1 1695 119 DYNAMIC ASSOCIATION OF P300 WITH THE PROMOTER OF THE G PROTEIN-COUPLED RAT DELTA OPIOID RECEPTOR GENE DURING NGF-INDUCED NEURONAL DIFFERENTIATION. THE G PROTEIN-COUPLED DELTA OPIOID RECEPTOR (DOR) PLAYS A CRITICAL ROLE IN PAIN CONTROL. EMERGING EVIDENCE SHOWS THAT DOR ALSO PLAYS A ROLE IN NEURONAL DIFFERENTIATION AND SURVIVAL. NERVE GROWTH FACTOR (NGF) IS KNOWN TO BE CRITICAL FOR THE DEVELOPMENT AND MAINTENANCE OF THE CENTRAL AND PERIPHERAL NERVOUS SYSTEMS. OUR PREVIOUS STUDIES HAVE SHOWN THAT SUSTAINED ACTIVATION OF NGF/PI3K/AKT/NF-KAPPAB SIGNALING IS ESSENTIAL FOR NGF-INDUCED DOR GENE EXPRESSION DURING NEURONAL DIFFERENTIATION AND THAT THE EPIGENETIC MODIFICATIONS AT HISTONE 3 LYSINE 9 TEMPORALLY CORRELATE WITH THE DOR GENE TRANSCRIPTION. IN THIS STUDY, WE CLONED THE RAT DOR GENE PROMOTER AND IDENTIFIED AN NGF-RESPONSIVE REGION SIMILAR TO THAT FROM THE MOUSE DOR GENE PROMOTER. WE FURTHER IDENTIFIED P300, A KNOWN NF-KAPPAB BINDING PARTNER WITH INTRINSIC HISTONE ACETYLTRANSFERASE ACTIVITY, TO BE DYNAMICALLY ASSOCIATED WITH THE DOR GENE. WE ALSO FOUND THAT ASSEMBLING OF RNA POLYMERASE II (POL II) AT THE PROMOTER TOOK PLACE BEFORE NGF STIMULATION, INDICATING THAT P300 COULD ONLY INTERACT WITH PREASSEMBLED POL II AT THE PROMOTER AFTER NGF STIMULATION. TAKEN TOGETHER, THESE RESULTS IMPLICATE THAT PREASSEMBLY OF THE POL II PREINITIATION COMPLEX, SUSTAINED ACTIVATION OF PI3K/AKT/NF-KAPPAB SIGNALING, AND DYNAMIC P300 ASSOCIATION AT THE PROMOTERS SEQUENTIALLY IS ONE OF THE MECHANISMS OF INDUCTION OF THE LATE PHASE GENES DURING NGF-INDUCED NEURONAL DIFFERENTIATION. 2010 2 4861 25 ORGANIC ANION TRANSPORTER 1 IS AN HDAC4-REGULATED MEDIATOR OF NOCICEPTIVE HYPERSENSITIVITY IN MICE. PERSISTENT PAIN IS SUSTAINED BY MALADAPTIVE CHANGES IN GENE TRANSCRIPTION RESULTING IN ALTERED FUNCTION OF THE RELEVANT CIRCUITS; THERAPIES ARE STILL UNSATISFACTORY. THE EPIGENETIC MECHANISMS AND AFFECTED GENES LINKING NOCICEPTIVE ACTIVITY TO TRANSCRIPTIONAL CHANGES AND PATHOLOGICAL SENSITIVITY ARE UNCLEAR. HERE, WE FOUND THAT, AMONG SEVERAL HISTONE DEACETYLASES (HDACS), SYNAPTIC ACTIVITY SPECIFICALLY AFFECTS HDAC4 IN MURINE SPINAL CORD DORSAL HORN NEURONS. NOXIOUS STIMULI THAT INDUCE LONG-LASTING INFLAMMATORY HYPERSENSITIVITY CAUSE NUCLEAR EXPORT AND INACTIVATION OF HDAC4. THE DEVELOPMENT OF INFLAMMATION-ASSOCIATED MECHANICAL HYPERSENSITIVITY, BUT NEITHER ACUTE NOR BASAL SENSITIVITY, IS IMPAIRED BY THE EXPRESSION OF A CONSTITUTIVELY NUCLEAR LOCALIZED HDAC4 MUTANT. NEXT GENERATION RNA-SEQUENCING REVEALED AN