1 3431 149 HYDROGEN SULFIDE ALLEVIATES HYPERTENSIVE KIDNEY DYSFUNCTION THROUGH AN EPIGENETIC MECHANISM. HYPERTENSION IS A MAJOR RISK FACTOR FOR CHRONIC KIDNEY DISEASE (CKD), AND RENAL INFLAMMATION IS AN INTEGRAL PART IN THIS PATHOLOGY. HYDROGEN SULFIDE (H(2)S) HAS BEEN SHOWN TO MITIGATE RENAL DAMAGE THROUGH REDUCTION IN BLOOD PRESSURE AND ROS; HOWEVER, THE EXACT MECHANISMS ARE NOT CLEAR. WHILE SEVERAL STUDIES HAVE UNDERLINED THE ROLE OF EPIGENETICS IN RENAL INFLAMMATION AND DYSFUNCTION, THE MECHANISMS THROUGH WHICH EPIGENETIC REGULATORS PLAY A ROLE IN HYPERTENSION ARE NOT WELL DEFINED. IN THIS STUDY, WE SOUGHT TO IDENTIFY WHETHER MICRORNAS ARE DYSREGULATED IN RESPONSE TO ANGIOTENSIN II (ANG II)-INDUCED HYPERTENSION IN THE KIDNEY AND WHETHER A H(2)S DONOR, GYY4137, COULD REVERSE THE MICRORNA ALTERATION AND KIDNEY FUNCTION. WILD-TYPE (C57BL/6J) MICE WERE TREATED WITHOUT OR WITH ANG II AND GYY4137 FOR 4 WK. BLOOD PRESSURE, RENAL BLOOD FLOW, AND RESISTIVE INDEX (RI) WERE MEASURED. MICRORNA MICROARRAYS WERE CONDUCTED AND SUBSEQUENT TARGET PREDICTION REVEALED GENES ASSOCIATED WITH A PROINFLAMMATORY RESPONSE. ANG II TREATMENT SIGNIFICANTLY INCREASED BLOOD PRESSURE, DECREASED BLOOD FLOW IN THE RENAL CORTEX, INCREASED RI, AND REDUCED RENAL FUNCTION. THESE EFFECTS WERE AMELIORATED IN MICE TREATED WITH GYY4137. MICROARRAY ANALYSIS REVEALED DOWNREGULATION OF MIR-129 IN ANG II-TREATED MICE AND UPREGULATION AFTER GYY4137 TREATMENT. QUANTITATION OF PROTEINS INVOLVED IN THE INFLAMMATORY RESPONSE AND DNA METHYLATION REVEALED UPREGULATION OF IL-17A AND DNA METHYLTRANSFERASE 3A, WHEREAS H(2)S PRODUCTION ENZYMES AND ANTI-INFLAMMATORY IL-10 WERE REDUCED. TAKEN TOGETHER, OUR DATA SUGGEST THAT DOWNREGULATION OF MIR-129 PLAYS A SIGNIFICANT ROLE IN ANG II-INDUCED RENAL INFLAMMATION AND FUNCTIONAL OUTCOMES AND THAT GYY4137 IMPROVES RENAL FUNCTION BY REVERSING MIR-129 EXPRESSION.NEW & NOTEWORTHY WE INVESTIGATED EPIGENETIC CHANGES THAT OCCUR IN THE HYPERTENSIVE KIDNEY AND HOW H(2)S SUPPLEMENTATION REVERSES ADVERSE EFFECTS. INFLAMMATION, ABERRANT METHYLATION, AND DYSFUNCTION WERE OBSERVED IN THE HYPERTENSIVE KIDNEY, AND THESE EFFECTS WERE ALLEVIATED WITH H(2)S SUPPLEMENTATION. WE IDENTIFY MIR-129 AS A POTENTIAL REGULATOR OF BLOOD PRESSURE AND H(2)S REGULATION. 2017 2 2297 38 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 3 1117 39 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 4 1567 47 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 5 6564 33 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 6 5972 34 TET REPRESSION AND INCREASED DNMT ACTIVITY SYNERGISTICALLY INDUCE ABERRANT DNA METHYLATION. CHRONIC INFLAMMATION IS DEEPLY INVOLVED IN VARIOUS