1 531 183 ASTROCYTE REACTIVITY FOLLOWING BLAST EXPOSURE INVOLVES ABERRANT HISTONE ACETYLATION. BLAST INDUCED NEUROTRAUMA (BINT) IS A PREVALENT INJURY WITHIN MILITARY AND CIVILIAN POPULATIONS. THE INJURY IS CHARACTERIZED BY PERSISTENT INFLAMMATION AT THE CELLULAR LEVEL WHICH MANIFESTS AS A MULTITUDE OF COGNITIVE AND FUNCTIONAL IMPAIRMENTS. EPIGENETIC REGULATION OF TRANSCRIPTION OFFERS AN IMPORTANT CONTROL MECHANISM FOR GENE EXPRESSION AND CELLULAR FUNCTION WHICH MAY UNDERLIE CHRONIC INFLAMMATION AND RESULT IN NEURODEGENERATION. WE HYPOTHESIZE THAT ALTERED HISTONE ACETYLATION PATTERNS MAY BE INVOLVED IN BLAST INDUCED INFLAMMATION AND THE CHRONIC ACTIVATION OF GLIAL CELLS. THIS STUDY AIMED TO ELUCIDATE CHANGES TO HISTONE ACETYLATION OCCURRING FOLLOWING INJURY AND THE ROLES THESE CHANGES MAY HAVE WITHIN THE PATHOLOGY. SPRAGUE DAWLEY RATS WERE SUBJECTED TO EITHER A 10 OR 17 PSI BLAST OVERPRESSURE WITHIN AN ADVANCED BLAST SIMULATOR (ABS). SHAM ANIMALS UNDERWENT THE SAME PROCEDURES WITHOUT BLAST EXPOSURE. MEMORY IMPAIRMENTS WERE MEASURED USING THE NOVEL OBJECT RECOGNITION (NOR) TEST AT 2 AND 7 DAYS POST-INJURY. TISSUES WERE COLLECTED AT 7 DAYS FOR WESTERN BLOT AND IMMUNOHISTOCHEMISTRY (IHC) ANALYSIS. SHAM ANIMALS SHOWED INTACT MEMORY AT EACH TIME POINT. THE NOVEL OBJECT DISCRIMINATION DECREASED SIGNIFICANTLY BETWEEN TWO AND 7 DAYS FOR EACH INJURY GROUP (P < 0.05). THIS IS INDICATIVE OF THE ONSET OF MEMORY IMPAIRMENT. WESTERN BLOT ANALYSIS SHOWED GLIAL FIBRILLARY ACIDIC PROTEIN (GFAP), A KNOWN MARKER OF ACTIVATED ASTROCYTES, WAS ELEVATED IN THE PREFRONTAL CORTEX (PFC) FOLLOWING BLAST EXPOSURE FOR BOTH INJURY GROUPS. ANALYSIS OF HISTONE PROTEIN EXTRACT SHOWED NO CHANGES IN THE LEVEL OF ANY TOTAL HISTONE PROTEINS WITHIN THE PFC. HOWEVER, ACETYLATION LEVELS OF HISTONE H2B, H3, AND H4 WERE DECREASED IN BOTH GROUPS (P < 0.05). CO-LOCALIZATION IMMUNOFLUORESCENCE WAS USED TO FURTHER INVESTIGATE ANY POTENTIAL CORRELATION BETWEEN DECREASED HISTONE ACETYLATION AND ASTROCYTE ACTIVATION. THESE EXPERIMENTS SHOWED A SIMILAR DECREASE IN H3 ACETYLATION IN ASTROCYTES EXPOSED TO A 17 PSI BLAST BUT NOT A 10 PSI BLAST. FURTHER INVESTIGATION OF GENE EXPRESSION BY POLYMERASE CHAIN REACTION (PCR) ARRAY, SHOWED DYSREGULATION OF SEVERAL CYTOKINE AND CYTOKINE RECEPTORS THAT ARE INVOLVED IN NEUROINFLAMMATORY PROCESSES. WE HAVE SHOWN ABERRANT HISTONE ACETYLATION PATTERNS INVOLVED IN BLAST INDUCED ASTROGLIOSIS AND COGNITIVE IMPAIRMENTS. FURTHER UNDERSTANDING OF THEIR ROLE IN THE INJURY PROGRESSION MAY LEAD TO NOVEL THERAPEUTIC TARGETS. 2016 2 4879 32 OVERLAPPING SIGNATURES OF CHRONIC PAIN IN THE DNA METHYLATION LANDSCAPE OF PREFRONTAL CORTEX AND PERIPHERAL T CELLS. WE TESTED THE HYPOTHESIS THAT EPIGENETIC MECHANISMS IN THE BRAIN AND THE IMMUNE SYSTEM ARE ASSOCIATED WITH CHRONIC PAIN. GENOME-WIDE DNA METHYLATION ASSESSED IN 9 MONTHS POST NERVE-INJURY (SNI) AND SHAM RATS, IN THE PREFRONTAL CORTEX (PFC) AS WELL AS IN T CELLS REVEALED A VAST DIFFERENCE IN THE DNA METHYLATION LANDSCAPE IN THE BRAIN BETWEEN THE GROUPS AND A REMARKABLE OVERLAP (72%) BETWEEN DIFFERENTIALLY METHYLATED PROBES IN T CELLS AND PREFRONTAL CORTEX. DNA METHYLATION STATES IN THE PFC SHOWED ROBUST CORRELATION WITH PAIN SCORE OF ANIMALS IN SEVERAL GENES INVOLVED IN PAIN. FINALLY, ONLY 11 DIFFERENTIALLY METHYLATED PROBES IN T CELLS WERE SUFFICIENT TO DISTINGUISH SNI OR SHAM INDIVIDUAL RATS. THIS STUDY SUPPORTS THE PLAUSIBILITY OF DNA METHYLATION INVOLVEMENT IN CHRONIC PAIN AND DEMONSTRATES THE POTENTIAL FEASIBILITY OF DNA METHYLATION MARKERS IN T CELLS AS NONINVASIVE BIOMARKERS OF CHRONIC PAIN SUSCEPTIBILITY. 