HDAC4-REGULATED GENE PROGRAM COMPRISING MEDIATORS OF SENSITIZATION INCLUDING THE ORGANIC ANION TRANSPORTER OAT1, KNOWN FOR ITS RENAL TRANSPORT FUNCTION. USING PHARMACOLOGICAL AND MOLECULAR TOOLS TO MODULATE OAT1 ACTIVITY OR EXPRESSION, WE CAUSALLY LINK OAT1 TO PERSISTENT INFLAMMATORY HYPERSENSITIVITY IN MICE. THUS, HDAC4 IS A KEY EPIGENETIC REGULATOR THAT TRANSLATES NOCICEPTIVE ACTIVITY INTO SENSITIZATION BY REGULATING OAT1, WHICH IS A POTENTIAL TARGET FOR PAIN-RELIEVING THERAPIES. 2022 3 2442 29 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 4 5347 27 RARBETA AGONIST DRUG (C286) DEMONSTRATES EFFICACY IN A PRE-CLINICAL NEUROPATHIC PAIN MODEL RESTORING MULTIPLE PATHWAYS VIA DNA REPAIR MECHANISMS. NEUROPATHIC PAIN (NP) IS ASSOCIATED WITH PROFOUND GENE EXPRESSION ALTERATIONS WITHIN THE NOCICEPTIVE SYSTEM. DNA MECHANISMS, SUCH AS EPIGENETIC REMODELING AND REPAIR PATHWAYS HAVE BEEN IMPLICATED IN NP. HERE WE HAVE USED A RAT MODEL OF PERIPHERAL NERVE INJURY TO STUDY THE EFFECT OF A RECENTLY DEVELOPED RARBETA AGONIST, C286, CURRENTLY UNDER CLINICAL RESEARCH, IN NP. A 4-WEEK TREATMENT INITIATED 2 DAYS AFTER THE INJURY NORMALIZED PAIN SENSATION. GENOME-WIDE AND PATHWAY ENRICHMENT ANALYSIS SHOWED THAT MULTIPLE MECHANISMS PERSISTENTLY ALTERED IN THE SPINAL CORD WERE RESTORED TO PREINJURY LEVELS BY THE AGONIST. CONCOMITANT UPREGULATION OF DNA REPAIR PROTEINS, ATM AND BRCA1, THE LATTER BEING REQUIRED FOR C286-MEDIATED PAIN MODULATION, SUGGESTS THAT EARLY DNA REPAIR MAY BE IMPORTANT TO PREVENT PHENOTYPIC EPIGENETIC IMPRINTS IN NP. THUS, C286 IS A PROMISING DRUG CANDIDATE FOR NEUROPATHIC PAIN AND DNA REPAIR MECHANISMS MAY BE USEFUL THERAPEUTIC TARGETS TO EXPLORE. 2019 5 4742 31 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 6 3141 34 GLOBAL GENE EXPRESSION AND CHROMATIN ACCESSIBILITY OF THE PERIPHERAL NERVOUS SYSTEM IN ANIMAL MODELS OF PERSISTENT PAIN. BACKGROUND: EFFORTS TO UNDERSTAND GENETIC VARIABILITY INVOLVED IN AN INDIVIDUAL'S SUSCEPTIBILITY TO CHRONIC PAIN SUPPORT A ROLE FOR UPSTREAM REGULATION BY EPIGENETIC MECHANISMS. METHODS: TO EXAMINE THE TRANSCRIPTOMIC AND EPIGENETIC BASIS OF CHRONIC PAIN THAT RESIDES IN THE PERIPHERAL NERVOUS SYSTEM, WE USED RNA-SEQ AND ATAC-SEQ OF THE RAT DORSAL ROOT GANGLION (DRG) TO IDENTIFY NOVEL MOLECULAR PATHWAYS ASSOCIATED WITH PAIN HYPERSENSITIVITY IN TWO WELL-STUDIED PERSISTENT PAIN MODELS INDUCED BY CHRONIC CONSTRICTION INJURY (CCI) OF THE SCIATIC NERVE AND INTRA-PLANTAR INJECTION OF COMPLETE FREUND'S ADJUVANT (CFA) IN RATS. RESULTS: OUR RNA-SEQ STUDIES IDENTIFY