLATION ACCOMPANIED WITH REDUCED MITOCHONDRIAL REACTIVE OXYGEN SPECIES (ROS) PRODUCTION. MECHANISTICALLY, ASSAY FOR TRANSPOSASE-ACCESSIBLE CHROMATIN (ATAC)-SEQ ANALYSIS SHOWED CHANGES IN CHROMATIN ACCESSIBILITY OF GENES ASSOCIATED WITH INFLAMMATORY AND METABOLIC PATHWAYS. OVERALL, OUR DATA SUGGEST THAT CHRONIC MODERATE EXERCISE CAN INFLUENCE THE INFLAMMATORY RESPONSES OF MACROPHAGES BY REPROGRAMMING THEIR METABOLIC AND EPIGENETIC LANDSCAPE.NEW & NOTEWORTHY IN THIS STUDY, WE EXPLAIN HOW LONG-TERM MODERATE EXERCISE TRAINING CAN REDUCE INFLAMMATION IN MOUSE MACROPHAGES BY REPROGRAMMING THE WAY THEY SENSE AND RESPOND TO THE PRESENCE OF PATHOGENS. WE COMPLETED A THOROUGH ANALYSIS AND SHOWED THAT THESE CHANGES PERSIST IN MACROPHAGES BECAUSE EXERCISE IMPROVES THE ABILITY OF CELLS TO UTILIZE OXYGEN WITHOUT PRODUCING DAMAGING COMPOUNDS, AND CHANGES THE WAY THEY ACCESS THEIR DNA. 2023 15 6895 17 [SYSTEMIC CONTROL OF THE MOLECULAR, CELL, AND EPIGENETIC MECHANISMS OF LONG-LASTING CONSEQUENCES OF STRESS]. BASED ON M.E. LOBASHEV'S VIEWS OF THE SYSTEMIC CONTROL OF GENETIC AND CYTOGENEITC PROCESSES AND A SUBSTANTIAL EFFECT OF EXCITABILITY ON PLASTIC CHANGES IN THE CENTRAL NERVOUS SYSTEM (CNS), THE EFFECT OF PROLONGED EMOTIONAL AND PAIN STRESS (PEPS) ON THE MOLECULAR, CELL, AND EPIGENETIC MECHANISMS OF INJURY MEMORY WAS STUDIED IN RAT STRAINS BRED FOR A CERTAIN EXCITABILITY OF THE NERVOUS SYSTEM. PEPS WAS FOR THE FIRST TIME FOUND TO CAUSE LONG-LASTING (2 MONTHS) MORPHOLOGICAL ALTERATIONS OF THE CA3 REGION OF THE HIPPOCAMPUS AND TO MODIFY THE GENOME ACTIVITY OF ITS PYRAMIDAL NEURONS. THE TWO PHENOMENA WERE POTENTIATED BY A GENETICALLY DETERMINED LOW FUNCTIONAL STATE OF THE CNS. THE POST-STRESS REGULATION OF THE GENOME FUNCTION IN HIPPOCAMPAL NEURONS WAS MEDIATED BY CHANGES IN HETEROCHROMATIN CONFORMATION, ACTIVATION OF METHYL-CPG-BINDING PROTEIN (MECP2) SYNTHESIS, AND SUBSEQUENT CHANGES IN ACETYLATION OF HISTONE H4. GENETICALLY DETERMINED HIGH EXCITABILITY OF THE NERVOUS SYSTEM PROVED TO BE A RISK FACTOR THAT AFFECTS THE SPECIFICS AND TIME COURSE OF THE OBSERVED MOLECULAR, CELL, AND GENETIC TRANSFORMATIONS OF NEURONS. THE RESULTS PROVIDE FOR A BETTER UNDERSTANDING OF THE EPIGENETIC MECHANISMS OF INJURY MEMORY, WHICH FORMS A PATHOGENETIC BASIS FOR POSTTRAUMATIC STRESS DISORDER AND OTHER HUMAN PSYCHOGENIC CONDITIONS CHARACTERIZED BY A PROLONGED DURATION. 