HUMAN DISORDERS, SUCH AS CANCER, NEURODEGENERATIVE DISORDERS, AND METABOLIC DISORDERS. INDUCTION OF EPIGENETIC ALTERATIONS, ESPECIALLY ABERRANT DNA METHYLATION, IS ONE OF THE MAJOR MECHANISMS, BUT HOW IT IS INDUCED IS STILL UNCLEAR. HERE, WE FOUND THAT EXPRESSION OF TET GENES, METHYLATION ERASERS, WAS DOWNREGULATED IN INFLAMED MOUSE AND HUMAN TISSUES, AND THAT THIS WAS CAUSED BY UPREGULATION OF TET-TARGETING MIRNAS SUCH AS MIR20A, MIR26B, AND MIR29C, LIKELY DUE TO ACTIVATION OF NF-KAPPAB SIGNALING DOWNSTREAM OF IL-1BETA AND TNF-ALPHA. HOWEVER, TET KNOCKDOWN INDUCED ONLY MILD ABERRANT METHYLATION. NITRIC OXIDE (NO), PRODUCED BY NOS2, ENHANCED ENZYMATIC ACTIVITY OF DNA METHYLTRANSFERASES (DNMTS), METHYLATION WRITERS, AND NO EXPOSURE INDUCED MINIMAL ABERRANT METHYLATION. IN CONTRAST, A COMBINATION OF TET KNOCKDOWN AND NO EXPOSURE SYNERGISTICALLY INDUCED ABERRANT METHYLATION, INVOLVING GENOMIC REGIONS NOT METHYLATED BY EITHER ALONE. THE RESULTS SHOWED THAT A VICIOUS COMBINATION OF TET REPRESSION, DUE TO NF-KAPPAB ACTIVATION, AND DNMT ACTIVATION, DUE TO NO PRODUCTION, IS RESPONSIBLE FOR ABERRANT METHYLATION INDUCTION IN HUMAN TISSUES. 2020 7 2926 34 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 8 5189 37 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 9 6431 42 THE USE OF TARGETED NEXT GENERATION SEQUENCING TO EXPLORE CANDIDATE REGULATORS OF TGF-BETA1'S IMPACT ON KIDNEY CELLS. AIMS/HYPOTHESIS: TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA1) PLAYS AN IMPORTANT REGULATORY ROLE IN THE PROGRESSION OF CHRONIC KIDNEY FAILURE. FURTHER, DAMAGE TO KIDNEY GLOMERULAR MESANGIAL CELLS IS CENTRAL TO THE PROGRESSION OF DIABETIC NEPHROPATHY. THE AIM OF THIS STUDY WAS TO EXPLORE THE GENETIC ASSOCIATIONS BETWEEN MRNA, MICRORNA, AND EPIGENETICS IN MESANGIAL CELLS IN RESPONSE TO TGF-BETA1. METHODS: THE REGULATORY EFFECTS OF TGF-BETA1 ON MESANGIAL CELLS WERE INVESTIGATED AT DIFFERENT MOLECULAR LEVELS BY TREATING MESANGIAL CELLS WITH TGF-BETA1 FOR 3 DAYS FOLLOWED BY GENOME-WIDE MIRNA, RNA, DNA METHYLATION, AND H3K27ME3 EXPRESSION PROFILING USING NEXT GENERATION SEQUENCING (NGS). RESULTS: OUR RESULTS PROVIDE THE FIRST COMPREHENSIVE, COMPUTATIONALLY INTEGRATED REPORT OF RNA-SEQ, MIRNA-SEQ, AND EPIGENOMIC ANALYSES ACROSS ALL GENETIC VARIATIONS, CONFIRMING THE OCCURRENCE OF DNA METHYLATION AND H3K27ME3 IN RESPONSE TO TGF-BETA1. OUR FINDINGS SHOW THAT THE EXPRESSION OF KLF7 AND GJA4 ARE INVOLVED IN TGF-BETA1 REGULATED DNA METHYLATION. OUR DATA ALSO PROVIDE EVIDENCE OF THE ASSOCIATION BETWEEN EPIGENETIC CHANGES AND THE EXPRESSION OF GENES CLOSELY RELATED TO TGF-BETA1 REGULATION. CONCLUSION: THIS STUDY HAS ADVANCED OUR CURRENT KNOWLEDGE OF MECHANISMS THAT CONTRIBUTE TO THE EXPRESSION OF TGF-BETA1-REGULATED GENES INVOLVED IN THE PATHOGENESIS OF KIDNEY DISEASE. THE MOLECULAR UNDERPINNINGS OF TGF-BETA1 STIMULATION OF KIDNEY CELLS WAS DETERMINED, THEREBY PROVIDING A ROBUST PLATFORM FOR FURTHER TARGET EXPLORATION. 