1 4634 209 NEUROINFLAMMATION REGULATES THE BALANCE BETWEEN HIPPOCAMPAL NEURON DEATH AND NEUROGENESIS IN AN EX VIVO MODEL OF THIAMINE DEFICIENCY. BACKGROUND: THIAMINE (VITAMIN B1) IS A COFACTOR FOR ENZYMES OF CENTRAL ENERGY METABOLISM AND ITS DEFICIENCY (TD) IMPAIRS OXIDATIVE PHOSPHORYLATION, INCREASES OXIDATIVE STRESS, AND ACTIVATES INFLAMMATORY PROCESSES THAT CAN LEAD TO NEURODEGENERATION. WERNICKE-KORSAKOFF SYNDROME (WKS) IS A CONSEQUENCE OF CHRONIC TD, WHICH LEADS TO EXTENSIVE NEURONAL DEATH, AND IS ASSOCIATED WITH NEUROPATHOLOGICAL DISORDERS, INCLUDING COGNITIVE DEFICITS AND AMNESIA. THE HIPPOCAMPUS IS ONE OF THE BRAIN AREAS MOST AFFECTED BY WKS. B1 REPLACEMENT MAY NOT BE ENOUGH TO PREVENT THE IRREVERSIBLE COGNITIVE DEFICIT ASSOCIATED WITH WKS. MATERIALS AND METHODS: AN ORGANOTYPIC HIPPOCAMPAL SLICE CULTURE (OHC) MODEL WAS DEVELOPED TO INVESTIGATE, USING IMMUNOFLUORESCENCE AND CONFOCAL MICROSCOPY AND TRANSCRIPTOME ANALYSIS, THE MOLECULAR MECHANISMS UNDERLYING THE NEURODEGENERATION ASSOCIATED WITH TD. THE EFFECT OF ANTI-INFLAMMATORY PHARMACOLOGICAL INTERVENTION WITH RESVERATROL (RSV) WAS ALSO ASSESSED IN B1-DEPRIVED OHCS. RESULTS: IN OHCS CULTURED WITHOUT B1, NEURONAL DENSITY DECAYED AFTER 5 DAYS AND, ON THE 7TH DAY, THE EPIGENETIC MARKINGS H3K4ME3 AND H3K9ME3 WERE ALTERED IN MATURE NEURONS LIKELY FAVORING GENE TRANSCRIPTION. BETWEEN THE 7TH AND THE 14TH DAY, A PULSE OF NEUROGENESIS WAS OBSERVED FOLLOWED BY A FURTHER MASSIVE NEURON LOSS. TRANSCRIPTOME ANALYSIS AT DAY NINE DISCLOSED 89 DIFFERENTIALLY EXPRESSED GENES IN RESPONSE TO B1 DEPRIVATION. GENES INVOLVED IN TRYPTOPHAN METABOLISM AND LYSINE DEGRADATION KEGG PATHWAYS, AND THOSE WITH GENE ONTOLOGY (GO) ANNOTATIONS RELATED TO THE ORGANIZATION OF THE EXTRACELLULAR MATRIX, CELL ADHESION, AND POSITIVE REGULATION OF SYNAPTIC TRANSMISSION WERE UPREGULATED. SEVERAL GENES OF THE TNF AND FOXO SIGNALING PATHWAYS AND WITH GO TERMS RELATED TO INFLAMMATION WERE INHIBITED IN RESPONSE TO B1 DEPRIVATION. NSD1, WHOSE PRODUCT METHYLATES HISTONE H3 LYSINE 36, WAS UPREGULATED AND THE EPIGENETIC MARKING H3K36ME3, ASSOCIATED WITH NEGATIVE REGULATION OF NEUROGENESIS, WAS INCREASED IN NEURONS. TREATING B1-DEPRIVED OHCS WITH RSV PROMOTED AN EARLIER NEUROGENESIS PULSE. CONCLUSION: NEUROREGENERATION OCCURS IN B1-DEFICIENT HIPPOCAMPAL TISSUE DURING A TIME WINDOW. THIS PHENOMENON DEPENDS ON REDUCING NEUROINFLAMMATION AND, LIKELY, ON METABOLIC CHANGES, ALLOWING ACETYL-COA SYNTHESIS FROM AMINO ACIDS TO ENSURE ENERGY SUPPLY VIA OXIDATIVE PHOSPHORYLATION. THUS, NEUROINFLAMMATION IS IMPLICATED AS A MAJOR REGULATOR OF HIPPOCAMPAL NEUROGENESIS IN TD OPENING A NEW SEARCH SPACE FOR TREATING WKS. 2022 2 2246 32 EPIGENETIC MODULATION OF INFLAMMATION AND SYNAPTIC PLASTICITY PROMOTES RESILIENCE AGAINST STRESS IN MICE. MAJOR DEPRESSIVE DISORDER IS ASSOCIATED WITH ABNORMALITIES IN THE BRAIN AND THE IMMUNE SYSTEM. CHRONIC STRESS IN ANIMALS SHOWED THAT EPIGENETIC AND INFLAMMATORY MECHANISMS PLAY IMPORTANT ROLES IN MEDIATING RESILIENCE AND SUSCEPTIBILITY TO DEPRESSION. HERE, THROUGH A HIGH-THROUGHPUT SCREENING, WE IDENTIFY TWO PHYTOCHEMICALS, DIHYDROCAFFEIC ACID (DHCA) AND MALVIDIN-3'-O-GLUCOSIDE (MAL-GLUC) THAT ARE EFFECTIVE IN PROMOTING RESILIENCE AGAINST STRESS BY MODULATING BRAIN SYNAPTIC PLASTICITY AND PERIPHERAL INFLAMMATION. DHCA/MAL-GLUC ALSO SIGNIFICANTLY REDUCES DEPRESSION-LIKE PHENOTYPES IN A MOUSE MODEL OF INCREASED SYSTEMIC INFLAMMATION INDUCED BY TRANSPLANTATION OF HEMATOPOIETIC PROGENITOR CELLS FROM STRESS-SUSCEPTIBLE MICE. DHCA REDUCES PRO-INFLAMMATORY INTERLEUKIN 6 (IL-6) GENERATIONS BY INHIBITING DNA METHYLATION AT THE CPG-RICH IL-6 SEQUENCES INTRONS 1 AND 3, WHILE MAL-GLUC MODULATES SYNAPTIC PLASTICITY BY INCREASING HISTONE ACETYLATION OF THE REGULATORY SEQUENCES OF THE RAC1 GENE. PERIPHERAL INFLAMMATION AND SYNAPTIC MALADAPTATION ARE IN LINE WITH NEWLY HYPOTHESIZED CLINICAL INTERVENTION TARGETS FOR DEPRESSION THAT ARE NOT ADDRESSED BY CURRENTLY AVAILABLE ANTIDEPRESSANTS. 