2016 3 2736 51 EXPLORING THE TRANSCRIPTOME OF RESIDENT SPINAL MICROGLIA AFTER COLLAGEN ANTIBODY-INDUCED ARTHRITIS. RECENT STUDIES HAVE SUGGESTED A SEXUALLY DIMORPHIC ROLE OF SPINAL GLIAL CELLS IN THE MAINTENANCE OF MECHANICAL HYPERSENSITIVITY IN RODENT MODELS OF CHRONIC PAIN. WE HAVE USED THE COLLAGEN ANTIBODY-INDUCED ARTHRITIS (CAIA) MOUSE MODEL TO EXAMINE DIFFERENCES BETWEEN MALES AND FEMALES IN THE CONTEXT OF SPINAL REGULATION OF ARTHRITIS-INDUCED PAIN. WE HAVE FOCUSED ON THE LATE PHASE OF THIS MODEL WHEN JOINT INFLAMMATION HAS RESOLVED, BUT MECHANICAL HYPERSENSITIVITY PERSISTS. ALTHOUGH THE INTENSITY OF SUBSTANCE P, CALCITONIN GENE-RELATED PEPTIDE, AND GALANIN IMMUNOREACTIVITY IN THE SPINAL CORD WAS NOT DIFFERENT FROM CONTROLS, THE INTENSITY OF MICROGLIA (IBA-1) AND ASTROCYTE (GLIAL FIBRILLARY ACIDIC PROTEIN) MARKERS WAS ELEVATED IN BOTH MALES AND FEMALES. INTRATHECAL ADMINISTRATION OF THE GLIAL INHIBITORS MINOCYCLINE AND PENTOXIFYLLINE REVERSED MECHANICAL THRESHOLDS IN MALE, BUT NOT IN FEMALE MICE. WE ISOLATED RESIDENT MICROGLIA FROM THE LUMBAR DORSAL HORNS AND OBSERVED A SIGNIFICANTLY LOWER NUMBER OF MICROGLIAL CELLS IN FEMALES BY FLOW CYTOMETRY ANALYSIS. HOWEVER, ALTHOUGH GENOME-WIDE RNA SEQUENCING RESULTS POINTED TO SEVERAL TRANSCRIPTIONAL DIFFERENCES BETWEEN MALE AND FEMALE MICROGLIA, NO CONVINCING DIFFERENCES WERE IDENTIFIED BETWEEN CONTROL AND CAIA GROUPS. TAKEN TOGETHER, THESE FINDINGS SUGGEST THAT THERE ARE SUBTLE SEX DIFFERENCES IN MICROGLIAL EXPRESSION PROFILES INDEPENDENT OF ARTHRITIS. OUR EXPERIMENTS FAILED TO IDENTIFY THE UNDERLYING MRNA CORRELATES OF MICROGLIAL ACTIONS IN THE LATE PHASE OF THE CAIA MODEL. IT IS LIKELY THAT TRANSCRIPTIONAL CHANGES ARE EITHER SUBTLE AND HIGHLY LOCALISED AND THEREFORE DIFFICULT TO IDENTIFY WITH BULK ISOLATION TECHNIQUES OR THAT OTHER FACTORS, SUCH AS CHANGES IN PROTEIN EXPRESSION OR EPIGENETIC MODIFICATIONS, ARE AT PLAY. 2019 4 2297 37 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 5 4173 47 MELATONIN INDUCES HISTONE HYPERACETYLATION IN THE RAT BRAIN. WE HAVE REPORTED THAT MELATONIN INDUCES HISTONE HYPERACETYLATION IN MOUSE NEURAL STEM CELLS, SUGGESTING AN EPIGENETIC ROLE FOR THIS PLEIOTROPIC HORMONE. TO SUPPORT SUCH A ROLE, IT IS NECESSARY TO DEMONSTRATE THAT MELATONIN PRODUCES SIMILAR EFFECTS IN VIVO. HISTONE ACETYLATION, FOLLOWING CHRONIC TREATMENT WITH MELATONIN (4MUG/ML IN DRINKING WATER FOR 17 DAYS), WAS EXAMINED BY WESTERN BLOTTING IN SELECTED RAT BRAIN REGIONS. MELATONIN INDUCED SIGNIFICANT INCREASES IN HISTONE H3 AND HISTONE H4 ACETYLATION IN THE HIPPOCAMPUS. HISTONE H4 WAS ALSO HYPERACETYLATED IN THE STRIATUM, BUT THERE WERE NO SIGNIFICANT CHANGES IN HISTONE H3 ACETYLATION IN THIS BRAIN REGION. NO SIGNIFICANT CHANGES IN THE ACETYLATION OF EITHER HISTONE H3 OR H4 WERE OBSERVED IN THE MIDBRAIN AND CEREBELLUM. AN EXAMINATION OF KINASE ACTIVATION, WHICH MAY BE RELATED TO THESE CHANGES, REVEALED THAT MELATONIN TREATMENT INCREASED THE LEVELS OF PHOSPHO-ERK (EXTRACELLULAR SIGNAL-REGULATED KINASE) IN THE HIPPOCAMPUS AND STRIATUM, BUT PHOSPHO-AKT (PROTEIN KINASE B) LEVELS WERE UNCHANGED. THESE FINDINGS SUGGEST THAT CHROMATIN REMODELING AND ASSOCIATED CHANGES IN THE EPIGENETIC REGULATION OF GENE EXPRESSION UNDERLIE THE MULTIPLE PHYSIOLOGICAL EFFECTS OF MELATONIN. 2013 6 6427 44 THE TRANSITION FROM ACUTE TO CHRONIC PAIN: DYNAMIC EPIGENETIC REPROGRAMMING OF THE MOUSE PREFRONTAL CORTEX UP TO 1 YEAR AFTER NERVE INJURY. CHRONIC PAIN IS ASSOCIATED WITH PERSISTENT STRUCTURAL AND FUNCTIONAL CHANGES THROUGHOUT THE NEUROAXIS, INCLUDING IN THE PREFRONTAL CORTEX (PFC). THE PFC IS IMPORTANT IN THE INTEGRATION OF SENSORY, COGNITIVE, AND EMOTIONAL INFORMATION AND IN CONDITIONED PAIN MODULATION. WE PREVIOUSLY REPORTED WIDESPREAD EPIGENETIC REPROGRAMMING IN THE PFC MANY MONTHS AFTER NERVE INJURY IN RODENTS. EPIGENETIC MODIFICATIONS, INCLUDING DNA METHYLATION, CAN DRIVE CHANGES IN GENE EXPRESSION WITHOUT MODIFYING DNA SEQUENCES. TO DATE, LITTLE IS KNOWN ABOUT EPIGENETIC DYSREGULATION AT THE ONSET OF ACUTE PAIN OR HOW IT PROGRESSES AS PAIN TRANSITIONS FROM ACUTE TO CHRONIC. WE HYPOTHESIZE THAT ACUTE PAIN AFTER INJURY RESULTS IN RAPID AND PERSISTENT EPIGENETIC REMODELLING IN THE PFC THAT EVOLVES AS PAIN BECOMES CHRONIC. WE FURTHER PROPOSE THAT UNDERSTANDING EPIGENETIC REMODELLING WILL PROVIDE INSIGHTS INTO THE MECHANISMS DRIVING PAIN-RELATED CHANGES IN THE BRAIN. EPIGENOME-WIDE ANALYSIS WAS PERFORMED IN THE MOUSE PFC 1 DAY, 2 WEEKS, 6 MONTHS, AND 1 YEAR AFTER PERIPHERAL INJURY USING THE SPARED NERVE INJURY IN MICE. SPARED NERVE INJURY RESULTED IN RAPID AND PERSISTENT CHANGES IN DNA METHYLATION, WITH ROBUST DIFFERENTIAL METHYLATION OBSERVED BETWEEN SPARED NERVE INJURY AND SHAM-OPERATED CONTROL MICE AT ALL TIME POINTS. HUNDREDS OF DIFFERENTIALLY METHYLATED GENES WERE IDENTIFIED, INCLUDING MANY WITH KNOWN FUNCTION IN PAIN. PATHWAY ANALYSIS REVEALED ENRICHMENT IN GENES RELATED TO STIMULUS RESPONSE AT EARLY TIME POINTS, IMMUNE FUNCTION AT LATER TIME POINTS, AND ACTIN AND CYTOSKELETAL REGULATION THROUGHOUT THE TIME COURSE. THESE RESULTS EMPHASIZE THE IMPORTANCE OF CONSIDERING PAIN CHRONICITY IN BOTH PAIN RESEARCH AND IN TREATMENT OPTIMIZATION. 