2018 10 3527 38 IL-6 ENHANCES THE NUCLEAR TRANSLOCATION OF DNA CYTOSINE-5-METHYLTRANSFERASE 1 (DNMT1) VIA PHOSPHORYLATION OF THE NUCLEAR LOCALIZATION SEQUENCE BY THE AKT KINASE. THE EPIGENETIC PROGRAMMING OF GENOMIC DNA IS ACCOMPLISHED, IN PART, BY SEVERAL DNA CYTOSINE-5-METHYLTRANSFERASES THAT ACT BY COVALENTLY MODIFYING CYTOSINES WITH THE ADDITION OF A METHYL GROUP. THIS COVALENT MODIFICATION IS MAINTAINED BY THE DNA CYTOSINE-5-METHYLTRANSFERASE-1 ENZYME (DNMT1), WHICH IS CAPABLE OF ACTING IN CONCERT WITH OTHER SIMILAR ENZYMES TO SILENCE IMPORTANT TUMOR SUPPRESSOR GENES. IL-6 IS A MULTIFUNCTIONAL MEDIATOR OF INFLAMMATION, ACTING THROUGH SEVERAL MAJOR SIGNALING CASCADES, INCLUDING THE PHOSPHATIDYLINOSITOL-3-KINASE PATHWAY (PI-3-K), WHICH ACTIVATES PROTEIN KINASE B (AKT/PKB) DOWNSTREAM. HERE, WE SHOW THAT THE SUBCELLULAR LOCALIZATION OF DNMT1 CAN BE ALTERED BY THE ADDITION OF IL-6, INCREASING THE RATE OF NUCLEAR TRANSLOCATION OF THE ENZYME FROM THE CYTOSOLIC COMPARTMENT. THE MECHANISM OF NUCLEAR TRANSLOCATION OF DNMT1 IS GREATLY ENHANCED BY PHOSPHORYLATION OF THE DNMT1 NUCLEAR LOCALIZATION SIGNAL (NLS) BY PKB/AKT KINASE. MUTAGENIC ALTERATION OF THE TWO AKT TARGET AMINO ACIDS WITHIN THE NLS RESULTS IN A MAJOR LOSS OF DNMT1 NUCLEAR TRANSLOCATION, WHILE THE CREATION OF A "PHOSPHO-MIMIC" AMINO ACID (MUTATION TO ACIDIC RESIDUES) RESTORES THIS COMPARTMENTATION ABILITY. THESE OBSERVATIONS SUGGEST AN INTERESTING HYPOTHESIS REGARDING HOW MEDIATORS OF CHRONIC INFLAMMATION MAY DISTURB THE DELICATE BALANCE OF CELLULAR COMPARTMENTALIZATION OF IMPORTANT PROTEINS, AND REVEALS A POTENTIAL MECHANISM FOR THE INDUCTION OR ENHANCEMENT OF TUMOR GROWTH VIA ALTERATION OF THE COMPONENTS INVOLVED IN THE EPIGENETIC PROGRAMMING OF A CELL. 2007 11 6794 39 [EFFECT OF BENZO(A)PYRENE ON THE EXPRESSION OF AHR-REGULATED MICRORNA IN FEMALE AND MALE RAT LUNGS]. SMOKING IS THE MAIN RISK FACTOR FOR LUNG CANCER, MAINLY DUE TO PRESENCE OF NITROSAMINES AND POLYCYCLIC AROMATIC HYDROCARBONS, INCLUDING BENZO[A]PYRENE (BP) IN TOBACCO SMOKE COMPOSITION. THE GENOTOXIC EFFECT OF BP IS BASED ON THE HIGH DNA-BINDING ABILITY OF ITS METABOLITES, WHILE THE EPIGENETIC EFFECTS ARE MEDIATED BY A CHANGE IN THE EXPRESSION OF CANCER RELATED GENES OR REGULATORY RNAS. IT HAS BEEN SHOWN THAT WOMEN HAVE A HIGHER RISK TO DEVELOP LUNG CANCER UPON SMOKING RATHER THAN MEN. WE HYPOTHESIZED THAT CROSSTALK BETWEEN SIGNALING PATHWAYS