2018 3 1162 39 CONTRASTING EFFECTS OF ACUTE AND CHRONIC STRESS ON THE TRANSCRIPTOME, EPIGENOME, AND IMMUNE RESPONSE OF ATLANTIC SALMON. STRESS EXPERIENCED DURING EARLY LIFE MAY HAVE LASTING EFFECTS ON THE IMMUNE SYSTEM, WITH IMPACTS ON HEALTH AND DISEASE DEPENDENT ON THE NATURE AND DURATION OF THE STRESSOR. THE EPIGENOME IS ESPECIALLY SENSITIVE TO ENVIRONMENTAL STIMULI DURING EARLY LIFE AND REPRESENTS A POTENTIAL MECHANISM THROUGH WHICH STRESS MAY CAUSE LONG-LASTING HEALTH EFFECTS. HOWEVER, THE EXTENT TO WHICH THE EPIGENOME RESPONDS DIFFERENTLY TO CHRONIC VS ACUTE STRESSORS IS UNCLEAR, ESPECIALLY FOR NON-MAMMALIAN SPECIES. WE EXAMINED THE EFFECTS OF ACUTE STRESS (COLD-SHOCK DURING EMBRYOGENESIS) AND CHRONIC STRESS (ABSENCE OF TANK ENRICHMENT DURING LARVAL-STAGE) ON GLOBAL GENE EXPRESSION (USING RNA-SEQ) AND DNA METHYLATION (USING RRBS) IN THE GILLS OF ATLANTIC SALMON (SALMO SALAR) FOUR MONTHS AFTER HATCHING. CHRONIC STRESS INDUCED PRONOUNCED TRANSCRIPTIONAL DIFFERENCES, WHILE ACUTE STRESS CAUSED FEW LASTING TRANSCRIPTIONAL EFFECTS. HOWEVER, BOTH ACUTE AND CHRONIC STRESS CAUSED LASTING AND CONTRASTING CHANGES IN THE METHYLOME. CRUCIALLY, WE FOUND THAT ACUTE STRESS ENHANCED TRANSCRIPTIONAL IMMUNE RESPONSE TO A PATHOGENIC CHALLENGE (BACTERIAL LIPOPOLYSACCHARIDE, LPS), WHILE CHRONIC STRESS SUPPRESSED IT. WE IDENTIFIED STRESS-INDUCED CHANGES IN PROMOTER AND GENE-BODY METHYLATION THAT WERE ASSOCIATED WITH ALTERED EXPRESSION FOR A SMALL PROPORTION OF IMMUNE-RELATED GENES, AND EVIDENCE OF WIDER EPIGENETIC REGULATION WITHIN SIGNALLING PATHWAYS INVOLVED IN IMMUNE RESPONSE. OUR RESULTS SUGGEST THAT STRESS CAN AFFECT IMMUNO-COMPETENCE THROUGH EPIGENETIC MECHANISMS, AND HIGHLIGHT THE MARKEDLY DIFFERENT EFFECTS OF CHRONIC LARVAL AND ACUTE EMBRYONIC STRESS. THIS KNOWLEDGE COULD BE USED TO HARNESS THE STIMULATORY EFFECTS OF ACUTE STRESS ON IMMUNITY, PAVING THE WAY FOR IMPROVED STRESS AND DISEASE MANAGEMENT THROUGH EPIGENETIC CONDITIONING. 2018 4 3093 30 GENOMIC AND EPIGENOMIC RESPONSES TO CHRONIC STRESS INVOLVE MIRNA-MEDIATED PROGRAMMING. STRESS REPRESENTS A CRITICAL INFLUENCE ON MOTOR SYSTEM FUNCTION AND HAS BEEN SHOWN TO IMPAIR MOVEMENT PERFORMANCE. WE HYPOTHESIZED THAT STRESS-INDUCED MOTOR IMPAIRMENTS ARE DUE TO BRAIN-SPECIFIC CHANGES IN MIRNA AND PROTEIN-ENCODING GENE EXPRESSION. HERE WE SHOW A CAUSAL LINK BETWEEN STRESS-INDUCED MOTOR IMPAIRMENT AND ASSOCIATED GENETIC AND EPIGENETIC RESPONSES IN RELEVANT CENTRAL MOTOR AREAS IN A RAT MODEL. EXPOSURE TO TWO WEEKS OF MILD RESTRAINT STRESS ALTERED THE EXPRESSION OF 39 GENES AND NINE MIRNAS IN THE CEREBELLUM. IN LINE WITH PERSISTENT BEHAVIOURAL IMPAIRMENTS, SOME CHANGES IN GENE AND MIRNA EXPRESSION WERE RESISTANT TO RECOVERY FROM STRESS. INTERESTINGLY, STRESS UP-REGULATED THE EXPRESSION OF ADIPOQ AND PROLACTIN RECEPTOR MRNAS IN THE CEREBELLUM. STRESS ALSO ALTERED THE EXPRESSION OF PRLR, MIR-186, AND MIR-709 IN HIPPOCAMPUS AND PREFRONTAL CORTEX. IN ADDITION, OUR FINDINGS DEMONSTRATE THAT MIR-186 TARGETS THE GENE EPS15. FURTHERMORE, WE FOUND AN AGE-DEPENDENT INCREASE IN EPHRINB3 AND GABAA4 RECEPTORS. THESE DATA SHOW THAT EVEN MILD STRESS RESULTS IN SUBSTANTIAL GENOMIC AND EPIGENOMIC CHANGES INVOLVING MIRNA EXPRESSION AND ASSOCIATED GENE TARGETS IN THE MOTOR SYSTEM. THESE FINDINGS SUGGEST A CENTRAL ROLE OF MIRNA-REGULATED GENE EXPRESSION IN THE STRESS RESPONSE AND IN ASSOCIATED NEUROLOGICAL FUNCTION. 