2020 7 5007 38 PERIPHERAL NERVE INJURY IS ASSOCIATED WITH CHRONIC, REVERSIBLE CHANGES IN GLOBAL DNA METHYLATION IN THE MOUSE PREFRONTAL CORTEX. CHANGES IN BRAIN STRUCTURE AND CORTICAL FUNCTION ARE ASSOCIATED WITH MANY CHRONIC PAIN CONDITIONS INCLUDING LOW BACK PAIN AND FIBROMYALGIA. THE MAGNITUDE OF THESE CHANGES CORRELATES WITH THE DURATION AND/OR THE INTENSITY OF CHRONIC PAIN. MOST STUDIES REPORT CHANGES IN COMMON AREAS INVOLVED IN PAIN MODULATION, INCLUDING THE PREFRONTAL CORTEX (PFC), AND PAIN-RELATED PATHOLOGICAL CHANGES IN THE PFC CAN BE REVERSED WITH EFFECTIVE TREATMENT. WHILE THE MECHANISMS UNDERLYING THESE CHANGES ARE UNKNOWN, THEY MUST BE DYNAMICALLY REGULATED. EPIGENETIC MODULATION OF GENE EXPRESSION IN RESPONSE TO EXPERIENCE AND ENVIRONMENT IS REVERSIBLE AND DYNAMIC. EPIGENETIC MODULATION BY DNA METHYLATION IS ASSOCIATED WITH ABNORMAL BEHAVIOR AND PATHOLOGICAL GENE EXPRESSION IN THE CENTRAL NERVOUS SYSTEM. DNA METHYLATION MIGHT ALSO BE INVOLVED IN MEDIATING THE PATHOLOGIES ASSOCIATED WITH CHRONIC PAIN IN THE BRAIN. WE THEREFORE TESTED A) WHETHER ALTERATIONS IN DNA METHYLATION ARE FOUND IN THE BRAIN LONG AFTER CHRONIC NEUROPATHIC PAIN IS INDUCED IN THE PERIPHERY USING THE SPARED NERVE INJURY MODAL AND B) WHETHER THESE INJURY-ASSOCIATED CHANGES ARE REVERSIBLE BY INTERVENTIONS THAT REVERSE THE PATHOLOGIES ASSOCIATED WITH CHRONIC PAIN. SIX MONTHS FOLLOWING PERIPHERAL NERVE INJURY, ABNORMAL SENSORY THRESHOLDS AND INCREASED ANXIETY WERE ACCOMPANIED BY DECREASED GLOBAL METHYLATION IN THE PFC AND THE AMYGDALA BUT NOT IN THE VISUAL CORTEX OR THE THALAMUS. ENVIRONMENTAL ENRICHMENT ATTENUATED NERVE INJURY-INDUCED HYPERSENSITIVITY AND REVERSED THE CHANGES IN GLOBAL PFC METHYLATION. FURTHERMORE, GLOBAL PFC METHYLATION CORRELATED WITH MECHANICAL AND THERMAL SENSITIVITY IN NEUROPATHIC MICE. IN SUMMARY, INDUCTION OF CHRONIC PAIN BY PERIPHERAL NERVE INJURY IS ASSOCIATED WITH EPIGENETIC CHANGES IN THE BRAIN. THESE CHANGES ARE DETECTED LONG AFTER THE ORIGINAL INJURY, AT A LONG DISTANCE FROM THE SITE OF INJURY AND ARE REVERSIBLE WITH ENVIRONMENTAL MANIPULATION. CHANGES IN BRAIN STRUCTURE AND CORTICAL FUNCTION THAT ARE ASSOCIATED WITH CHRONIC PAIN CONDITIONS MAY THEREFORE BE MEDIATED BY EPIGENETIC MECHANISMS. 2013 8 6246 40 THE METHYL DONOR S-ADENOSYL METHIONINE REVERSES THE DNA METHYLATION SIGNATURE OF CHRONIC NEUROPATHIC PAIN IN MOUSE FRONTAL CORTEX. CHRONIC PAIN IS ASSOCIATED WITH PERSISTENT BUT REVERSIBLE STRUCTURAL AND FUNCTIONAL CHANGES IN THE PREFRONTAL CORTEX (PFC). THIS STABLE YET MALLEABLE PLASTICITY IMPLICATES EPIGENETIC MECHANISMS, INCLUDING DNA METHYLATION, AS A POTENTIAL MEDIATOR OF CHRONIC PAIN-INDUCED CORTICAL PATHOLOGY. WE PREVIOUSLY DEMONSTRATED THAT CHRONIC ORAL ADMINISTRATION OF THE METHYL DONOR S-ADENOSYL METHIONINE (SAM) ATTENUATES LONG-TERM PERIPHERAL NEUROPATHIC PAIN AND ALTERS GLOBAL FRONTAL CORTICAL DNA METHYLATION. HOWEVER, THE SPECIFIC GENES AND PATHWAYS ASSOCIATED WITH THE RESOLUTION OF CHRONIC PAIN BY SAM REMAIN UNEXPLORED. OBJECTIVE: TO DETERMINE THE EFFECT OF LONG-TERM THERAPEUTIC EXPOSURE TO SAM ON THE DNA METHYLATION OF INDIVIDUAL GENES AND PATHWAYS IN A MOUSE NEUROPATHIC PAIN MODEL. METHODS: MALE CD-1 MICE RECEIVED SPARED NERVE INJURY OR SHAM SURGERY. THREE MONTHS AFTER INJURY, ANIMALS RECEIVED SAM (20 MG/KG, ORAL, 3X A WEEK) OR VEHICLE FOR 16 WEEKS FOLLOWED BY EPIGENOME-WIDE ANALYSIS OF FRONTAL CORTEX. RESULTS: PERIPHERAL NEUROPATHIC PAIN WAS ASSOCIATED WITH 4000 DIFFERENTIALLY METHYLATED GENOMIC REGIONS THAT WERE ENRICHED IN INTRACELLULAR SIGNALING, CELL MOTILITY AND MIGRATION, CYTOSKELETAL