ACTIVATED BY BP AND ESTROGENS COULD UNDERLIE THE SEX-DEPENDENT DIFFERENCES IN MIRNAS EXPRESSION. TO TEST THIS HYPOTHESIS, MALE AND FEMALE RATS WERE SUBJECTED TO SHORT-TERM OR LONG-TERM BP EXPOSURE. USING IN SILICO ANALYSIS, MIRNAS CONTAINING THE ER- AND AHR-BINDING SITES IN THE PROMOTERS OF THE GENES (OR HOST GENES) WERE SELECTED. DURING CHRONIC EXPOSURE OF BP THE EXPRESSION OF MIR-22-3P, -29A-3P, -126A-3P, -193B-5P IN THE LUNGS OF MALE RATS WERE SIGNIFICANTLY INCREASED, WHILE THE LEVEL OF MIRNA-483-3P WERE DECREASED. EXPRESSION OF MIRNA-483-3P WAS UP-REGULATED DURING CHRONIC BP EXPOSURE IN THE LUNGS OF FEMALE RATS AND THE LEVELS OF OTHER STUDIED MIRNAS WERE UNCHANGED. IN TURN, CHANGES IN THE EXPRESSION OF MIRNAS WERE FOLLOWED BY CHANGES IN THE EXPRESSION OF THEIR TARGET GENES, INCLUDING PTEN, EMP2, IGF1, ITGA6, SLC34A2, AND THE OBSERVED CHANGES IN FEMALE AND MALE RAT LUNGS WERE VARIED. THUS, OUR RESULTS SUGGEST THAT SEX-DEPENDENT EPIGENETIC EFFECTS OF BP MAY BE BASED ON DIFFERENT EXPRESSION OF AHR- AND ER- REGULATED MIRNAS. 2020 12 2119 36 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 13 1584 31 DNA METHYLATION PROFILES OF SELECTED PRO-INFLAMMATORY CYTOKINES IN ALZHEIMER DISEASE. BY MEANS OF FUNCTIONAL GENOMICS ANALYSIS, WE RECENTLY DESCRIBED THE MRNA EXPRESSION PROFILES OF VARIOUS GENES INVOLVED IN THE NEUROINFLAMMATORY RESPONSE IN THE BRAINS OF SUBJECTS WITH LATE-ONSET ALZHEIMER DISEASE (LOAD). SOME OF THESE GENES, NAMELY INTERLEUKIN (IL)-1BETA AND IL-6, SHOWED DISTINCT EXPRESSION PROFILES WITH PEAK EXPRESSION DURING THE FIRST STAGES OF THE DISEASE AND CONTROL-LIKE LEVELS AT LATER STAGES. IL-1BETA AND IL-6 GENES ARE MODULATED BY DNA METHYLATION IN DIFFERENT CHRONIC AND DEGENERATIVE DISEASES; IT IS ALSO WELL KNOWN THAT LOAD MAY HAVE AN EPIGENETIC BASIS. INDEED, WE AND OTHERS HAVE PREVIOUSLY REPORTED GENE-SPECIFIC DNA METHYLATION ALTERATIONS IN LOAD AND IN RELATED ANIMAL MODELS. BASED ON THESE DATA, WE STUDIED THE DNA METHYLATION PROFILES, AT SINGLE CYTOSINE RESOLUTION, OF IL-1BETA AND IL-6 5'-FLANKING REGION BY BISULPHITE MODIFICATION IN THE CORTEX OF HEALTHY CONTROLS AND LOAD PATIENTS AT 2 DIFFERENT DISEASE STAGES: BRAAK I-II/A AND BRAAK V-VI/C. OUR ANALYSIS PROVIDES EVIDENCE THAT NEUROINFLAMMATION IN LOAD IS ASSOCIATED WITH (AND POSSIBLY MEDIATED BY) EPIGENETIC MODIFICATIONS. 