2012 5 2776 49 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 6 5205 46 PRENATAL STRESS CHANGES THE GLYCOPROTEIN GPM6A GENE EXPRESSION AND INDUCES EPIGENETIC CHANGES IN RAT OFFSPRING BRAIN. PRENATAL STRESS (PS) EXERTS STRONG IMPACT ON FETAL BRAIN DEVELOPMENT AND ON ADULT OFFSPRING BRAIN FUNCTIONS. PREVIOUS WORK DEMONSTRATED THAT CHRONIC STRESS ALTERS THE MRNA EXPRESSION OF GPM6A, A NEURONAL GLYCOPROTEIN INVOLVED IN FILOPODIUM EXTENSION. IN THIS WORK, WE ANALYZED THE EFFECT OF PS ON GPM6A EXPRESSION AND THE EPIGENETIC MECHANISMS INVOLVED. PREGNANT WISTAR RATS RECEIVED RESTRAINT STRESS DURING THE LAST WEEK OF GESTATION. MALE OFFSPRING WERE SACRIFICED ON POSTNATAL DAYS 28 AND 60. HIPPOCAMPUS AND PREFRONTAL CORTEX SAMPLES WERE ANALYZED FOR GENE EXPRESSION (QPCR FOR MRNAS AND MICRORNAS), METHYLATION STATUS (BISULFITE CONVERSION) AND PROTEIN LEVELS. HIPPOCAMPAL NEURONS IN CULTURE WERE USED TO ANALYZE MICRORNA OVEREXPRESSION EFFECTS. PRENATAL STRESS INDUCED CHANGES IN GPM6A LEVELS IN BOTH TISSUES AND AT BOTH AGES ANALYZED, INDICATING A PERSISTENT EFFECT. TWO CPG ISLANDS IN THE GPM6A GENE WERE IDENTIFIED. VARIATIONS IN THE METHYLATION PATTERN AT THREE SPECIFIC CPGS WERE FOUND IN HIPPOCAMPUS, BUT NOT IN PFC SAMPLES FROM PS OFFSPRING. MICRORNAS PREDICTED TO TARGET GPM6A WERE IDENTIFIED IN SILICO. QPCR MEASUREMENTS SHOWED THAT PS MODIFIED THE EXPRESSION OF SEVERAL MICRORNAS IN BOTH TISSUES, BEING MICRORNA-133B THE MOST SIGNIFICANTLY ALTERED. FURTHER STUDIES OVEREXPRESSING THIS MICRORNA IN NEURONAL CULTURES SHOWED A REDUCTION IN GMP6A MRNA AND PROTEIN LEVEL. MOREOVER FILOPODIUM DENSITY WAS ALSO REDUCED, SUGGESTING THAT GPM6A FUNCTION WAS AFFECTED. GESTATIONAL STRESS AFFECTED GPM6A GENE EXPRESSION IN OFFSPRING LIKELY THROUGH CHANGES IN METHYLATION STATUS AND IN POSTTRANSCRIPTIONAL REGULATION BY MICRORNAS. THUS, OUR FINDINGS PROPOSE GPM6A AS A NOVEL TARGET FOR EPIGENETIC REGULATION DURING PRENATAL STRESS. 2014 7 2886 30 GABA-AALPHA5 MIGHT BE INVOLVED IN LEARNING-MEMORY DYSFUNCTION IN THE OFFSPRINGS OF CHRONIC ETHANOL-TREATED RATS VIA GABA-AALPHA5 HISTONE H3K9 ACETYLATION. RECENTLY, NUMEROUS STUDIES HAVE BEEN FOCUSED ON THE RELATIONSHIP BETWEEN GABA-A RECEPTORS AND ALCOHOL-INDUCED SPATIAL LEARNING AND MEMORY DEFICITS. GABA-AALPHA5, A SUBUNIT OF GABA-A RECEPTORS, IS CONSIDERED TO PLAY AN IMPORTANT ROLE IN ALCOHOL-INDUCED COGNITIVE IMPAIRMENT, HOWEVER, THE MECHANISM REMAINS OBSCURE. IN THIS STUDY, WE FOUND THAT THE EXPRESSION OF GABA-AALPHA5 INCREASED IN RATS TREATED WITH CHRONIC ETHANOL VIA HISTONE H3K9 ACETYLATION. FURTHERMORE, THIS EPIGENETIC MODIFICATION COULD BE INHERITED BY THE NEXT GENERATIONS, WHICH EVENTUALLY EXHIBIT SIMILAR SPATIAL LEARNING AND MEMORY DEFICITS IN THE OFFSPRINGS. IN SUMMARY, OUR RESULTS SUGGESTED THAT GABA-AALPHA5 MIGHT BE INVOLVED IN CHRONIC ETHANOL TREATMENT-INDUCED LEARNING-MEMORY DYSFUNCTION AND FOR THE FIRST TIME PROVED THAT LEARNING-MEMORY DYSFUNCTION COULD BE INHERITED BY THE OFFSPRINGS VIA HISTONE H3K9 ACETYLATION. HOPEFULLY, IN THE NEAR FUTURE, GABA-AALPHA5 INHIBITORS WOULD BE AN EFFECTIVE WAY TO TREAT ALCOHOL-INDUCED COGNITION IMPAIRMENT. 2019 8 1584 27 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 9 1182 40 CONVERGING AND DIFFERENTIAL BRAIN PHOSPHOLIPID DYSREGULATION IN THE PATHOGENESIS OF REPETITIVE MILD TRAUMATIC BRAIN INJURY AND ALZHEIMER'S DISEASE. REPETITIVE MILD TRAUMATIC BRAIN INJURY (RMTBI) IS A MAJOR EPIGENETIC RISK FACTOR FOR ALZHEIMER'S DISEASE (AD). THE PRECISE NATURE OF HOW RMTBI LEADS TO OR PRECIPITATES AD PATHOLOGY IS CURRENTLY UNKNOWN. NUMEROUS NEUROLOGICAL CONDITIONS HAVE SHOWN AN IMPORTANT ROLE FOR DYSFUNCTIONAL PHOSPHOLIPID METABOLISM AS A DRIVING FACTOR FOR THE PATHOGENESIS OF NEURODEGENERATIVE DISEASES. HOWEVER, THE PRECISE ROLE IN RMTBI AND AD REMAINS ELUSIVE. WE HYPOTHESIZED THAT A DETAILED PHOSPHOLIPID CHARACTERIZATION WOULD REVEAL PROFILES OF RESPONSE TO INJURY IN TBI THAT OVERLAP WITH AGE-DEPENDENT CHANGES IN AD AND THUS PROVIDE INSIGHTS INTO THE TBI-AD RELATIONSHIP. WE EMPLOYED A LIPIDOMIC APPROACH EXAMINING BRAIN PHOSPHOLIPID PROFILES FROM MOUSE MODELS OF RMTBI AND AD. CORTEX AND HIPPOCAMPAL TISSUE WERE COLLECTED AT 24 H, 3, 6, 9, AND 12 MONTHS POST-RMTBI, AND AT AGES REPRESENTING 'PRE', 'PERI' AND 'POST' ONSET OF AMYLOID