2009 16 4210 25 METFORMIN AND VITAMIN D MODULATE INFLAMMATION AND AUTOPHAGY DURING ADIPOSE-DERIVED STEM CELL DIFFERENTIATION. ADIPOSE-DERIVED STEM CELLS (ADSCS) CAME OUT FROM THE REGENERATIVE MEDICINE LANDSCAPE FOR THEIR ABILITY TO DIFFERENTIATE INTO SEVERAL PHENOTYPES, CONTRIBUTING TO TISSUE REGENERATION BOTH IN VITRO AND IN VIVO. DYSREGULATION IN STEM CELL RECRUITMENT AND DIFFERENTIATION DURING ADIPOGENESIS IS LINKED TO A CHRONIC LOW-GRADE INFLAMMATION AND MACROPHAGE INFILTRATION INSIDE THE ADIPOSE TISSUE, INSULIN RESISTANCE, CARDIOVASCULAR DISEASE AND OBESITY. IN THE PRESENT PAPER WE AIMED TO EVALUATE THE ROLE OF METFORMIN AND VITAMIN D, ALONE OR IN COMBINATION, IN MODULATING INFLAMMATION AND AUTOPHAGY IN ADSCS DURING ADIPOGENIC COMMITMENT. ADSCS WERE CULTURED FOR 21 DAYS IN THE PRESENCE OF A SPECIFIC ADIPOGENIC DIFFERENTIATION MEDIUM, TOGETHER WITH METFORMIN, OR VITAMIN D, OR BOTH. WE THEN ANALYZED THE EXPRESSION OF FOXO1 AND HEAT SHOCK PROTEINS (HSP) AND THE SECRETION OF PROINFLAMMATORY CYTOKINES IL-6 AND TNF-ALPHA BY ELISA. AUTOPHAGY WAS ALSO ASSESSED BY SPECIFIC WESTERN BLOT ANALYSIS OF ATG12, LC3B I, AND LC3B II EXPRESSION. OUR RESULTS SHOWED THE ABILITY OF THE CONDITIONED MEDIA TO MODULATE ADIPOGENIC DIFFERENTIATION, FINELY TUNING THE INFLAMMATORY RESPONSE AND AUTOPHAGY. WE OBSERVED A MODULATION IN HSP MRNA LEVELS, AND A SIGNIFICANT DOWNREGULATION IN CYTOKINE SECRETION. TAKEN TOGETHER, OUR FINDINGS SUGGEST THE POSSIBLE APPLICATION OF THESE MOLECULES IN CLINICAL PRACTICE TO COUNTERACT UNCONTROLLED LIPOGENESIS AND PREVENT OBESITY AND OBESITY-RELATED METABOLIC DISORDERS. 2021 17 2717 42 EXERCISE: PUTTING ACTION INTO OUR EPIGENOME. MOST HUMAN PHENOTYPES ARE INFLUENCED BY A COMBINATION OF GENOMIC AND ENVIRONMENTAL FACTORS. ENGAGING IN REGULAR PHYSICAL EXERCISE PREVENTS MANY CHRONIC DISEASES, DECREASES MORTALITY RISK AND INCREASES LONGEVITY. HOWEVER, THE MECHANISMS INVOLVED ARE POORLY UNDERSTOOD. THE MODULATING EFFECT OF PHYSICAL (AEROBIC AND RESISTANCE) EXERCISE ON GENE EXPRESSION HAS BEEN KNOWN FOR SOME TIME NOW AND HAS PROVIDED US WITH AN UNDERSTANDING OF THE BIOLOGICAL RESPONSES TO PHYSICAL EXERCISE. EMERGING RESEARCH DATA SUGGEST THAT EPIGENETIC MODIFICATIONS ARE EXTREMELY IMPORTANT FOR BOTH DEVELOPMENT AND DISEASE IN HUMANS. IN THE CURRENT REVIEW, WE SUMMARISE FINDINGS ON THE EFFECT OF EXERCISE ON EPIGENETIC MODIFICATIONS AND THEIR EFFECTS ON GENE EXPRESSION. CURRENT