A VARIETY OF BIOLOGICAL PROCESS RELATED TO SYNAPSE ORGANIZATION, MEMBRANE POTENTIAL, TRANSMEMBRANE TRANSPORT, AND ION BINDING. INTERESTINGLY, GENES THAT ENCODE TRANSCRIPTIONAL REGULATORS WERE DISPROPORTIONATELY DOWNREGULATED IN BOTH MODELS. OUR ATAC-SEQ DATA PROVIDE A COMPREHENSIVE MAP OF CHROMATIN ACCESSIBILITY CHANGES IN THE DRG. A TOTAL OF 1123 REGIONS SHOWED CHANGES IN CHROMATIN ACCESSIBILITY IN ONE OR BOTH MODELS WHEN COMPARED TO THE NAIVE AND 31 SHARED DIFFERENTIALLY ACCESSIBLE REGIONS (DAR)S. FUNCTIONAL ANNOTATION OF THE DARS IDENTIFIED DISPARATE MOLECULAR FUNCTIONS ENRICHED FOR EACH PAIN MODEL WHICH SUGGESTS THAT CHROMATIN STRUCTURE MAY BE ALTERED DIFFERENTLY FOLLOWING SCIATIC NERVE INJURY AND HIND PAW INFLAMMATION. MOTIF ANALYSIS IDENTIFIED 17 DNA SEQUENCES KNOWN TO BIND TRANSCRIPTION FACTORS IN THE CCI DARS AND 33 IN THE CFA DARS. TWO MOTIFS WERE SIGNIFICANTLY ENRICHED IN BOTH MODELS. CONCLUSIONS: OUR IMPROVED UNDERSTANDING OF THE CHANGES IN CHROMATIN ACCESSIBILITY THAT OCCUR IN CHRONIC PAIN STATES MAY IDENTIFY REGULATORY GENOMIC ELEMENTS THAT PLAY ESSENTIAL ROLES IN MODULATING GENE EXPRESSION IN THE DRG. 2021 7 2246 25 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 8 4499 30 MORPHINE WITHDRAWAL PRODUCES ERK-DEPENDENT AND ERK-INDEPENDENT EPIGENETIC MARKS IN NEURONS OF THE NUCLEUS ACCUMBENS AND LATERAL SEPTUM. EPIGENETIC CHANGES SUCH AS COVALENT MODIFICATIONS OF HISTONE PROTEINS REPRESENT COMPLEX MOLECULAR SIGNATURES THAT PROVIDE A CELLULAR MEMORY OF PREVIOUSLY EXPERIENCED STIMULI WITHOUT IRREVERSIBLE CHANGES OF THE GENETIC CODE. IN THIS STUDY WE SHOW THAT NEW GENE EXPRESSION INDUCED IN VIVO BY MORPHINE WITHDRAWAL OCCURS WITH CONCOMITANT EPIGENETIC MODIFICATIONS IN BRAIN REGIONS CRITICALLY INVOLVED IN DRUG-DEPENDENT BEHAVIORS. WE FOUND THAT NALOXONE-PRECIPITATED WITHDRAWAL, BUT NOT CHRONIC MORPHINE ADMINISTRATION, CAUSED A STRONG INDUCTION OF PHOSPHO-HISTONE H3 IMMUNOREACTIVITY IN THE NUCLEUS ACCUMBENS (NAC) SHELL/CORE AND IN THE LATERAL SEPTUM (LS), A CHANGE THAT WAS ACCOMPANIED BY AUGMENTED H3 ACETYLATION (LYS14) IN NEURONS OF THE NAC SHELL. MORPHINE WITHDRAWAL INDUCED THE PHOSPHORYLATION OF THE EPIGENETIC FACTOR METHYL-CPG-BINDING PROTEIN 2 (MECP2) IN SER421 BOTH IN THE LS AND THE NAC SHELL. THESE EPIGENETIC CHANGES WERE ACCOMPANIED BY THE ACTIVATION OF MEMBERS OF THE ERK PATHWAY AS WELL AS INCREASED EXPRESSION OF THE IMMEDIATE EARLY GENES (IEG) C-FOS AND ACTIVITY-REGULATED CYTOSKELETON-ASSOCIATED PROTEIN (ARC/ARG3.1). USING A PHARMACOLOGICAL APPROACH, WE FOUND THAT H3 