PATHOLOGY (I.E., 3, 9, 15 MONTHS-OLD). TOTAL LEVELS OF PHOSPHATIDYLCHOLINE (PC), PHOSPHATIDYLETHANOLAMINE (PE), LYSOPE, AND PHOSPHATIDYLINOSITOL (PI), INCLUDING THEIR MONOUNSATURATED, POLYUNSATURATED AND SATURATED FATTY ACID (FA) CONTAINING SPECIES WERE SIGNIFICANTLY INCREASED AT ACUTE AND/OR CHRONIC TIME POINTS POST-INJURY IN BOTH BRAIN REGIONS. HOWEVER, LEVELS OF MOST PHOSPHOLIPID SPECIES IN PS1/APP MICE WERE NOMINAL IN THE HIPPOCAMPUS, WHILE IN THE CORTEX, LEVELS WERE SIGNIFICANTLY DECREASED AT AGES POST-ONSET OF AMYLOID PATHOLOGY. SPHINGOMYELIN AND LYSOPC LEVELS SHOWED COINCIDENTAL TRENDS IN OUR RMTBI AND AD MODELS WITHIN THE HIPPOCAMPUS, AN INCREASE AT ACUTE AND/OR CHRONIC TIME POINTS EXAMINED. THE RATIO OF ARACHIDONIC ACID (OMEGA-6 FA) TO DOCOSAHEXAENOIC ACID (OMEGA-3 FA)-CONTAINING PE SPECIES WAS INCREASED AT EARLY TIME POINTS IN THE HIPPOCAMPUS OF INJURED VERSUS SHAM MICE, AND IN PS1/APP MICE THERE WAS A COINCIDENTAL INCREASE COMPARED TO WILD TYPE LITTERMATES AT ALL TIME POINTS. THIS STUDY DEMONSTRATES SOME OVERLAPPING AND DIVERSE PHOSPHOLIPID PROFILES IN RMTBI AND AD MODELS. FUTURE STUDIES ARE REQUIRED TO CORROBORATE OUR FINDINGS IN HUMAN POST-MORTEM TISSUE. INVESTIGATION OF SECONDARY MECHANISMS TRIGGERED BY ABERRANT DOWNSTREAM ALTERATIONS IN BIOACTIVE METABOLITES OF THESE PHOSPHOLIPIDS, AND THEIR MODULATION AT THE APPROPRIATE TIME-WINDOWS OF OPPORTUNITY COULD HELP FACILITATE DEVELOPMENT OF NOVEL THERAPEUTIC STRATEGIES TO AMELIORATE THE NEURODEGENERATIVE CONSEQUENCES OF RMTBI OR THE POTENTIAL TRIGGERING OF AD PATHOGENESIS BY RMTBI. 2019 10 2673 52 ETHANOL-INDUCED MODULATION OF GPR55 EXPRESSION IN HUMAN MONOCYTE-DERIVED DENDRITIC CELLS IS ACCOMPANIED BY H4K12 ACETYLATION. INFLAMMATION SUPPORTS THE PROGRESSION OF ALCOHOL-RELATED ORGAN INJURY. RECENT RESEARCH FINDINGS HAVE LINKED ETHANOL EXPOSURE TO CHANGES IN HISTONE ACETYLATION AND DEACETYLATION IN THE BRAIN AND IN PERIPHERAL TISSUES, LEADING TO ETHANOL-DEPENDENCE RELATED DAMAGE. ONE OF THE MECHANISMS THAT HAS BEEN SHOWN TO PLAY A MAJOR ROLE DURING INFLAMMATION IS THE CANNABINOID SYSTEM. PREVIOUS RESEARCH HAS DEMONSTRATED THAT ETHANOL CAN MODULATE CANNABINOID RECEPTORS' FUNCTIONS. OUR LAB HAS SHOWN THAT THE G PROTEIN-COUPLED RECEPTOR (GPR55), A NOVEL CANNABINOID RECEPTOR, IS UPREGULATED IN BINGE DRINKERS AND IN CELLS TREATED ACUTELY WITH ETHANOL. ADDITIONALLY, OUR GROUP HAS ALSO UNCOVERED THAT CHRONIC ETHANOL EXPOSURE LEADS TO AN INCREASE IN HISTONE MODIFICATIONS, SUCH AS ACETYLATION. HOWEVER, THE REGULATORY MECHANISM OF GPR55 WITHIN THE IMMUNE SYSTEM UNDER THE INFLUENCE OF ETHANOL IS POORLY UNDERSTOOD. SINCE CHANGES IN HISTONE MODIFICATIONS MIGHT LEAD TO CHANGES IN GENE EXPRESSION, WE HYPOTHESIZE THAT THE MECHANISM OF ETHANOL-INDUCED UPREGULATION OF GPR55 IS LINKED TO EPIGENETIC CHANGES ON HISTONE PROTEINS. TAKING INTO ACCOUNT PREVIOUS FINDINGS FROM OUR LAB, THE GOAL OF THE PRESENT STUDY WAS TO DETERMINE WHETHER THERE IS ANY RELEVANT ASSOCIATION BETWEEN HISTONE HYPERACETYLATION AND THE REGULATION OF THE NOVEL CANNABINOID RECEPTOR GPR55 IN MONOCYTE-DERIVED DENDRITIC CELLS (MDDCS) OF HUMAN ORIGIN TREATED ACUTELY WITH ETHANOL. THEREFORE, MONOCYTES WERE ISOLATED FROM BUFFY COATS AND ALLOWED TO DIFFERENTIATE INTO MDDCS. THE CELLS WERE TREATED WITH ETHANOL FOR 24 H, HARVESTED, FIXED, AND STAINED WITH ANTIBODIES AGAINST GPR55. AS EXPECTED, BASED ON PREVIOUS FINDINGS, CONFOCAL MICROSCOPY SHOWED THAT ETHANOL EXPOSURE INCREASES GPR55 EXPRESSION. IN ORDER TO DEMONSTRATE THE CORRELATION BETWEEN HISTONE ACETYLATION AND GPR55 EXPRESSION REGULATION, THE CELLS WERE TREATED WITH ETHANOL, HARVESTED, AND THEN THE CHROMATIN WAS EXTRACTED AND FRACTIONATED FOR CHROMATIN IMMUNOPRECIPITATION (CHIP) ASSAY, FOLLOWED BY REAL-TIME QPCR FOR THE ANALYSIS OF DNA FRAGMENTS. THE RESULTS SHOWED AN ENRICHMENT OF THE HISTONE MODIFICATION H4K12AC IN THE GPR55 GENE OF MDDCS TREATED WITH