STRUCTURE, AND CELL ADHESION PATHWAYS. A THIRD OF THESE DIFFERENTIALLY METHYLATED REGIONS WERE REVERSED BY SAM TREATMENT (1415 REGIONS REPRESENTING 1013 GENES). MORE THAN 100 GENES WITH KNOWN PAIN-RELATED FUNCTION WERE DIFFERENTIALLY METHYLATED AFTER NERVE INJURY; 29 OF THESE WERE REVERSED BY SAM TREATMENT INCLUDING SCN10A, TRPA1, NTRK1, AND GFAP. CONCLUSION: THESE RESULTS SUGGEST A ROLE FOR THE EPIGENOME IN THE MAINTENANCE OF CHRONIC PAIN AND ADVANCE EPIGENETIC MODULATORS SUCH AS SAM AS A NOVEL APPROACH TO TREAT CHRONIC PAIN. 2021 9 808 31 CHANGED HISTONE ACETYLATION PATTERNS IN NORMAL-APPEARING WHITE MATTER AND EARLY MULTIPLE SCLEROSIS LESIONS. THE EPIGENETIC IDENTITY OF OLIGODENDROCYTES IS MODULATED BY POSTTRANSLATIONAL MODIFICATIONS OF HISTONES. ACETYLATION OF HISTONE H3 RESULTS FROM THE BALANCE BETWEEN THE ACTIVITY OF HISTONE ACETYLTRANSFERASES (HATS) AND HISTONE DEACETYLASES AND MODULATES TRANSCRIPTIONAL ACTIVATION. WE HAVE PREVIOUSLY SHOWN THAT, IN RODENTS, HISTONE DEACETYLATION FAVORS OLIGODENDROCYTE DIFFERENTIATION, WHEREAS ACETYLATION IS ASSOCIATED WITH INCREASED LEVELS OF TRANSCRIPTIONAL INHIBITORS OF OLIGODENDROCYTE DIFFERENTIATION. HERE, WE REPORT, IN HUMANS BRAINS, A SHIFT TOWARD HISTONE ACETYLATION IN THE WHITE MATTER OF THE FRONTAL LOBES OF AGED SUBJECTS AND IN PATIENTS WITH CHRONIC MULTIPLE SCLEROSIS (MS). INCREASED IMMUNOREACTIVITY FOR ACETYLATED HISTONE H3 WAS OBSERVED IN THE NUCLEI OF NOGOA+ OLIGODENDROCYTES IN A SUBSET OF MS SAMPLES. THESE CHANGES WERE ASSOCIATED WITH HIGH LEVELS OF TRANSCRIPTIONAL INHIBITORS OF OLIGODENDROCYTE DIFFERENTIATION (I.E., TCF7L2, ID2, AND SOX2) AND HIGHER HAT TRANSCRIPT LEVELS (I.E., CBP, P300) IN FEMALE MS PATIENTS COMPARED WITH NON-NEUROLOGICAL CONTROLS AND CORRELATED WITH DISEASE DURATION. CHROMATIN IMMUNOPRECIPITATION FROM SAMPLES OF MS PATIENTS REVEALED ENRICHMENT OF ACETYL-HISTONE H3 AT THE PROMOTER OF THE INCREASED TARGET GENES (I.E., TCF7L2). THE DATA IN CHRONIC LESIONS CONTRASTED WITH FINDINGS IN EARLY MS LESIONS, WHERE A MARKED OLIGODENDROGLIAL HISTONE DEACETYLATION WAS OBSERVED. TOGETHER, THESE DATA SUGGEST THAT HISTONE DEACETYLATION IS A PROCESS THAT OCCURS AT THE EARLY STAGES OF THE DISEASE AND WHOSE EFFICIENCY DECREASES WITH DISEASE DURATION. 2011 10 920 31 CHRONIC HYPOXIA FACILITATES ALZHEIMER'S DISEASE THROUGH DEMETHYLATION OF GAMMA-SECRETASE BY DOWNREGULATING DNA METHYLTRANSFERASE 3B. INTRODUCTION: ENVIRONMENTAL FACTORS AND EPIGENETIC MECHANISMS ARE BELIEVED TO CONTRIBUTE TO ALZHEIMER'S DISEASE (AD). WE PREVIOUSLY DOCUMENTED THAT PRENATAL HYPOXIA AGGRAVATED THE COGNITIVE IMPAIRMENT AND NEUROPATHOLOGY IN OFFSPRING MICE. HERE, WE INVESTIGATE THE CHRONIC HYPOXIA-INDUCED EPIGENETIC MODIFICATIONS IN AD. METHODS: THE 3-MONTH-OLD APP(SWE)/PS1(DE9) MICE WERE EXPOSED TO HYPOXIC ENVIRONMENT 6 HOUR/DAY FOR 30 DAYS, FOLLOWED BY LEARNING AND MEMORY TESTS AND BIOCHEMICAL AND NEUROPATHOLOGY MEASUREMENT AT THE AGE OF 4, 6, AND 9 MONTHS. RESULTS: WE FOUND HYPOXIA EXAGGERATED THE NEUROPATHOLOGY AND COGNITIVE IMPAIRMENT IN AD MICE. CHRONIC HYPOXIA INDUCED DEMETHYLATION ON GENOMIC DNA AND DECREASED THE EXPRESSION OF DNA METHYLTRANSFERASE 3B (DNMT3B) IN VIVO. WE FURTHER FOUND THAT DNMTS INHIBITION ELEVATED THE PROTEIN LEVELS OF AMYLOID PRECURSOR PROTEIN, BETA- AND GAMMA-SECRETASES, WHEREAS OVEREXPRESSION OF DNMT3B SUPPRESSED THE LEVELS OF THEM IN VITRO. DISCUSSION: OUR STUDY SUGGESTS CHRONIC HYPOXIA CAN AGGRAVATE AD PROGRESSION THROUGH DEMETHYLATION OF GENES ENCODING GAMMA-SECRETASE COMPONENTS BY DOWNREGULATION OF DNMT3B. 2016 11 344 42 ALTERED BDNF METHYLATION IN PATIENTS WITH CHRONIC MUSCULOSKELETAL PAIN AND HIGH BIOPSYCHOSOCIAL COMPLEXITY. PURPOSE: THE INTERMED INSTRUMENT, WHICH WAS DEVELOPED TO MEASURE PATIENT'S BIOPSYCHOSOCIAL (BPS) COMPLEXITY, REPRESENTS A POWERFUL DIAGNOSTIC AND THERAPEUTIC TOOL. EPIGENETIC CHANGES ARE THE INTERFACE BETWEEN SIGNALS FROM THE ENVIRONMENT AND GENETIC MODIFICATIONS, AFFECTING GENE EXPRESSION, IN PARTICULAR, BY DNA METHYLATION OF CPG DINUCLEOTIDES IN PROMOTOR REGIONS OF THE CORRESPONDING GENES. THE BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) GENE