RESEARCH DATA SUGGEST EPIGENETIC MODIFICATIONS (DNA METHYLATION AND HISTONE ACETYLATION) AND MICRORNAS (MIRNAS) ARE RESPONSIVE TO ACUTE AEROBIC AND RESISTANCE EXERCISE IN BRAIN, BLOOD, SKELETAL AND CARDIAC MUSCLE, ADIPOSE TISSUE AND EVEN BUCCAL CELLS. SIX MONTHS OF AEROBIC EXERCISE ALTERS WHOLE-GENOME DNA METHYLATION IN SKELETAL MUSCLE AND ADIPOSE TISSUE AND DIRECTLY INFLUENCES LIPOGENESIS. SOME MIRNAS ARE RELATED TO MAXIMAL OXYGEN CONSUMPTION (VO(2MAX)) AND VO(2MAX) TRAINABILITY, AND ARE DIFFERENTIALLY EXPRESSED AMONGST INDIVIDUALS WITH HIGH AND LOW VO(2MAX). REMARKABLY, MIRNA EXPRESSION PROFILES DISCRIMINATE BETWEEN LOW AND HIGH RESPONDERS TO RESISTANCE EXERCISE (MIR-378, -26A, -29A AND -451) AND CORRELATE TO GAINS IN LEAN BODY MASS (MIR-378). THE EMERGING FIELD OF EXERCISE EPIGENOMICS IS EXPECTED TO PROSPER AND ADDITIONAL STUDIES MAY ELUCIDATE THE CLINICAL RELEVANCE OF MIRNAS AND EPIGENETIC MODIFICATIONS, AND DELINEATE MECHANISMS BY WHICH EXERCISE CONFERS A HEALTHIER PHENOTYPE AND IMPROVES PERFORMANCE. 2014 18 2022 30 EPIGENETIC CHANGES ASSOCIATED WITH DISEASE PROGRESSION IN A MOUSE MODEL OF CHILDHOOD ALLERGIC ASTHMA. DEVELOPMENT OF ASTHMA IN CHILDHOOD IS LINKED TO VIRAL INFECTIONS OF THE LOWER RESPIRATORY TRACT IN EARLY LIFE, WITH SUBSEQUENT CHRONIC EXPOSURE TO ALLERGENS. PROGRESSION TO PERSISTENT ASTHMA IS ASSOCIATED WITH A TH2-BIASED IMMUNOLOGICAL RESPONSE AND STRUCTURAL REMODELLING OF THE AIRWAYS. THE UNDERLYING MECHANISMS ARE UNCLEAR, BUT COULD INVOLVE EPIGENETIC CHANGES. TO INVESTIGATE THIS, WE EMPLOYED A RECENTLY DEVELOPED MOUSE MODEL IN WHICH SELF-LIMITED NEONATAL INFECTION WITH A PNEUMOVIRUS, FOLLOWED BY SENSITISATION TO OVALBUMIN VIA THE RESPIRATORY TRACT AND LOW-LEVEL CHRONIC CHALLENGE WITH AEROSOLISED ANTIGEN, LEADS TO DEVELOPMENT OF AN ASTHMATIC PHENOTYPE. WE ASSESSED EXPRESSION OF MICRORNA BY CELLS IN THE PROXIMAL AIRWAYS, COMPARING CHANGES OVER THE PERIOD OF DISEASE PROGRESSION, AND USED TARGET PREDICTION DATABASES TO IDENTIFY GENES LIKELY TO BE UP- OR DOWNREGULATED AS A CONSEQUENCE OF ALTERED REGULATION OF MICRORNA. IN PARALLEL, WE ASSESSED DNA METHYLATION IN PULMONARY CD4(+) T CELLS. WE FOUND THAT A LIMITED NUMBER OF MICRORNAS EXHIBITED MARKED UP- OR DOWNREGULATION FOLLOWING EARLY-LIFE INFECTION AND SENSITISATION, FOR MANY OF WHICH THE LEVELS OF EXPRESSION WERE FURTHER CHANGED FOLLOWING CHRONIC CHALLENGE WITH THE SENSITIZING