ETHANOL. FURTHERMORE, SIRNA AGAINST THE HISTONE ACETYLTRANSFERASE TIP60 (RESPONSIBLE FOR THE ACETYLATION OF H4K12) RESULTED IN A DOWNREGULATION OF GPR55. IN CONJUNCTION, THESE RESULTS INDICATE THAT IN THE PRESENCE OF ETHANOL, THE UPREGULATION OF GPR55 EXPRESSION IS ACCOMPANIED BY H4K12 ACETYLATION, WHICH MIGHT HAVE A SIGNIFICANT EFFECT IN THE ABILITY OF THIS INNATE IMMUNE SYSTEM'S CELLS TO COPE WITH CELLULAR STRESS INDUCED BY ETHANOL. HOWEVER, THE CAUSALITY OF ETHANOL REGULATION OF H4K12AC IN GPR55 EXPRESSION CHANGES STILL LACKS FURTHER ELUCIDATION; THEREFORE, ADDITIONAL EXPERIMENTAL APPROACHES TO CONFIRM A SIGNIFICANT CAUSALITY BETWEEN H4K12 ACETYLATION AND ETHANOL REGULATION OF GPR55 ARE CURRENTLY UNDERGOING IN OUR LAB. 2018 11 4742 40 NOVEL HISTONE MODIFICATIONS IN MICROGLIA DERIVED FROM A MOUSE MODEL OF CHRONIC PAIN. AS THE RESIDENT IMMUNE CELLS IN THE CENTRAL NERVOUS SYSTEM, MICROGLIA PLAY AN IMPORTANT ROLE IN THE MAINTENANCE OF ITS HOMEOSTASIS. DYSREGULATION OF MICROGLIA HAS BEEN ASSOCIATED WITH THE DEVELOPMENT AND MAINTENANCE OF CHRONIC PAIN. HOWEVER, THE RELEVANT MOLECULAR PATHWAYS REMAIN POORLY DEFINED. IN THIS STUDY, WE USED A MASS SPECTROMETRY-BASED PROTEOMIC APPROACH TO SCREEN POTENTIAL CHANGES OF HISTONE PROTEIN MODIFICATIONS IN MICROGLIA ISOLATED FROM THE BRAIN OF CONTROL AND CISPLATIN-INDUCED NEUROPATHIC PAIN ADULT C57BL/6J MALE MICE. WE IDENTIFIED SEVERAL NOVEL MICROGLIAL HISTONE MODIFICATIONS ASSOCIATED WITH PAIN, INCLUDING STATISTICALLY SIGNIFICANTLY DECREASED HISTONE H3.1 LYSINE 27 MONO-METHYLATION (H3.1K27ME1, 54.8% OF CONTROL) AND H3 LYSINE 56 TRI-METHYLATION (7.5% OF CONTROL), AS WELL AS A TREND SUGGESTING INCREASED H3 TYROSINE 41 NITRATION. WE FURTHER INVESTIGATED THE FUNCTIONAL ROLE OF H3.1K27ME1 AND FOUND THAT TREATMENT OF CULTURED MICROGLIAL CELLS FOR 4 CONSECUTIVE DAYS WITH 1-10 MUM OF NCDM-64, A POTENT AND SELECTIVE INHIBITOR OF LYSINE DEMETHYLASE 7A, AN ENZYME RESPONSIBLE FOR THE DEMETHYLATION OF H3K27ME1, DOSE-DEPENDENTLY ELEVATED ITS LEVELS WITH A GREATER THAN A TWO-FOLD INCREASE OBSERVED AT 10 MUM COMPARED TO VEHICLE-TREATED CONTROL CELLS. MOREOVER, PRETREATMENT OF MICE WITH NCDM-64 (10 OR 25 MG/KG/DAY, I.P.) PRIOR TO CISPLATIN TREATMENT PREVENTED THE DEVELOPMENT OF NEUROPATHIC PAIN IN MICE. THE IDENTIFICATION OF SPECIFIC CHROMATIN MARKS IN MICROGLIA ASSOCIATED WITH CHRONIC PAIN MAY YIELD CRITICAL INSIGHT INTO THE CONTRIBUTION OF MICROGLIA TO THE DEVELOPMENT AND MAINTENANCE OF PAIN, AND OPENS NEW AVENUES FOR THE DEVELOPMENT OF NOVEL NONOPIOID THERAPEUTICS FOR THE EFFECTIVE MANAGEMENT OF CHRONIC PAIN. 2022 12 2395 52 EPIGENETIC REPROGRAMMING IN MIST1(-/-) MICE PREDICTS THE MOLECULAR RESPONSE TO CERULEIN-INDUCED PANCREATITIS. GENE EXPRESSION IS AFFECTED BY MODIFICATIONS TO HISTONE CORE PROTEINS WITHIN CHROMATIN. CHANGES IN THESE MODIFICATIONS, OR EPIGENETIC REPROGRAMMING, CAN DICTATE CELL FATE AND PROMOTE SUSCEPTIBILITY TO DISEASE. THE GOAL OF THIS STUDY WAS TO DETERMINE THE EXTENT OF EPIGENETIC REPROGRAMMING IN RESPONSE TO CHRONIC STRESS THAT OCCURS FOLLOWING ABLATION OF MIST1 (MIST1(-/-) ), WHICH IS REPRESSED IN PANCREATIC DISEASE. CHROMATIN IMMUNOPRECIPITATION FOR TRIMETHYLATION OF LYSINE RESIDUE 4 ON HISTONE 3 (H3K4ME3) IN PURIFIED ACINAR CELLS FROM WILD TYPE AND MIST1(-/-) MICE WAS FOLLOWED BY NEXT GENERATION SEQUENCING (CHIP-SEQ) OR CHIP-QPCR. H3K4ME3-ENRICHED GENES WERE ASSESSED FOR EXPRESSION BY QRT-PCR IN PANCREATIC TISSUE BEFORE AND AFTER INDUCTION OF CERULEIN-INDUCED PANCREATITIS. WHILE MOST OF H3K4ME3-ENRICHMENT IS RESTRICTED TO TRANSCRIPTIONAL START SITES, >25% OF ENRICHMENT SITES ARE FOUND WITHIN, DOWNSTREAM OR BETWEEN ANNOTATED GENES. LESS THAN 10% OF THESE SITES WERE ALTERED IN MIST1(-/-) ACINI, WITH MOST CHANGES IN H3K4ME3 ENRICHMENT NOT REFLECTING ALTERED GENE EXPRESSION. INGENUITY PATHWAY ANALYSIS OF GENES DIFFERENTIALLY-ENRICHED FOR H3K4ME3 REVEALED AN ASSOCIATION WITH PANCREATITIS AND PANCREATIC DUCTAL ADENOCARCINOMA IN MIST1(-/-) TISSUE. MOST OF THESE GENES WERE NOT DIFFERENTIALLY EXPRESSED BUT SEVERAL WERE READILY INDUCED BY ACUTE EXPERIMENTAL PANCREATITIS, WITH SIGNIFICANTLY INCREASED EXPRESSION IN MIST1(-/-) TISSUE RELATIVE TO WILD TYPE MICE. WE SUGGEST THAT THE CHRONIC CELL STRESS OBSERVED IN THE ABSENCE OF MIST1 RESULTS IN EPIGENETIC REPROGRAMMING OF GENES INVOLVED IN PROMOTING PANCREATITIS TO A POISED STATE, THEREBY INCREASING THE SENSITIVITY TO EVENTS THAT PROMOTE DISEASE. 