2017 14 2776 45 EXTRAUTERINE GROWTH RESTRICTION ON PULMONARY VASCULAR ENDOTHELIAL DYSFUNCTION IN ADULT MALE RATS: THE ROLE OF EPIGENETIC MECHANISMS. OBJECTIVE: EARLY POSTNATAL LIFE IS CONSIDERED AS A CRITICAL TIME WINDOW FOR THE DETERMINATION OF LONG-TERM METABOLIC STATES AND ORGAN FUNCTIONS. EXTRAUTERINE GROWTH RESTRICTION (EUGR) CAUSES THE DEVELOPMENT OF ADULT-ONSET CHRONIC DISEASES, INCLUDING PULMONARY HYPERTENSION. HOWEVER, THE EFFECTS OF NUTRITIONAL DISADVANTAGES DURING THE EARLY POSTNATAL PERIOD ON PULMONARY VASCULAR CONSEQUENCES IN LATER LIFE ARE NOT FULLY UNDERSTOOD. OUR STUDY WAS DESIGNED TO TEST WHETHER EPIGENETICS DYSREGULATION MEDIATES THE CELLULAR MEMORY OF THIS EARLY POSTNATAL EVENT. METHODS AND RESULTS: TO TEST THIS HYPOTHESIS, WE ISOLATED PULMONARY VASCULAR ENDOTHELIAL CELLS BY MAGNETIC-ACTIVATED CELL SORTING FROM EUGR AND CONTROL RATS. A POSTNATAL INSULT, NUTRITIONAL RESTRICTION-INDUCED EUGR CAUSED DEVELOPMENT OF AN INCREASED PULMONARY ARTERY PRESSURE AT 9 WEEKS OF AGE IN MALE SPRAGUE-DAWLEY RATS. METHYL-DNA IMMUNE PRECIPITATION CHIP, GENOME-SCALE MAPPING STUDIES TO SEARCH FOR DIFFERENTIALLY METHYLATED LOCI BETWEEN CONTROL AND EUGR RATS, REVEALED SIGNIFICANT DIFFERENCE IN CYTOSINE METHYLATION BETWEEN EUGR AND CONTROL RATS. EUGR CHANGES THE CYTOSINE METHYLATION AT APPROXIMATELY 500 LOCI IN MALE RATS AT 9 WEEKS OF AGE, PRECEDING THE DEVELOPMENT OF PULMONARY HYPERTENSION AND THESE REPRESENT THE CANDIDATE LOCI FOR MEDIATING THE PATHOGENESIS OF PULMONARY VASCULAR DISEASE THAT OCCURS LATER IN LIFE. GENE ONTOLOGY ANALYSIS ON DIFFERENTIALLY METHYLATED GENES SHOWED THAT HYPERMETHYLATED GENES IN EUGR ARE VASCULAR DEVELOPMENT-ASSOCIATED GENES AND HYPOMETHYLATED GENES IN EUGR ARE LATE-DIFFERENTIATION-ASSOCIATED AND SIGNAL TRANSDUCTION GENES. WE VALIDATED CANDIDATE DYSREGULATED LOCI WITH THE QUANTITATIVE ASSAYS OF CYTOSINE METHYLATION AND GENE EXPRESSIONS. CONCLUSION: THESE RESULTS DEMONSTRATE THAT EPIGENETICS DYSREGULATION IS A STRONG MECHANISM FOR PROPAGATING THE CELLULAR MEMORY OF EARLY POSTNATAL EVENTS, CAUSING CHANGES IN THE EXPRESSION OF GENES AND LONG-TERM SUSCEPTIBILITY TO PULMONARY HYPERTENSION, AND FURTHER PROVIDING A NEW INSIGHT INTO THE PREVENTION AND TREATMENT OF EUGR-RELATED PULMONARY HYPERTENSION. 2014 15 2002 31 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 16 141 39 ABERRANT DNA METHYLATION OF MTOR PATHWAY GENES PROMOTES INFLAMMATORY ACTIVATION OF IMMUNE CELLS IN DIABETIC KIDNEY DISEASE. DNA METHYLATION HAS BEEN IMPLICATED IN THE PATHOGENESIS OF DIABETIC KIDNEY DISEASE (DKD), BUT THE UNDERLYING MECHANISMS REMAIN UNCLEAR. IN THIS STUDY, WE TESTED THE HYPOTHESIS THAT ABERRANT DNA METHYLATION IN PERIPHERAL IMMUNE CELLS CONTRIBUTES TO DKD PROGRESSION. WE SHOWED THAT LEVELS OF DNA METHYLTRANSFERASE 1 (DNMT1), A KEY ENZYME FOR DNA METHYLATION, WERE INCREASED ALONG WITH INFLAMMATORY ACTIVITY OF PERIPHERAL BLOOD MONONUCLEAR CELLS IN DKD PATIENTS. INHIBITION OF DNMT1 WITH 5-AZA-2'-DEOXYCYTIDINE (5-AZA) MARKEDLY INCREASED THE PROPORTION OF CD4(+)CD25(+) REGULATORY T