ANTIGEN. TARGETS OF THESE MICRORNAS INCLUDED GENES INVOLVED IN IMMUNE OR INFLAMMATORY RESPONSES (E.G. GATA3, KITL) AND IN TISSUE REMODELLING (E.G. IGF1, TGFBR1), AS WELL AS GENES FOR VARIOUS TRANSCRIPTION FACTORS AND SIGNALLING PROTEINS. IN PULMONARY CD4(+) T CELLS, THERE WAS SIGNIFICANT DEMETHYLATION AT PROMOTER SITES FOR INTERLEUKIN-4 AND INTERFERON-GAMMA, THE LATTER INCREASING FOLLOWING CHRONIC CHALLENGE. WE CONCLUDE THAT, IN THIS MODEL, PROGRESSION TO AN ASTHMATIC PHENOTYPE IS LINKED TO EPIGENETIC REGULATION OF GENES ASSOCIATED WITH INFLAMMATION AND STRUCTURAL REMODELLING, AND WITH T-CELL COMMITMENT TO A TH2 IMMUNOLOGICAL RESPONSE. EPIGENETIC CHANGES ASSOCIATED WITH THIS PATTERN OF GENE ACTIVATION MIGHT PLAY A ROLE IN THE DEVELOPMENT OF CHILDHOOD ASTHMA. 2013 19 6226 16 THE LINK BETWEEN EPIGENETICS, PAIN SENSITIVITY AND CHRONIC PAIN. INCREASING EVIDENCE SUGGESTS AN ASSOCIATION BETWEEN GENE EXPRESSION AND CLINICAL PAIN. EPIGENETIC MODIFICATIONS ARE THE MAIN MODULATORS OF GENE EXPRESSION OR PROTEIN TRANSLATION IN RESPONSE TO ENVIRONMENTAL STIMULI AND PATHOPHYSIOLOGICAL CONDITIONS. PRECLINICAL AND CLINICAL STUDIES INDICATE THAT EPIGENETIC MODIFICATIONS COULD ALSO IMPACT THE DEVELOPMENT OF PAIN, THE TRANSITION FROM ACUTE TO CHRONIC PAIN, AND THE MAINTENANCE HEREOF. 2022 20 2297 29 EPIGENETIC REGULATION OF ACUTE INFLAMMATORY PAIN. ACUTE PAIN IS ASSOCIATED WITH TISSUE DAMAGE, WHICH RESULTS IN THE RELEASE OF INFLAMMATORY MEDIATORS. RECENT STUDIES POINT TO THE INVOLVEMENT OF EPIGENETIC MECHANISMS (DNA METHYLATION) IN THE DEVELOPMENT OF PAIN. WE HAVE FOUND THAT DURING ACUTE INFLAMMATORY PAIN INDUCED BY THE APPLICATION OF 10% MUSTARD OIL ON THE TONGUES OF RATS, LEVELS OF DNMT3A AND 3B WERE ELEVATED MARKEDLY (36 AND 42 % RESPECTIVELY), WHEREAS THE LEVEL OF DNMT1 WAS NOT CHANGED SIGNIFICANTLY. PREVIOUS INJECTION OF XEFOCAM WITH 0,4 MG/KG DOSE DECREASED LEVELS OF DNMT3A AND 3B (25 AND 24% RESPECTIVELY). THE LEVEL OF DNMT1 WAS NOT CHANGED SIGNIFICANTLY COMPARED TO THE CONTROL GROUP. THE FINDINGS SUPPORT THE IDEA THAT INHIBITORS OF DNA-METHYLTRANSFERASES COULD BE USEFUL FOR PAIN MANAGEMENT. OUR DATA SUGGEST THAT NSAIDS (ALONE OR IN COMBINATION WITH DNMT INHIBITORS) MAY BE PROPOSED AS POSSIBLE EPIGENETIC REGULATORY AGENTS, WHICH MAY PLAY A ROLE IN EPIGENETIC MECHANISMS INDIRECTLY THROUGH ALTERING THE ACTIVITY OF INFLAMMATORY MEDIATORS INVOLVED IN PAIN DEVELOPMENT. 2014