2014 13 2442 43 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 14 984 49 CHRONIC PSYCHOLOGICAL STRESS ALTERS GENE EXPRESSION IN RAT COLON EPITHELIAL CELLS PROMOTING CHROMATIN REMODELING, BARRIER DYSFUNCTION AND INFLAMMATION. CHRONIC STRESS IS COMMONLY ASSOCIATED WITH ENHANCED ABDOMINAL PAIN (VISCERAL HYPERSENSITIVITY), BUT THE CELLULAR MECHANISMS UNDERLYING HOW CHRONIC STRESS INDUCES VISCERAL HYPERSENSITIVITY ARE POORLY UNDERSTOOD. IN THIS STUDY, WE EXAMINED CHANGES IN GENE EXPRESSION IN COLON EPITHELIAL CELLS FROM A RAT MODEL USING RNA-SEQUENCING TO EXAMINE STRESS-INDUCED CHANGES TO THE TRANSCRIPTOME. FOLLOWING CHRONIC STRESS, THE MOST SIGNIFICANTLY UP-REGULATED GENES INCLUDED ATG16L1, COQ10B, DCAF13, NAT2, PTBP2, RRAS2, SPINK4 AND DOWN-REGULATED GENES INCLUDING ABAT, CITED2, CNNM2, DAB2IP, PLEKHM1, SCD2, AND TAB2. THE PRIMARY ALTERED BIOLOGICAL PROCESSES REVEALED BY NETWORK ENRICHMENT ANALYSIS WERE INFLAMMATION/IMMUNE RESPONSE, TISSUE MORPHOGENESIS AND DEVELOPMENT, AND NUCLEOSOME/CHROMATIN ASSEMBLY. THE MOST SIGNIFICANTLY DOWN-REGULATED PROCESS WAS THE DIGESTIVE SYSTEM DEVELOPMENT/FUNCTION, WHEREAS THE MOST SIGNIFICANTLY UP-REGULATED PROCESSES WERE INFLAMMATORY RESPONSE, ORGANISMAL INJURY, AND CHROMATIN REMODELING MEDIATED BY H3K9 METHYLATION. FURTHERMORE, A SUBPOPULATION OF STRESSED RATS DEMONSTRATED VERY SIGNIFICANTLY ALTERED GENE EXPRESSION AND TRANSCRIPT ISOFORMS, ENRICHED FOR THE DIFFERENTIAL EXPRESSION OF GENES INVOLVED IN THE INFLAMMATORY RESPONSE, INCLUDING UPREGULATION OF CYTOKINE AND CHEMOKINE RECEPTOR GENE EXPRESSION COUPLED WITH DOWNREGULATION OF EPITHELIAL ADHERENS AND TIGHT JUNCTION MRNAS. IN SUMMARY, THESE FINDINGS SUPPORT THAT CHRONIC STRESS IS ASSOCIATED WITH INCREASED LEVELS OF CYTOKINES AND CHEMOKINES, THEIR DOWNSTREAM SIGNALING PATHWAYS COUPLED TO DYSREGULATION OF INTESTINAL CELL DEVELOPMENT AND FUNCTION. EPIGENETIC REGULATION OF CHROMATIN REMODELING LIKELY PLAYS A PROMINENT ROLE IN THIS PROCESS. RESULTS ALSO SUGGEST THAT SUPER ENHANCERS PLAY A PRIMARY ROLE IN CHRONIC STRESS-ASSOCIATED INTESTINAL BARRIER DYSFUNCTION. 2022 15 6895 35 [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 5188 51 PRENATAL ALCOHOL EXPOSURE ALTERS EXPRESSION OF NEUROGENESIS-RELATED GENES IN AN EX VIVO CELL CULTURE MODEL. PRENATAL ALCOHOL EXPOSURE CAN LEAD TO LONG-LASTING CHANGES IN FUNCTIONAL AND GENETIC PROGRAMS OF THE BRAIN, WHICH MAY UNDERLIE BEHAVIORAL ALTERATIONS SEEN IN FETAL ALCOHOL SPECTRUM DISORDER (FASD). ABERRANT FETAL PROGRAMMING DURING GESTATIONAL ALCOHOL EXPOSURE IS A POSSIBLE MECHANISM BY WHICH ALCOHOL IMPARTS TERATOGENIC EFFECTS ON THE BRAIN; HOWEVER, CURRENT METHODS USED TO INVESTIGATE THE EFFECTS OF ALCOHOL ON DEVELOPMENT OFTEN RELY ON EITHER DIRECT APPLICATION OF ALCOHOL IN VITRO OR ACUTE HIGH DOSES IN VIVO. IN THIS STUDY, WE USED OUR ESTABLISHED MODERATE PRENATAL ALCOHOL EXPOSURE (PAE) MODEL, RESULTING IN MATERNAL BLOOD ALCOHOL CONTENT OF APPROXIMATELY 20 MM, AND SUBSEQUENT EX VIVO CELL CULTURE TO ASSESS EXPRESSION OF GENES RELATED TO NEUROGENESIS. PROLIFERATING AND DIFFERENTIATING NEURAL PROGENITOR CELL CULTURE CONDITIONS WERE ESTABLISHED FROM TELENCEPHALIC TISSUE DERIVED FROM EMBRYONIC DAY (E) 15-17 TISSUE EXPOSED TO ALCOHOL VIA MATERNAL DRINKING THROUGHOUT PREGNANCY. GENE EXPRESSION ANALYSIS ON MRNA DERIVED IN VITRO WAS PERFORMED USING A MICROARRAY, AND