PHOSPHORYLATION AND IEG EXPRESSION WERE PARTIALLY DEPENDENT ON ERK ACTIVATION, WHILE MECP2 PHOSPHORYLATION WAS FULLY ERK-INDEPENDENT. THESE FINDINGS PROVIDE NEW IMPORTANT INFORMATION ON THE ROLE OF THE ERK PATHWAY IN THE REGULATION OF EPIGENETIC MARKS AND GENE EXPRESSION THAT MAY CONCUR TO REGULATE IN VIVO THE CELLULAR CHANGES UNDERLYING THE ONSET OF THE OPIOID WITHDRAWAL SYNDROME. 2013 9 2395 33 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 10 226 28 ACUTE TRANSCRIPTOMIC AND EPIGENETIC ALTERATIONS AT T12 AFTER RAT T10 SPINAL CORD CONTUSIVE INJURY. SPINAL CORD INJURY IS A SEVERELY DEBILITATING CONDITION AFFECTING A SIGNIFICANT POPULATION IN THE USA. SPINAL CORD INJURY PATIENTS OFTEN HAVE INCREASED RISK OF DEVELOPING PERSISTENT NEUROPATHIC PAIN AND OTHER NEURODEGENERATIVE CONDITIONS BEYOND THE PRIMARY LESION CENTER LATER IN THEIR LIFE. THE MOLECULAR MECHANISM CONFERRING TO THE "LATENT" DAMAGES AT DISTAL TISSUES, HOWEVER, REMAINS ELUSIVE. HERE, WE STUDIED MOLECULAR CHANGES CONFERRING ABNORMAL FUNCTIONALITY AT DISTAL SPINAL CORD (T12) BEYOND THE LESION CENTER (T10) BY COMBINING NEXT-GENERATION SEQUENCING (RNA- AND BISULFITE SEQUENCING), SUPER-RESOLUTION MICROSCOPY, AND IMMUNOFLUORESCENCE STAINING AT 7 DAYS POST INJURY. WE OBSERVED SIGNIFICANT TRANSCRIPTOMIC CHANGES PRIMARILY ENRICHED IN NEUROINFLAMMATION AND SYNAPTOGENESIS ASSOCIATED PATHWAYS. TRANSCRIPTION FACTORS (TFS) THAT REGULATE NEUROGENESIS AND NEURON PLASTICITY, INCLUDING EGR1, KLF4, AND MYC, ARE SIGNIFICANTLY UPREGULATED. ALONG WITH GLOBAL CHANGES IN CHROMATIN ARRANGEMENTS AND DNA METHYLATION, INCLUDING 5-METHYLCYTOSINE (5MC) AND 5-HYDROXYMETHYLCYTOSINE (5HMC), BISULFITE SEQUENCING FURTHER REVEALS THE INVOLVEMENT OF DNA METHYLATION CHANGES IN REGULATING CYTOKINE, GROWTH FACTOR, AND ION CHANNEL EXPRESSION. COLLECTIVELY, OUR RESULTS PAVE THE WAY TOWARDS UNDERSTANDING TRANSCRIPTOMIC AND EPIGENOMIC MECHANISM IN CONFERRING LONG-TERM DISEASE RISKS AT DISTAL TISSUES AWAY FROM THE PRIMARY LESION CENTER AND SHED LIGHT ON POTENTIAL MOLECULAR TARGETS THAT GOVERN THE REGULATORY MECHANISM AT DISTAL SPINAL CORD TISSUES. 2023 11 5065 26 PHOTOPERIOD-INDUCED NEUROTRANSMITTER PLASTICITY DECLINES WITH AGING: AN EPIGENETIC REGULATION? NEUROPLASTICITY HAS CLASSICALLY BEEN UNDERSTOOD TO ARISE THROUGH CHANGES IN SYNAPTIC STRENGTH OR SYNAPTIC CONNECTIVITY. A NEWLY DISCOVERED FORM OF NEUROPLASTICITY, NEUROTRANSMITTER SWITCHING, INVOLVES CHANGES IN NEUROTRANSMITTER IDENTITY. CHRONIC EXPOSURE TO DIFFERENT PHOTOPERIODS ALTERS THE NUMBER OF DOPAMINE (TYROSINE