PLAYS A CRUCIAL ROLE IN THE CENTRAL SENSITIZATION (CS) OF PAIN. IN THIS STUDY, WE HYPOTHESIZED THAT CHRONIC PAIN MODIFIES THE METHYLATION LEVELS OF THE BDNF GENE IN A MANNER THAT IS INTERCONNECTED WITH THE BPS STATUS. PATIENTS AND METHODS: FIFTY-EIGHT CHRONIC MUSCULOSKELETAL PAIN PATIENTS (CMSP) WERE ENROLLED IN THE STUDY. DNA WAS EXTRACTED FROM BLOOD SAMPLES, THE METHYLATION LEVELS OF 13 CPG SITES IN THE BDNF PROMOTER WERE MEASURED BY PYROSEQUENCING, AND ASSOCIATION STUDIES WITH VARIOUS PATIENT PARAMETERS AND THE INTERMED SCORES WERE PERFORMED. RESULTS: INTERESTINGLY, A NEGATIVE CORRELATION (-0.40) WAS FOUND BETWEEN THE TOTAL INTERMED SCORES AND THE AVERAGE CPG METHYLATION VALUES OF THE BDNF GENE, BUT NO CORRELATION WAS OBSERVED WITH THE SEVERITY OF PAIN, DEGREE OF ANXIETY, DEPRESSION, OR KINESIOPHOBIA AND CATASTROPHISM. MOREOVER, THE ASSOCIATION WAS INDEPENDENT OF AGE, SEX AND LEVEL OF COMORBIDITIES. CONCLUSION: THIS RESULT SHOWS THAT CMSP, IN ASSOCIATION WITH ITS BIOPSYCHOSOCIAL CONTEXT, EPIGENETICALLY DECREASES THE DEGREE OF METHYLATION OF THE BDNF PROMOTER AND SHOULD THEREFORE INCREASE THE LEVEL OF BDNF TRANSCRIPTION. IT ALSO SUGGESTS A ROLE OF THE INTERMED TOOL TO DETECT A RELATIONSHIP BETWEEN THE BPS COMPLEXITY AND THE EPIGENETIC CONTROL OF A TARGET GENE. THE POSSIBLE UPREGULATION OF BDNF EXPRESSION MIGHT BE, AT LEAST IN PART, THE SIGNAL FOR CHRONIC PAIN-INDUCED CENTRAL SENSITIZATION (CS). THIS COULD PARTLY EXPLAIN WHY PATIENTS WITH A HIGHER LEVEL OF COMPLEXITY FEEL MORE PAIN THAN THOSE WITH LOWER COMPLEXITY. 2020 12 1186 46 COORDINATED DYNAMIC GENE EXPRESSION CHANGES IN THE CENTRAL NUCLEUS OF THE AMYGDALA DURING ALCOHOL WITHDRAWAL. BACKGROUND: CHRONIC ALCOHOL USE CAUSES WIDESPREAD CHANGES IN THE CELLULAR BIOLOGY OF THE AMYGDALA'S CENTRAL NUCLEUS (CEA), A GABAERGIC CENTER THAT INTEGRATES AUTONOMIC PHYSIOLOGY WITH THE EMOTIONAL ASPECTS OF MOTIVATION AND LEARNING. WHILE ALCOHOL-INDUCED NEUROCHEMICAL CHANGES PLAY A ROLE IN DEPENDENCE AND DRINKING BEHAVIOR, LITTLE IS KNOWN ABOUT THE CEA'S DYNAMIC CHANGES DURING WITHDRAWAL, A PERIOD OF EMOTIONAL AND PHYSIOLOGIC DISTURBANCE. METHODS: WE USED A QRT-PCR PLATFORM TO MEASURE 139 TRANSCRIPTS IN 92 RAT CEA SAMPLES FROM CONTROL (N = 33), CHRONICALLY ALCOHOL EXPOSED (N = 26), AND WITHDRAWN RATS (T = 4, 8, 18, 32, AND 48 HOURS; N = 5, 10, 7, 6, 5). THIS FOCUSED TRANSCRIPT SET ALLOWED US TO IDENTIFY SIGNIFICANT DYNAMIC EXPRESSION PATTERNS DURING THE FIRST 48 HOURS OF WITHDRAWAL AND PROPOSE POTENTIAL REGULATORY MECHANISMS. RESULTS: CHRONIC ALCOHOL EXPOSURE CAUSES A LIMITED NUMBER OF SMALL MAGNITUDE EXPRESSION CHANGES. IN CONTRAST, WITHDRAWAL RESULTS IN A GREATER NUMBER OF LARGE CHANGES WITHIN 4 HOURS OF REMOVAL OF THE ALCOHOL DIET. SIXTY-FIVE OF THE 139 MEASURED TRANSCRIPTS (47%) SHOWED DIFFERENTIAL REGULATION DURING WITHDRAWAL. OVER THE 48-HOUR PERIOD, DYNAMIC CHANGES IN THE EXPRESSION OF GAMMA-AMINOBUTYRIC ACID TYPE A (GABA(A) ), IONOTROPIC GLUTAMATE AND NEUROPEPTIDE SYSTEM-RELATED G-PROTEIN-COUPLED RECEPTOR SUBUNITS, AND THE RAS/RAF SIGNALING PATHWAY WERE SEEN AS WELL AS DOWNSTREAM TRANSCRIPTION FACTORS (TFS) AND EPIGENETIC REGULATORS. FOUR TEMPORALLY CORRELATED GENE CLUSTERS WERE IDENTIFIED WITH SHARED FUNCTIONAL ROLES INCLUDING NMDA RECEPTORS, MAPKKK AND CHEMOKINE SIGNALING CASCADES, AND MEDIATORS OF LONG-TERM POTENTIATION, AMONG OTHERS. CLUSTER PROMOTER REGIONS SHARED OVERREPRESENTED BINDING SITES FOR MULTIPLE TFS INCLUDING CEBP, USF-1, SMAD3, AP-2, AND C-ETS, SUGGESTING A POTENTIAL REGULATORY ROLE. CONCLUSIONS: DURING ALCOHOL WITHDRAWAL, THE CEA EXPERIENCES RAPID CHANGES IN MRNA EXPRESSION OF THESE FUNCTIONALLY RELATED TRANSCRIPTS THAT WERE NOT PREDICTED BY MEASUREMENT DURING CHRONIC EXPOSURE. THIS STUDY PROVIDES NEW INSIGHT INTO DYNAMIC EXPRESSION CHANGES DURING ALCOHOL WITHDRAWAL AND SUGGESTS NOVEL REGULATORY RELATIONSHIPS THAT POTENTIALLY IMPACT THE ASPECTS OF EMOTIONAL MODULATION. 