CELLS IN PERIPHERAL BLOOD MONONUCLEAR CELLS IN CULTURE AND IN DIABETIC ANIMALS. ADOPTIVE TRANSFER OF IMMUNE CELLS FROM 5-AZA-TREATED ANIMALS SHOWED BENEFICIAL EFFECTS ON THE HOST IMMUNE SYSTEM, RESULTING IN A SIGNIFICANT IMPROVEMENT OF DKD. USING GENOME-WIDE DNA METHYLATION ASSAYS, WE IDENTIFIED THE DIFFERENTIALLY METHYLATED CYTOSINES IN THE PROMOTER REGIONS OF MAMMALIAN TARGET OF RAPAMYCIN (MTOR) REGULATORS IN PERIPHERAL BLOOD MONONUCLEAR CELLS OF DIABETIC PATIENTS. FURTHER, MRNA ARRAYS CONFIRMED THE CONSISTENT INDUCTION OF GENES EXPRESSED IN THE MTOR PATHWAY. IMPORTANTLY, DOWN-REGULATION OF DNMT1 EXPRESSION VIA RNA INTERFERENCE RESULTED IN PROMINENT CYTOSINE DEMETHYLATION OF MTOR NEGATIVE REGULATORS AND SUBSEQUENT DECREASE OF MTOR ACTIVITY. LASTLY, MODULATION OF MTOR RESULTED IN CHANGES IN THE EFFECT OF 5-AZA ON DIABETIC IMMUNE CELLS. THUS, UP-REGULATION OF DNMT1 IN DIABETIC IMMUNE CELLS INDUCES ABERRANT CYTOSINE METHYLATION OF THE UPSTREAM REGULATORS OF MTOR, LEADING TO PATHOGENIC ACTIVATION OF THE MTOR PATHWAY AND CONSEQUENT INFLAMMATION IN DIABETIC KIDNEYS. HENCE, THIS STUDY HIGHLIGHTS THERAPEUTIC POTENTIAL OF TARGETING EPIGENETIC EVENTS IN IMMUNE SYSTEM FOR TREATING DKD. 2019 17 1615 33 DNA METHYLTRANSFERASE 3B PLAYS A PROTECTIVE ROLE AGAINST HEPATOCARCINOGENESIS CAUSED BY CHRONIC INFLAMMATION VIA MAINTAINING MITOCHONDRIAL HOMEOSTASIS. MOST HEPATOCELLULAR CARCINOMAS (HCCS) DEVELOP ON THE BASIS OF CHRONIC HEPATITIS, BUT THE MECHANISM OF EPIGENETIC REGULATION IN INFLAMMATORY HEPATOCARCINOGENESIS HAS YET TO BE ELUCIDATED. AMONG DE NOVO DNA METHYLTRANSFERASES (DNMTS), DNMT3B HAS LATELY BEEN REPORTED TO ACT SPECIFICALLY ON ACTIVELY TRANSCRIBED GENES, SUGGESTING THE POSSIBILITY THAT IT PLAYS A ROLE IN THE PATHOGENESIS OF CANCER. WE CONFIRMED THAT DNMT3B ISOFORMS LACKING ITS CATALYTIC DOMAIN WERE HIGHLY EXPRESSED IN HCCS COMPARED WITH NON-TUMOROUS LIVER TISSUE. TO ELUCIDATE THE ROLE OF DNMT3B IN HEPATOCARCINOGENESIS, WE GENERATED A GENETICALLY ENGINEERED MOUSE MODEL WITH HEPATOCYTE-SPECIFIC DNMT3B DELETION. THE LIVER OF THE DNMT3B-DEFICIENT MICE EXHIBITED AN EXACERBATION OF THIOACETAMIDE-INDUCED HEPATITIS, PROGRESSION OF LIVER FIBROSIS AND A HIGHER INCIDENCE OF HCC COMPARED WITH THE LIVER OF THE CONTROL MICE. WHOLE-GENOME BISULFITE SEQUENCING VERIFIED A LOWER CG METHYLATION LEVEL IN THE DNMT3B-DEFICIENT LIVER, DEMONSTRATING DIFFERENTIALLY METHYLATED REGIONS THROUGHOUT THE GENOME. TRANSCRIPTOME ANALYSIS REVEALED DECREASED EXPRESSION OF GENES RELATED TO OXIDATIVE PHOSPHORYLATION IN THE DNMT3B-DEFICIENT LIVER. MOREOVER, PRIMARY HEPATOCYTES ISOLATED FROM THE DNMT3B-DEFICIENT MICE SHOWED REDUCED MITOCHONDRIAL RESPIRATORY CAPACITY, LEADING TO THE ENHANCEMENT OF OXIDATIVE STRESS IN THE LIVER TISSUE. OUR FINDINGS SUGGEST THE PROTECTIVE ROLE OF DNMT3B AGAINST CHRONIC INFLAMMATION AND HCC DEVELOPMENT VIA MAINTAINING MITOCHONDRIAL HOMEOSTASIS. 