QUANTITATIVE PCR WAS CONDUCTED FOR GENES TO VALIDATE THE MICROARRAY. STUDENT'S T TESTS WERE PERFORMED FOR STATISTICAL COMPARISON OF EACH EXPOSURE UNDER EACH CULTURE CONDITION USING A 95% CONFIDENCE INTERVAL. ELEVEN PERCENT OF GENES ON THE ARRAY HAD SIGNIFICANTLY ALTERED MRNA EXPRESSION IN THE PRENATAL ALCOHOL-EXPOSED NEURAL PROGENITOR CULTURE UNDER PROLIFERATING CONDITIONS. THESE INCLUDE REDUCED EXPRESSION OF ADORA2A, CXCL1, DLG4, HES1, NPTX1, AND VEGFA AND INCREASED EXPRESSION OF FGF13, NDN, AND SOX3; BIOINFORMATICS ANALYSIS INDICATED THAT THESE GENES ARE INVOLVED IN CELL GROWTH AND PROLIFERATION. DECREASED LEVELS OF DNMT1 AND DNMT3A WERE ALSO FOUND UNDER PROLIFERATING CONDITIONS. UNDER DIFFERENTIATING CONDITIONS, 7.3% OF GENES HAD DECREASED MRNA EXPRESSION; THESE INCLUDE CDK5RAP3, GDNF, HEY2, HEYL, PARD6B, AND PTN, WHICH ARE ASSOCIATED WITH SURVIVAL AND DIFFERENTIATION AS INDICATED BY BIOINFORMATICS ANALYSIS. THIS STUDY IS THE FIRST TO USE CHRONIC LOW TO MODERATE PAE, TO MORE ACCURATELY REFLECT MATERNAL ALCOHOL CONSUMPTION, AND SUBSEQUENT NEURAL PROGENITOR CELL CULTURE TO DEMONSTRATE THAT PAE THROUGHOUT GESTATION ALTERS EXPRESSION OF GENES INVOLVED IN NEURAL DEVELOPMENT AND EMBRYONIC NEUROGENESIS. 2014 17 905 36 CHRONIC EXPOSURE TO CANNABINOIDS DURING ADOLESCENCE CAUSES LONG-LASTING BEHAVIORAL DEFICITS IN ADULT MICE. REGULAR USE OF MARIJUANA DURING ADOLESCENCE ENHANCES THE RISK OF LONG-LASTING NEUROBIOLOGICAL CHANGES IN ADULTHOOD. THE PRESENT STUDY WAS AIMED AT ASSESSING THE EFFECT OF LONG-TERM ADMINISTRATION OF THE SYNTHETIC CANNABINOID WIN55212.2 DURING ADOLESCENCE IN YOUNG ADULT MICE. ADOLESCENT MICE AGED 5 WEEKS WERE SUBJECTED DAILY TO THE PHARMACOLOGICAL ACTION OF WIN55212.2 FOR 3 WEEKS AND WERE THEN LEFT UNDISTURBED IN THEIR HOME CAGE FOR A 5-WEEK PERIOD AND FINALLY EVALUATED BY BEHAVIORAL TESTING. MICE THAT RECEIVED THE DRUG DURING ADOLESCENCE SHOWED MEMORY IMPAIRMENT IN THE MORRIS WATER MAZE, AS WELL AS A DOSE-DEPENDENT MEMORY IMPAIRMENT IN FEAR CONDITIONING. IN ADDITION, THE ADMINISTRATION OF 3 MG/KG WIN55212.2 IN ADOLESCENCE INCREASED ADULT HIPPOCAMPAL AEA LEVELS AND PROMOTED DNA HYPERMETHYLATION AT THE INTRAGENIC REGION OF THE INTRACELLULAR SIGNALING MODULATOR RGS7, WHICH WAS ACCOMPANIED BY A LOWER RATE OF MRNA TRANSCRIPTION OF THIS GENE, SUGGESTING A POTENTIAL CAUSAL RELATION. ALTHOUGH THE CONCRETE MECHANISMS UNDERLYING THE BEHAVIORAL OBSERVATIONS REMAIN TO BE ELUCIDATED, WE DEMONSTRATE THAT LONG-TERM ADMINISTRATION OF 3 MG/KG OF WIN DURING ADOLESCENCE LEADS TO INCREASED ENDOCANNABINOID LEVELS AND ALTERED RGS7 EXPRESSION IN ADULTHOOD AND ESTABLISH A POTENTIAL LINK TO EPIGENETIC CHANGES. 2017 18 5468 31 RESISTANCE TRAINING AND REDOX HOMEOSTASIS: CORRELATION WITH AGE-ASSOCIATED GENOMIC CHANGES. REGULAR PHYSICAL ACTIVITY IS EFFECTIVE AS PREVENTION AND TREATMENT FOR DIFFERENT CHRONIC CONDITIONS RELATED TO THE AGEING PROCESSES. IN FACT, A SEDENTARY LIFESTYLE HAS BEEN LINKED TO A WORSENING OF CELLULAR AGEING BIOMARKERS SUCH AS TELOMERE LENGTH (TL) AND/OR SPECIFIC EPIGENETIC CHANGES (E.G. DNA METHYLATION), WITH INCREASE OF THE PROPENSITY TO AGING-RELATED DISEASES AND PREMATURE DEATH. EXTENDING OUR PREVIOUS FINDINGS, WE AIMED TO TEST THE HYPOTHESIS THAT 12 WEEKS OF LOW FREQUENCY, MODERATE INTENSITY, EXPLOSIVE-TYPE RESISTANCE TRAINING (EMRT) MAY ATTENUATE AGE-ASSOCIATED GENOMIC CHANGES. TO THIS AIM, TL, GLOBAL DNA METHYLATION, TRF2, KU80, SIRT1, SIRT2 AND GLOBAL PROTEIN ACETYLATION, AS WELL AS OTHER PROTEINS INVOLVED IN APOPTOTIC PATHWAY (BCL-2, BAX AND CASPASE-3), ANTIOXIDANT RESPONSE (TRXR1 AND MNSOD) AND OXIDATIVE DAMAGE (MYELOPEROXIDASE) WERE EVALUATED BEFORE AND AFTER EMRT IN WHOLE BLOOD OR PERIPHERAL MONONUCLEAR CELLS (PBMCS) OF ELDERLY SUBJECTS. OUR FINDINGS CONFIRM THE POTENTIAL OF EMRT TO INDUCE AN ADAPTIVE CHANGE IN THE ANTIOXIDANT PROTEIN SYSTEMS AT SYSTEMIC LEVEL AND SUGGEST A PUTATIVE ROLE OF RESISTANCE TRAINING IN THE REDUCTION OF GLOBAL DNA METHYLATION. MOREOVER, WE OBSERVED THAT EMRT COUNTERACTS THE TELOMERES' SHORTENING IN A MANNER THAT PROVED TO BE DIRECTLY CORRELATED WITH THE AMELIORATION OF REDOX HOMEOSTASIS AND EFFICACY OF TRAINING REGIME, EVALUATED AS IMPROVEMENT OF BOTH MUSCLE'S POWER/STRENGTH AND FUNCTIONAL PARAMETERS. 