HYDROXYLASE, TH+) AND SOMATOSTATIN (SST+) NEURONS IN THE PARAVENTRICULAR NUCLEUS (PAVN) OF THE HYPOTHALAMUS OF ADULT RATS AND RESULTS IN DISCRETE BEHAVIORAL CHANGES. HERE, WE INVESTIGATE WHETHER PHOTOPERIOD-INDUCED NEUROTRANSMITTER SWITCHING PERSISTS DURING AGING AND WHETHER EPIGENETIC MECHANISMS OF HISTONE ACETYLATION AND DNA METHYLATION MAY CONTRIBUTE TO THIS NEUROTRANSMITTER PLASTICITY. WE SHOW THAT THIS PLASTICITY IN RATS IS ROBUST AT 1 AND AT 3 MONTHS BUT REDUCED IN TH+ NEURONS AT 12 MONTHS AND COMPLETELY ABOLISHED IN BOTH TH+ AND SST+ NEURONS BY 18 MONTHS. DE NOVO EXPRESSION OF DNMT3A CATALYZING DNA METHYLATION AND ANTI-ACETYLH3 ASSESSING HISTONE 3 ACETYLATION WERE OBSERVED FOLLOWING SHORT-DAY PHOTOPERIOD EXPOSURE IN BOTH TH+ AND SST+ NEURONS AT 1 AND 3 MONTHS WHILE AN OVERALL INCREASE IN DNMT3A IN SST+ NEURONS PARALLELED NEUROPLASTICITY REDUCTION AT 12 AND 18 MONTHS. HISTONE ACETYLATION INCREASED IN TH+ NEURONS AND DECREASED IN SST+ NEURONS FOLLOWING SHORT-DAY EXPOSURE AT 3 MONTHS WHILE THE TOTAL NUMBER OF ANTI-ACETYLH3+ PAVN NEURONS REMAINED CONSTANT. RECIPROCAL HISTONE ACETYLATION IN TH+ AND SST+ NEURONS INDICATES THE IMPORTANCE OF STUDYING EPIGENETIC REGULATION AT THE CIRCUIT LEVEL FOR IDENTIFIED CELL PHENOTYPES. THE FINDINGS MAY BE USEFUL FOR DEVELOPING APPROACHES FOR NONINVASIVE TREATMENT OF DISORDERS CHARACTERIZED BY NEUROTRANSMITTER DYSFUNCTION. 2020 12 1117 28 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 13 984 33 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 14 3093 28 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 15 2673 41 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 16 2297 28 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 17 6411 36 THE SITE SPECIFIC DEMETHYLATION IN THE 5'-REGULATORY AREA OF NMDA RECEPTOR 2B SUBUNIT GENE ASSOCIATED WITH CIE-INDUCED UP-REGULATION OF TRANSCRIPTION. BACKGROUND: THE NMDA RECEPTOR REPRESENTS A PARTICULARLY IMPORTANT SITE OF ETHANOL ACTION IN THE CNS. WE RECENTLY REPORTED THAT NMDA RECEPTOR 2B (NR2B) GENE EXPRESSION WAS PERSISTENTLY UP-REGULATED FOLLOWING CHRONIC INTERMITTENT ETHANOL (CIE) TREATMENT. INCREASING EVIDENCE THAT EPIGENETIC MECHANISMS ARE INVOLVED IN DYNAMIC AND LONG-LASTING REGULATION OF GENE EXPRESSION IN MULTIPLE NEUROADAPTIVE PROCESSES PROMPTED US TO INVESTIGATE THE ROLE OF DNA METHYLATION IN MEDIATING CIE-INDUCED UP-REGULATION OF NR2B GENE TRANSCRIPTION. TO DISSECT THE CHANGES OF DNA METHYLATION IN THE NR2B GENE, WE HAVE SCREENED A LARGE NUMBER OF CPG SITES WITHIN ITS 5'-REGULATORY