2020 18 3658 37 INDUCTION OF ABERRANT TRIMETHYLATION OF HISTONE H3 LYSINE 27 BY INFLAMMATION IN MOUSE COLONIC EPITHELIAL CELLS. A FIELD FOR CANCERIZATION (FIELD DEFECT), WHERE GENETIC AND EPIGENETIC ALTERATIONS ARE ACCUMULATED IN NORMAL-APPEARING TISSUES, IS INVOLVED IN HUMAN CARCINOGENESIS, ESPECIALLY CANCERS ASSOCIATED WITH CHRONIC INFLAMMATION. ALTHOUGH ABERRANT DNA METHYLATION IS INVOLVED IN THE FIELD DEFECT AND INDUCED BY CHRONIC INFLAMMATION, IT IS STILL UNCLEAR FOR TRIMETHYLATION OF HISTONE H3 LYSINE 27 (H3K27ME3), WHICH IS INVOLVED IN GENE REPRESSION INDEPENDENT OF DNA METHYLATION AND FUNCTIONS AS A PRE-MARK FOR ABERRANT DNA METHYLATION. IN THIS STUDY, USING A MOUSE COLITIS MODEL INDUCED BY DEXTRAN SULFATE SODIUM (DSS), WE AIMED TO CLARIFY WHETHER ABERRANT H3K27ME3 IS INDUCED BY INFLAMMATION AND INVOLVED IN A FIELD DEFECT. CHIP-ON-CHIP ANALYSIS OF COLONIC EPITHELIAL CELLS REVEALED THAT H3K27ME3 LEVELS WERE INCREASED OR DECREASED FOR 266 GENOMIC REGIONS BY AGING, AND MORE EXTENSIVELY (23 INCREASED AND 3574 DECREASED REGIONS) BY COLITIS. SUCH INCREASE OR DECREASE OF H3K27ME3 WAS INDUCED AS EARLY AS 2 WEEKS AFTER THE INITIATION OF DSS TREATMENT, AND PERSISTED AT LEAST FOR 16 WEEKS EVEN AFTER THE INFLAMMATION DISAPPEARED. SOME OF THE ABERRANT H3K27ME3 IN COLONIC EPITHELIAL CELLS WAS CARRIED OVER INTO COLON TUMORS. FURTHERMORE, H3K27ME3 ACQUIRED AT DAPK1 BY COLITIS WAS FOLLOWED BY INCREASED DNA METHYLATION, SUPPORTING ITS FUNCTION AS A PRE-MARK FOR ABERRANT DNA METHYLATION. THESE RESULTS DEMONSTRATED THAT ABERRANT H3K27ME3 CAN BE INDUCED BY EXPOSURE TO A SPECIFIC ENVIRONMENT, SUCH AS COLITIS, AND SUGGESTED THAT ABERRANT HISTONE MODIFICATION, IN ADDITION TO ABERRANT DNA METHYLATION, IS INVOLVED IN THE FORMATION OF A FIELD DEFECT. 2012 19 2442 34 EPIGENETIC STABILITY IN THE ADULT MOUSE CORTEX UNDER CONDITIONS OF PHARMACOLOGICALLY INDUCED HISTONE ACETYLATION. HISTONE ACETYLATION IS CONSIDERED A MAJOR EPIGENETIC PROCESS THAT AFFECTS BRAIN DEVELOPMENT AND SYNAPTIC PLASTICITY, AS WELL AS LEARNING AND MEMORY. THE TRANSCRIPTIONAL EFFECTORS AND MORPHOLOGICAL CHANGES RESPONSIBLE FOR PLASTICITY AS A RESULT OF LONG-TERM MODIFICATIONS TO HISTONE ACETYLATION ARE NOT FULLY UNDERSTOOD. TO THIS END, WE PHARMACOLOGICALLY INHIBITED HISTONE DEACETYLATION USING TRICHOSTATIN A IN ADULT (6-MONTH-OLD) MICE AND FOUND SIGNIFICANT INCREASES IN THE LEVELS OF THE ACETYLATED HISTONE MARKS H3LYS9, H3LYS14 AND H4LYS12. HIGH-RESOLUTION TRANSCRIPTOME ANALYSIS OF DIVERSE