2013 13 213 40 ACUTE AND CHRONIC ELECTROCONVULSIVE SEIZURES (ECS) DIFFERENTIALLY REGULATE THE EXPRESSION OF EPIGENETIC MACHINERY IN THE ADULT RAT HIPPOCAMPUS. BACKGROUND: ELECTROCONVULSIVE SEIZURE TREATMENT IS A FAST-ACTING ANTIDEPRESSANT THERAPY THAT EVOKES RAPID TRANSCRIPTIONAL, NEUROGENIC, AND BEHAVIORAL CHANGES. EPIGENETIC MECHANISMS CONTRIBUTE TO ALTERED GENE REGULATION, WHICH UNDERLIES THE NEUROGENIC AND BEHAVIORAL EFFECTS OF ELECTROCONVULSIVE SEIZURE. WE HYPOTHESIZED THAT ELECTROCONVULSIVE SEIZURE MAY MODULATE THE EXPRESSION OF EPIGENETIC MACHINERY, THUS ESTABLISHING POTENTIAL ALTERATIONS IN THE EPIGENETIC LANDSCAPE. METHODS: WE EXAMINED THE INFLUENCE OF ACUTE AND CHRONIC ELECTROCONVULSIVE SEIZURE ON THE GENE EXPRESSION OF HISTONE MODIFIERS, NAMELY HISTONE ACETYLTRANSFERASES, HISTONE DEACETYLASES, HISTONE METHYLTRANSFERASES, AND HISTONE (LYSINE) DEMETHYLASES AS WELL AS DNA MODIFYING ENZYMES, INCLUDING DNA METHYLTRANSFERASES, DNA DEMETHYLASES, AND METHYL-CPG-BINDING PROTEINS IN THE HIPPOCAMPI OF ADULT MALE WISTAR RATS USING QUANTITATIVE REAL TIME-PCR ANALYSIS. FURTHER, WE EXAMINED THE INFLUENCE OF ACUTE AND CHRONIC ELECTROCONVULSIVE SEIZURE ON GLOBAL AND RESIDUE-SPECIFIC HISTONE ACETYLATION AND METHYLATION LEVELS WITHIN THE HIPPOCAMPUS, A BRAIN REGION IMPLICATED IN THE CELLULAR AND BEHAVIORAL EFFECTS OF ELECTROCONVULSIVE SEIZURE. RESULTS: ACUTE AND CHRONIC ELECTROCONVULSIVE SEIZURE INDUCED A PRIMARILY UNIQUE, AND IN CERTAIN CASES BIDIRECTIONAL, REGULATION OF HISTONE AND DNA MODIFIERS, AND METHYL-CPG-BINDING PROTEINS, WITH AN OVERLAPPING PATTERN OF GENE REGULATION RESTRICTED TO SIRT4, MLL3, JMJD3, GADD45B, TET2, AND TET3. GLOBAL HISTONE ACETYLATION AND METHYLATION LEVELS WERE PREDOMINANTLY UNCHANGED, WITH THE EXCEPTION OF A SIGNIFICANT DECLINE IN H3K9 ACETYLATION IN THE HIPPOCAMPUS FOLLOWING CHRONIC ELECTROCONVULSIVE SEIZURE. CONCLUSIONS: ELECTROCONVULSIVE SEIZURE TREATMENT EVOKES THE TRANSCRIPTIONAL REGULATION OF SEVERAL HISTONE AND DNA MODIFIERS, AND METHYL-CPG-BINDING PROTEINS WITHIN THE HIPPOCAMPUS, WITH A PREDOMINANTLY DISTINCT PATTERN OF REGULATION INDUCED BY ACUTE AND CHRONIC ELECTROCONVULSIVE SEIZURE. 2016 14 1731 52 DYSREGULATION OF THE HISTONE DEMETHYLASE KDM6B IN ALCOHOL DEPENDENCE IS ASSOCIATED WITH EPIGENETIC REGULATION OF INFLAMMATORY SIGNALING PATHWAYS. EPIGENETIC ENZYMES OVERSEE LONG-TERM CHANGES IN GENE EXPRESSION BY INTEGRATING GENETIC AND ENVIRONMENTAL CUES. WHILE THERE ARE HUNDREDS OF ENZYMES THAT CONTROL HISTONE AND DNA MODIFICATIONS, THEIR POTENTIAL ROLES IN SUBSTANCE ABUSE AND ALCOHOL DEPENDENCE REMAIN UNDEREXPLORED. A FEW RECENT STUDIES HAVE SUGGESTED THAT EPIGENETIC PROCESSES COULD UNDERLIE TRANSCRIPTOMIC AND BEHAVIORAL HALLMARKS OF ALCOHOL ADDICTION. IN THE PRESENT STUDY, WE SOUGHT TO IDENTIFY EPIGENETIC ENZYMES IN THE BRAIN THAT ARE DYSREGULATED DURING PROTRACTED ABSTINENCE AS A CONSEQUENCE OF CHRONIC AND INTERMITTENT ALCOHOL EXPOSURE. THROUGH QUANTITATIVE MRNA EXPRESSION ANALYSIS OF OVER 100 EPIGENETIC ENZYMES, WE IDENTIFIED 11 THAT ARE SIGNIFICANTLY ALTERED IN ALCOHOL-DEPENDENT RATS COMPARED WITH CONTROLS. FOLLOW-UP STUDIES OF ONE OF THESE ENZYMES, THE HISTONE DEMETHYLASE KDM6B, SHOWED THAT THIS ENZYME EXHIBITS REGION-SPECIFIC DYSREGULATION IN THE PREFRONTAL CORTEX AND NUCLEUS ACCUMBENS OF ALCOHOL-DEPENDENT RATS. KDM6B WAS ALSO UPREGULATED IN THE HUMAN ALCOHOLIC BRAIN. UPREGULATION OF KDM6B PROTEIN IN ALCOHOL-DEPENDENT RATS WAS ACCOMPANIED BY A DECREASE OF TRIMETHYLATION LEVELS AT HISTONE H3, LYSINE 27 (H3K27ME3), CONSISTENT WITH THE KNOWN DEMETHYLASE SPECIFICITY OF KDM6B. SUBSEQUENT EPIGENETIC (CHROMATIN IMMUNOPRECIPITATION [CHIP]-SEQUENCING) ANALYSIS SHOWED THAT ALCOHOL-INDUCED CHANGES IN H3K27ME3 WERE SIGNIFICANTLY ENRICHED AT GENES IN THE IL-6 SIGNALING PATHWAY, CONSISTENT WITH THE WELL-CHARACTERIZED ROLE OF KDM6B IN MODULATION OF INFLAMMATORY RESPONSES. KNOCKDOWN OF KDM6B IN CULTURED MICROGLIAL CELLS DIMINISHED IL-6 INDUCTION IN RESPONSE TO AN INFLAMMATORY STIMULUS. OUR FINDINGS IMPLICATE A NOVEL KDM6B-MEDIATED EPIGENETIC SIGNALING PATHWAY INTEGRATED WITH INFLAMMATORY SIGNALING PATHWAYS THAT ARE KNOWN TO UNDERLIE THE DEVELOPMENT OF ALCOHOL ADDICTION. 