AREA FOLLOWING CIE TREATMENT. METHODS: PRIMARY CORTICAL CULTURED NEURONS WERE SUBJECTED TO ETHANOL TREATMENT IN A CIE PARADIGM. BISULFITE CONVERSION FOLLOWED BY PYROSEQUENCING WAS USED FOR QUANTITATIVE MEASUREMENT AND ANALYSIS OF CPG METHYLATION STATUS WITHIN THE 5'-REGULATORY AREA OF THE NR2B GENE; CHROMATIN IMMUNOPRECIPITATION (CHIP) ASSAY WAS USED TO EXAMINE DNA LEVELS ASSOCIATED WITH METHYLATION AND TRANSCRIPTION FACTOR BINDING. ELECTROPHORETIC MOBILITY SHIFT ASSAY (EMSA) AND IN VITRO DNA METHYLATION ASSAYS WERE PERFORMED TO DETERMINE THE DIRECT IMPACT OF DNA METHYLATION ON THE INTERACTION BETWEEN DNA AND TRANSCRIPTION FACTOR AND PROMOTER ACTIVITY. RESULTS: ANALYSIS OF INDIVIDUAL CPG METHYLATION SITES WITHIN THE NR2B 5'REGULATORY AREA REVEALED THREE REGIONS WITH CLUSTERS OF SITE-SPECIFIC CPG DEMETHYLATION FOLLOWING CIE TREATMENT AND WITHDRAWAL. THIS WAS CONFIRMED BY CHIP SHOWING SIMILAR DECREASES OF METHYLATED DNA IN THE SAME REGIONS. THE CIE-INDUCED DEMETHYLATION IS CHARACTERIZED BY BEING LOCATED NEAR CERTAIN TRANSCRIPTION FACTOR BINDING SEQUENCES, AP-1 AND CRE, AND OCCURRED DURING TREATMENT AS WELL AS AFTER ETHANOL WITHDRAWAL. FURTHERMORE, THE INCREASE IN VITRO OF METHYLATED DNA DECREASED TRANSCRIPTION FACTOR BINDING ACTIVITY AND PROMOTER ACTIVITY. AN ADDITIONAL CHIP ASSAY INDICATED THAT THE CIE-INDUCED DNA DEMETHYLATION IS ACCOMPANIED BY INCREASED OCCUPATION BY TRANSCRIPTION FACTORS. CONCLUSIONS: THESE RESULTS SUGGEST AN IMPORTANT ROLE OF DNA DEMETHYLATION IN MEDIATING CIE-INDUCED NR2B GENE UP-REGULATION, THUS IMPLICATING A NOVEL MOLECULAR SITE OF ALCOHOL ACTION. 2010 18 3076 31 GENOME-WIDE EPIGENOMIC ANALYSES IN PATIENTS WITH NOCICEPTIVE AND NEUROPATHIC CHRONIC PAIN SUBTYPES REVEALS ALTERATIONS IN METHYLATION OF GENES INVOLVED IN THE NEURO-MUSCULOSKELETAL SYSTEM. NOCICEPTIVE PAIN INVOLVES THE ACTIVATION OF NOCICEPTORS WITHOUT DAMAGE TO THE NERVOUS SYSTEM, WHEREAS NEUROPATHIC PAIN IS RELATED TO AN ALTERATION IN THE CENTRAL OR PERIPHERAL NERVOUS SYSTEM. CHRONIC PAIN ITSELF AND THE TRANSITION FROM ACUTE TO CHRONIC PAIN MAY BE EPIGENETICALLY CONTROLLED. IN THIS CROSS-SECTIONAL STUDY, A GENOME-WIDE DNA METHYLATION ANALYSIS WAS PERFORMED USING THE BLOOD DNA REDUCED REPRESENTATION BISULFITE SEQUENCING (RRBS) TECHNIQUE. THREE PROSPECTIVE COHORTS INCLUDING 20 HEALTHY CONTROLS (CTL), 18 PATIENTS WITH CHRONIC NOCICEPTIVE PAIN (NOCI), AND 19 PATIENTS WITH CHRONIC NEUROPATHIC PAIN (NEURO) WERE COMPARED AT BOTH THE SINGLE CPG AND DIFFERENTIALLY METHYLATED REGION (DMR) LEVELS. GENES WITH DMRS WERE