BRAIN REGIONS UNCOVERED FEW DIFFERENCES IN GENE EXPRESSION BETWEEN TREATED AND CONTROL ANIMALS, NONE OF WHICH WERE PLASTICITY RELATED. INSTEAD, AFTER INCREASED HISTONE ACETYLATION, WE DETECTED A LARGE NUMBER OF NOVEL TRANSCRIPTIONALLY ACTIVE REGIONS, WHICH CORRESPOND TO LONG NON-CODING RNAS (LNCRNAS). WE ALSO SURPRISINGLY FOUND NO SIGNIFICANT CHANGES IN DENDRITIC SPINE PLASTICITY IN LAYERS 1 AND 2/3 OF THE VISUAL CORTEX USING LONG-TERM IN VIVO TWO-PHOTON IMAGING. OUR RESULTS INDICATE THAT CHRONIC PHARMACOLOGICALLY INDUCED HISTONE ACETYLATION CAN BE DECOUPLED FROM GENE EXPRESSION AND INSTEAD, MAY POTENTIALLY EXERT A POST-TRANSCRIPTIONAL EFFECT THROUGH THE DIFFERENTIAL PRODUCTION OF LNCRNAS. 2016 20 2590 36 EPIGENETICS OF PROTEASOME INHIBITION IN THE LIVER OF RATS FED ETHANOL CHRONICALLY. AIM: TO EXAMINE THE EFFECTS OF ETHANOL-INDUCED PROTEASOME INHIBITION, AND THE EFFECTS OF PROTEASOME INHIBITION IN THE REGULATION OF EPIGENETIC MECHANISMS. METHODS: RATS WERE FED ETHANOL FOR 1 MO USING THE TSUKAMOTO-FRENCH MODEL AND WERE COMPARED TO RATS GIVEN THE PROTEASOME INHIBITOR PS-341 (BORTEZOMIB, VELCADE(TM)) BY INTRAPERITONEAL INJECTION. MICROARRAY ANALYSIS AND REAL TIME PCR WERE PERFORMED AND PROTEASOME ACTIVITY ASSAYS AND WESTERN BLOT ANALYSIS WERE PERFORMED USING ISOLATED NUCLEI. RESULTS: CHRONIC ETHANOL FEEDING CAUSED A SIGNIFICANT INHIBITION OF THE UBIQUITIN PROTEASOME PATHWAY IN THE NUCLEUS, WHICH LED TO CHANGES IN THE TURNOVER OF TRANSCRIPTIONAL FACTORS, HISTONE-MODIFYING ENZYMES, AND, THEREFORE, AFFECTED EPIGENETIC MECHANISMS. CHRONIC ETHANOL FEEDING WAS RELATED TO AN INCREASE IN HISTONE ACETYLATION, AND IT IS HYPOTHESIZED THAT THE PROTEASOME PROTEOLYTIC ACTIVITY REGULATED HISTONE MODIFICATIONS BY CONTROLLING THE STABILITY OF HISTONE MODIFYING ENZYMES, AND, THEREFORE, REGULATED THE CHROMATIN STRUCTURE, ALLOWING EASY ACCESS TO CHROMATIN BY RNA POLYMERASE, AND, THUS, PROPER GENE EXPRESSION. PROTEASOME INHIBITION BY PS-341 INCREASED HISTONE ACETYLATION SIMILAR TO CHRONIC ETHANOL FEEDING. IN ADDITION, PROTEASOME INHIBITION CAUSED DRAMATIC CHANGES IN HEPATIC REMETHYLATION REACTIONS AS THERE WAS A SIGNIFICANT DECREASE IN THE ENZYMES RESPONSIBLE FOR THE REGENERATION OF S-ADENOSYLMETHIONINE, AND, IN PARTICULAR, A SIGNIFICANT DECREASE IN THE BETAINE-HOMOCYSTEINE METHYLTRANSFERASE ENZYME. THIS SUGGESTED THAT HYPOMETHYLATION WAS ASSOCIATED WITH PROTEASOME INHIBITION, AS INDICATED BY THE DECREASE IN HISTONE METHYLATION. CONCLUSION: THE ROLE OF PROTEASOME INHIBITION IN REGULATING EPIGENETIC MECHANISMS, AND ITS LINK TO LIVER INJURY IN ALCOHOLIC LIVER DISEASE, IS THUS A PROMISING APPROACH TO STUDY LIVER INJURY DUE TO CHRONIC ETHANOL CONSUMPTION. 2009