2021 15 345 50 ALTERED BRAIN EXPRESSION OF DNA METHYLATION AND HYDROXYMETHYLATION EPIGENETIC ENZYMES IN A RAT MODEL OF NEUROPATHIC PAIN. THE ROLE OF EPIGENETICS IN CHRONIC PAIN AT THE SUPRASPINAL LEVEL IS YET TO BE FULLY CHARACTERIZED. DNA HISTONE METHYLATION IS CRUCIALLY REGULATED BY DE NOVO METHYLTRANSFERASES (DNMT1-3) AND TEN-ELEVEN TRANSLOCATION DIOXYGENASES (TET1-3). EVIDENCE HAS SHOWN THAT METHYLATION MARKERS ARE ALTERED IN DIFFERENT CNS REGIONS RELATED TO NOCICEPTION, NAMELY THE DORSAL ROOT GANGLIA, THE SPINAL CORD, AND DIFFERENT BRAIN AREAS. DECREASED GLOBAL METHYLATION WAS FOUND IN THE DRG, THE PREFRONTAL CORTEX, AND THE AMYGDALA, WHICH WAS ASSOCIATED WITH DECREASED DNMT1/3A EXPRESSION. IN CONTRAST, INCREASED METHYLATION LEVELS AND MRNA LEVELS OF TET1 AND TET3 WERE LINKED TO AUGMENTED PAIN HYPERSENSITIVITY AND ALLODYNIA IN INFLAMMATORY AND NEUROPATHIC PAIN MODELS. SINCE EPIGENETIC MECHANISMS MAY BE RESPONSIBLE FOR THE REGULATION AND COORDINATION OF VARIOUS TRANSCRIPTIONAL MODIFICATIONS DESCRIBED IN CHRONIC PAIN STATES, WITH THIS STUDY, WE AIMED TO EVALUATE THE FUNCTIONAL ROLE OF TET1-3 AND DNMT1/3A GENES IN NEUROPATHIC PAIN IN SEVERAL BRAIN AREAS. IN A SPARED NERVE INJURY RAT MODEL OF NEUROPATHIC PAIN, 21 DAYS AFTER SURGERY, WE FOUND INCREASED TET1 EXPRESSION IN THE MEDIAL PREFRONTAL CORTEX AND DECREASED EXPRESSION IN THE CAUDATE-PUTAMEN AND THE AMYGDALA; TET2 WAS UPREGULATED IN THE MEDIAL THALAMUS; TET3 MRNA LEVELS WERE REDUCED IN THE MEDIAL PREFRONTAL CORTEX AND THE CAUDATE-PUTAMEN; AND DNMT1 WAS DOWNREGULATED IN THE CAUDATE-PUTAMEN AND THE MEDIAL THALAMUS. NO STATISTICALLY SIGNIFICANT CHANGES IN EXPRESSION WERE OBSERVED WITH DNMT3A. OUR RESULTS SUGGEST A COMPLEX FUNCTIONAL ROLE FOR THESE GENES IN DIFFERENT BRAIN AREAS IN THE CONTEXT OF NEUROPATHIC PAIN. THE NOTION OF DNA METHYLATION AND HYDROXYMETHYLATION BEING CELL-TYPE SPECIFIC AND NOT TISSUE SPECIFIC, AS WELL AS THE POSSIBILITY OF CHRONOLOGICALLY DIFFERENTIAL GENE EXPRESSION AFTER THE ESTABLISHMENT OF NEUROPATHIC OR INFLAMMATORY PAIN MODELS, OUGHT TO BE ADDRESSED IN FUTURE STUDIES. 2023 16 3981 32 LONG-TERM EPIGENETIC THERAPY WITH ORAL ZEBULARINE HAS MINIMAL SIDE EFFECTS AND PREVENTS INTESTINAL TUMORS IN MICE. RECENT SUCCESSES IN THE APPLICATION OF EPIGENETIC DRUGS FOR THE TREATMENT OF MYELODYSPLASTIC SYNDROME HAVE RAISED QUESTIONS ON THE SAFETY OF LONG-TERM ADMINISTRATION OF DNA METHYLATION INHIBITORS. WE TREATED PREWEANED CANCER PRONE APC(MIN/+) (MIN) MICE CONTINUOUSLY WITH THE DNA METHYLATION INHIBITOR ZEBULARINE IN THEIR DRINKING WATER TO DETERMINE THE EFFECTS OF THE DRUG ON NORMAL MOUSE DEVELOPMENT AS WELL AS CANCER PREVENTION. ZEBULARINE CAUSED A TISSUE-SPECIFIC REDUCTION IN DNA METHYLATION AT B1 SHORT INTERSPERSED NUCLEOTIDE ELEMENTS IN THE SMALL AND LARGE INTESTINES OF FEMALE MIN MICE BUT NOT IN OTHER ORGANS EXAMINED AFTER CHRONIC ORAL TREATMENT. NO SIGNIFICANT DIFFERENCE IN THE AVERAGE WEIGHTS OF MICE WAS OBSERVED DURING THE TREATMENT. IN ADDITION, ANALYSIS OF GLOBAL GENE EXPRESSION OF COLONIC EPITHELIAL CELLS FROM THE FEMALES INDICATED THAT ONLY 3% TO 6% OF THE GENES WERE AFFECTED IN THEIR EXPRESSION. WE DID NOT DETECT TOXICITY AND ABNORMALITIES FROM THE HISTOPATHOLOGIC ANALYSIS OF LIVER AND INTESTINAL TISSUES. LASTLY, WE TESTED WHETHER PREVENTION OF TUMORIGENESIS CAN BE ACHIEVED WITH CHRONIC ORAL ADMINISTRATION OF ZEBULARINE IN MIN MICE. THE AVERAGE NUMBER OF POLYPS IN MIN FEMALES DECREASED FROM 58 TO 1, WHEREAS THE AVERAGE POLYP NUMBER REMAINED UNAFFECTED IN MIN MALES POSSIBLY DUE TO DIFFERENTIAL ACTIVITY OF ALDEHYDE OXIDASE. TAKEN TOGETHER, OUR RESULTS SHOW FOR THE FIRST TIME THAT LONG-TERM ORAL ADMINISTRATION OF ZEBULARINE CAUSES A GENDER-SPECIFIC ABROGATION OF INTESTINAL TUMORS WHILE CAUSING A TISSUE-SPECIFIC DNA DEMETHYLATION. IMPORTANTLY, PROLONGED TREATMENT OF MICE WITH EPIGENETIC DRUGS RESULTED IN ONLY MINOR DEVELOPMENTAL AND HISTOLOGIC CHANGES. 