SEEN IN THE NOCI AND NEURO GROUPS BELONGED TO THE NEURO-MUSCULOSKELETAL SYSTEM AND DIFFERED BETWEEN NOCI AND NEURO PATIENTS. OUR RESULTS DEMONSTRATE THAT THE EPIGENETIC DISTURBANCES ACCOMPANYING NOCICEPTIVE PAIN ARE VERY DIFFERENT FROM THOSE ACCOMPANYING NEUROPATHIC PAIN. IN THE FORMER, AMONG OTHERS, THE EPIGENETIC DISTURBANCE OBSERVED WOULD AFFECT THE FUNCTION OF THE OPIOID ANALGESIC SYSTEM, WHEREAS IN THE LATTER IT WOULD AFFECT THAT OF THE GABAERGIC REWARD SYSTEM. THIS STUDY PRESENTS BIOLOGICAL FINDINGS THAT HELP TO CHARACTERIZE NOCI- AND NEURO-AFFECTED PATHWAYS AND OPENS THE POSSIBILITY OF DEVELOPING EPIGENETIC DIAGNOSTIC ASSAYS. PERSPECTIVE: OUR RESULTS HELP TO EXPLAIN THE VARIOUS BIOLOGICAL PATHWAYS MODIFICATIONS UNDERLYING THE DIFFERENT CLINICAL MANIFESTATIONS OF NOCICEPTIVE AND NEUROPATHIC PAINS. FURTHERMORE, THE NEW TARGETS IDENTIFIED IN OUR STUDY MIGHT HELP TO DISCOVER MORE SPECIFIC TREATMENTS FOR NOCICEPTIVE OR NEUROPATHIC PAINS. 2022 19 164 39 ABNORMAL HISTONE METHYLATION IS RESPONSIBLE FOR INCREASED VASCULAR ENDOTHELIAL GROWTH FACTOR 165A SECRETION FROM AIRWAY SMOOTH MUSCLE CELLS IN ASTHMA. VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF), A KEY ANGIOGENIC MOLECULE, IS ABERRANTLY EXPRESSED IN SEVERAL DISEASES INCLUDING ASTHMA WHERE IT CONTRIBUTES TO BRONCHIAL VASCULAR REMODELING AND CHRONIC INFLAMMATION. ASTHMATIC HUMAN AIRWAY SMOOTH MUSCLE CELLS HYPERSECRETE VEGF, BUT THE MECHANISM IS UNCLEAR. IN THIS STUDY, WE DEFINED THE MECHANISM IN HUMAN AIRWAY SMOOTH MUSCLE CELLS FROM NONASTHMATIC AND ASTHMATIC PATIENTS. WE FOUND THAT ASTHMATIC CELLS LACKED A REPRESSION COMPLEX AT THE VEGF PROMOTER, WHICH WAS PRESENT IN NONASTHMATIC CELLS. RECRUITMENT OF G9A, TRIMETHYLATION OF HISTONE H3 AT LYSINE 9 (H3K9ME3), AND A RESULTANT DECREASE IN RNA POLYMERASE II AT THE VEGF PROMOTER WAS CRITICAL TO REPRESSION OF VEGF SECRETION IN NONASTHMATIC CELLS. AT THE ASTHMATIC PROMOTER, H3K9ME3 WAS ABSENT BECAUSE OF FAILED RECRUITMENT OF G9A; RNA POLYMERASE II BINDING, IN ASSOCIATION WITH TATA-BINDING PROTEIN-ASSOCIATED FACTOR 1, WAS INCREASED; H3K4ME3 WAS PRESENT; AND SP1 BINDING WAS EXAGGERATED AND SUSTAINED. IN CONTRAST, DNA METHYLATION AND HISTONE ACETYLATION WERE SIMILAR IN ASTHMATIC AND NONASTHMATIC CELLS. THIS IS THE FIRST STUDY, TO OUR KNOWLEDGE, TO SHOW THAT AIRWAY CELLS IN ASTHMA HAVE ALTERED EPIGENETIC REGULATION OF REMODELING GENE(S). HISTONE METHYLATION AT GENES SUCH AS VEGF MAY BE AN IMPORTANT NEW THERAPEUTIC TARGET. 2012 20 6895 24 [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