2016 19 989 34 CHRONIC SOCIAL DEFEAT STRESS DIFFERENTIALLY REGULATES THE EXPRESSION OF BDNF TRANSCRIPTS AND EPIGENETIC MODIFYING ENZYMES IN SUSCEPTIBLE AND RESILIENT MICE. OBJECTIVES: ALTHOUGH STRESS IS CONSIDERED A PRIMARY RISK FACTOR FOR NEUROPSYCHIATRIC DISORDERS, A MAJORITY OF INDIVIDUALS ARE RESILIENT TO THE EFFECTS OF STRESS EXPOSURE AND SUCCESSFULLY ADAPT TO ADVERSE LIFE EVENTS, WHILE OTHERS, THE SO-CALLED SUSCEPTIBLE INDIVIDUALS, MAY HAVE PROBLEMS TO PROPERLY ADAPT TO ENVIRONMENTAL CHANGES. HOWEVER, THE MECHANISMS UNDERLYING THESE DIFFERENT RESPONSES TO STRESS EXPOSURE ARE POORLY UNDERSTOOD.METHODS: ADULT MALE C57BL/6J MICE WERE EXPOSED TO CHRONIC SOCIAL DEFEAT STRESS PROTOCOL AND LEVELS OF BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) TRANSCRIPTS AND EPIGENETIC MODIFYING ENZYMES WERE ANALYSED BY REAL-TIME PCR IN THE HIPPOCAMPUS (HPC) AND PREFRONTAL CORTEX (PFC) OF SUSCEPTIBLE AND RESILIENT MICE.RESULTS: WE FOUND A SELECTIVE REDUCTION OF BDNF-6 TRANSCRIPT IN THE HPC AND AN INCREASE OF BDNF-4 TRANSCRIPT IN THE PFC OF SUSCEPTIBLE MICE. MOREOVER, SUSCEPTIBLE MICE SHOWED A SELECTIVE REDUCTION OF THE G9A MRNA LEVELS IN THE HPC, WHILE HDAC-5 AND DNMT3A MRNA LEVELS WERE SPECIFICALLY REDUCED IN THE PFC.CONCLUSIONS: OVERALL, OUR RESULTS, SHOWING A DIFFERENT EXPRESSION OF BDNF TRANSCRIPTS AND EPIGENETIC MODIFYING ENZYMES IN SUSCEPTIBLE AND RESILIENT MICE, SUGGEST THAT STRESS RESILIENCE IS NOT SIMPLY A LACK OF ACTIVATION OF STRESS-RELATED PATHWAYS, BUT IS RELATED TO THE ACTIVATION OF ADDITIONAL DIFFERENT SPECIFIC MECHANISMS. 2019 20 433 38 ANTIDEPRESSANT TREATMENT IS ASSOCIATED WITH EPIGENETIC ALTERATIONS OF HOMER1 PROMOTER IN A MOUSE MODEL OF CHRONIC DEPRESSION. BACKGROUND: UNDERSTANDING THE NEUROBIOLOGY OF DEPRESSION AND THE MECHANISM OF ACTION OF THERAPEUTIC MEASURES IS CURRENTLY A RESEARCH PRIORITY. WE HAVE SHOWN THAT THE EXPRESSION OF THE SYNAPTIC PROTEIN HOMER1A CORRELATES WITH DEPRESSION-LIKE BEHAVIOR AND ITS INDUCTION IS A COMMON MECHANISM OF ACTION OF DIFFERENT ANTIDEPRESSANT TREATMENTS. HOWEVER, THE MECHANISM OF HOMER1A REGULATION IS STILL UNKNOWN. METHODS: WE COMBINED THE CHRONIC DESPAIR MOUSE MODEL (CDM) OF CHRONIC DEPRESSION WITH DIFFERENT ANTIDEPRESSANT TREATMENTS. DEPRESSION-LIKE BEHAVIOR WAS CHARACTERIZED BY FORCED SWIM AND TAIL SUSPENSION TESTS, AND VIA AUTOMATIC MEASUREMENT OF SUCROSE PREFERENCE IN INTELLICAGE. THE HOMER1 MRNA EXPRESSION AND PROMOTER DNA METHYLATION WERE ANALYZED IN CORTEX AND PERIPHERAL BLOOD BY QRT-PCR AND PYROSEQUENCING. RESULTS: CDM MICE SHOW DECREASED HOMER1A AND HOMER1B/C MRNA EXPRESSION IN CORTEX AND BLOOD SAMPLES, WHILE CHRONIC TREATMENT WITH IMIPRAMINE AND FLUOXETINE OR ACUTE KETAMINE APPLICATION INCREASES THEIR LEVEL ONLY IN THE CORTEX. THE QUANTITATIVE ANALYSES OF THE METHYLATION OF 7 CPG SITES, LOCATED ON THE HOMER1 PROMOTER REGION CONTAINING SEVERAL CRE BINDING SITES, SHOW A SIGNIFICANT INCREASE IN DNA METHYLATION IN THE CORTEX OF CDM MICE. IN CONTRAST, ANTIDEPRESSANT TREATMENTS REDUCE THE METHYLATION LEVEL. LIMITATIONS: HOMER1 EXPRESSION AND PROMOTOR METHYLATION WERE NOT ANALYZED IN DIFFERENT BLOOD CELL TYPES. OTHER CPG SITES OF HOMER1 PROMOTER SHOULD BE INVESTIGATED IN FUTURE STUDIES. OUR EXPERIMENTAL APPROACH DOES NOT DISTINGUISH BETWEEN METHYLATION AND HYDROXYMETHYLATION. CONCLUSIONS: WE DEMONSTRATE THAT STRESS-INDUCED DEPRESSION-LIKE BEHAVIOR AND ANTIDEPRESSANT TREATMENTS ARE ASSOCIATED WITH EPIGENETIC ALTERATIONS OF HOMER1 PROMOTER, PROVIDING NEW INSIGHTS INTO THE MECHANISM OF ANTIDEPRESSANT TREATMENT. 2021