2008 17 2417 36 EPIGENETIC SIGNATURE OF CHRONIC CEREBRAL HYPOPERFUSION AND BENEFICIAL EFFECTS OF S-ADENOSYLMETHIONINE IN RATS. CHRONIC CEREBRAL HYPOPERFUSION IS ASSOCIATED WITH COGNITIVE DECLINE IN AGING AND AGE-RELATED NEURODEGENERATIVE DISEASE. EPIGENETIC MECHANISMS ARE INVOLVED IN THE MAINTENANCE OF LONG-TERM HYPOXIA-ADAPTED CELLULAR PHENOTYPES. IN THE PRESENT STUDY, THE EPIGENETIC SIGNATURES SUCH AS DNA METHYLATION AND HISTONE ACETYLATION, AS WELL AS S-ADENOSYLMETHIONINE (SAM) CYCLE USING CHRONIC CEREBRAL HYPOPERFUSION RAT MODEL WERE EXPLORED. CHRONIC CEREBRAL HYPOXIA-INDUCED GLOBAL DNA HYPERMETHYLATION ASSOCIATED WITH THE INCREASE OF DNA METHYLTRANSFERASE (DNMT) 3A AS WELL AS ALTERATION OF SAM CYCLE. MEANWHILE, AN ENHANCED LEVEL OF GLOBAL HISTONE H4 ACETYLATION ACCOMPANIED WITH THE UPREGULATION OF HISTONE ACETYLTRANSFERASE, P300/CREB-BINDING PROTEIN (CBP), AND THE DOWNREGULATION OF HISTONE DEACETYLASES (HDACS), WAS ALSO OBSERVED. SAM COULD IMPROVE SPATIAL CAPACITY THROUGH THE UPREGULATION OF ACETYLCHOLINE AND BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) RATHER THAN ALTERATION OF DNA METHYLATION LEVELS. IN CONCLUSION, WE HAVE DEMONSTRATED A GENOME-WIDE ADJUSTMENT OF DNA METHYLATION AND HISTONE ACETYLATION UNDER CHRONIC CEREBRAL HYPOXIC CONDITIONS IN A RAT'S BRAIN. THESE EPIGENETIC SIGNATURES MAY REPRESENT AN ADDITIONAL MECHANISM TO PROMOTE AND MAINTAIN A HYPOXIC-ADAPTED CELLULAR RESPONDS WITH A POTENTIAL ROLE IN MEMORY DEFICITS. 2014 18 4628 40 NEUROEPIGENETIC ALTERATIONS IN THE PREFRONTAL CORTEX OF TYPE 2 DIABETIC MICE THROUGH DNA HYPERMETHYLATION. BACKGROUND: DNA METHYLATION CHANGES HAVE KNOWN TO DOWNREGULATE SEVERAL REGULATORY PROTEINS EPIGENETICALLY DURING VARIOUS NEURODEGENERATIVE DISORDERS. OUR STUDY AIMS TO UNDERSTAND THE EFFECT OF THIS GLOBAL DNA METHYLATION ON THE CEREBRAL COMPLICATIONS OF TYPE 2 DIABETES MICE, AND ITS NOTABLE EFFECT ON MAINTAINING THE SYNAPTIC FIDELITY. METHODS AND RESULTS: CHRONIC HIGH FAT DIET AND STREPTOZOTOCIN-INDUCED DIABETIC MICE WERE STUDIED FOR THE NEUROBEHAVIORAL AND NEUROANATOMIC PARAMETERS PERTAINING TO PREFRONTAL CORTEX, SUBSEQUENTLY ELUCIDATING THE ASSOCIATED CHANGES IN DNA METHYLATION WITHIN THESE DIABETIC BRAINS. FURTHER, THE IMPACT OF THIS EPIGENETIC DYSREGULATION ON HSF1, BDNF AND PSD95 WERE STUDIED BY ASSESSING THE BINDING AFFINITY AND LEVEL OF % METHYLATION WITHIN THE PROMOTER SITE OF THEIR RESPECTIVE GENES. OUR STUDY SUGGEST INCREASED DNMT ABERRATIONS WITHIN THE PREFRONTAL CORTEX, WITH INCREASED MECP2 LEVELS, CONFIRMING DNA HYPERMETHYLATION. THIS WAS IN ACCORDANCE WITH THE ALTERED NEUROBEHAVIORAL CHANGES. FURTHER, THE HYPERMETHYLATION WAS FOUND TO PARTICIPATE IN GENE SILENCING OF HSF1, BDNF AND PSD95 PROTEINS, RESPONSIBLE FOR MAINTAINING THE SYNAPTIC FIDELITY. CONCLUSION: OVERALL, OUR STUDY CONCLUDES THE PLAUSIBLE INVOLVEMENT OF NEUROEPIGENETIC ALTERATIONS IN THE PREFRONTAL CORTEX (PFC) OF THE TYPE 2 DIABETES MICE, SPECIFICALLY DNA HYPERMETHYLATION. PFC PLAYS A CENTRAL ROLE IN MODULATING COGNITIVE AND OTHER EXECUTIVE FUNCTIONS THROUGH ITS CONNECTION WITH SEVERAL BRAIN REGIONS, AND THUS THERAPEUTIC STRATEGIES TARGETING EPIGENETIC MODULATIONS IN IT, CAN PAVE A WAY IN CONTROLLING SEVERAL NEUROLOGICAL ALTERATIONS IN THE BRAIN. 2022 19 4604 41 NEGATIVE EVIDENCE FOR A FUNCTIONAL ROLE OF NEURONAL DNMT3A IN PERSISTENT PAIN. TRADITIONALLY, NEUROSCIENCE HAS HAD TO RELY ON MIXED TISSUE ANALYSIS TO EXAMINE TRANSCRIPTIONAL AND EPIGENETIC CHANGES IN THE CONTEXT OF NERVOUS SYSTEM FUNCTION OR PATHOLOGY. HOWEVER, PARTICULARLY WHEN STUDYING CHRONIC PAIN CONDITIONS, THIS APPROACH CAN BE FLAWED, SINCE IT NEGLECTS TO TAKE INTO ACCOUNT THE SHIFTING CONTRIBUTION OF DIFFERENT CELL TYPES ACROSS EXPERIMENTAL CONDITIONS. HERE, WE DEMONSTRATE THIS USING THE EXAMPLE OF DNA METHYLTRANSFERASES (DNMTS) - A GROUP OF EPIGENETIC MODIFIERS CONSISTING OF DNMT1, DNMT3A, AND DNMT3B IN MAMMALIAN CELLS. WE USED SENSORY NEURON-SPECIFIC KNOCKOUT MICE FOR DNMT3A/3B AS WELL AS PHARMACOLOGICAL BLOCKADE OF DNMT1 TO STUDY THEIR ROLE IN NOCICEPTION. IN CONTRAST TO PREVIOUS ANALYSES ON WHOLE TISSUE, WE FIND THAT DNMT3A AND 3B PROTEIN IS NOT EXPRESSED IN ADULT DRG NEURONS, THAT NONE OF THE DNA METHYLTRANSFERASES ARE REGULATED WITH INJURY AND THAT INTERFERING WITH THEIR FUNCTION HAS NO EFFECT ON NOCICEPTION. OUR RESULTS THEREFORE CURRENTLY DO NOT SUPPORT A ROLE FOR NEURONAL DNA METHYLTRANSFERASES IN PAIN PROCESSING IN ADULT ANIMALS. 2018 20 2590 41 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