1 2685 128 EVIDENCE FOR EPIGENETIC REGULATION OF GENE EXPRESSION AND FUNCTION IN CHRONIC EXPERIMENTAL DIABETIC NEUROPATHY. DIABETIC POLYNEUROPATHY (DPN) IS A COMMON BUT IRREVERSIBLE NEURODEGENERATIVE COMPLICATION OF DIABETES MELLITUS. HERE WE SHOW THAT FEATURES OF SENSORY NEURON DAMAGE IN MICE WITH CHRONIC DPN MAY HAVE ALTERED EPIGENETIC MICRO RNA (MIRNA) TRANSCRIPTIONAL CONTROL. WE PROFILED SENSORY NEURON MESSENGER RNA AND MIRNA PROFILES IN MICE WITH TYPE I DIABETES MELLITUS AND FINDINGS OF DPN. DIABETIC SENSORY DORSAL ROOT GANGLIA NEURONS SHOWED A PATTERN OF ALTERED MESSENGER RNA PROFILES ASSOCIATED WITH UPREGULATED CYTOPLASMIC SITES OF MIRNA-MEDIATED MESSENGER RNA PROCESSING (GW/P BODIES). DORSAL ROOT GANGLIA MIRNA MICROARRAY IDENTIFIED SIGNIFICANT CHANGES IN EXPRESSION AMONG MICE WITH DIABETES, THE MOST PROMINENT OF WHICH WERE A 39% DOWNREGULATION OF MMU-LET-7I AND A 255% INCREASE IN MMU-MIR-341; BOTH WERE IDENTIFIED IN SENSORY NEURONS. TO COUNTERACT THESE ALTERATIONS, WE REPLENISHED LET-7I MIRNA BY INTRANASAL ADMINISTRATION; IN A SEPARATE EXPERIMENT, WE ADDED AN ANTI-MIR THAT ANTAGONIZED ELEVATED MMU-341 AFTER 5 MONTHS OF DIABETES. BOTH APPROACHES INDEPENDENTLY IMPROVED ELECTROPHYSIOLOGIC, STRUCTURAL, AND BEHAVIORAL ABNORMALITIES WITHOUT ALTERING HYPERGLYCEMIA; CONTROL SEQUENCES DID NOT HAVE THESE EFFECTS. DISSOCIATED ADULT SENSORY NEURONS EXPOSED TO AN EXOGENOUS MMU-LET-7I MIMIC DISPLAYED ENHANCED GROWTH AND BRANCHING, INDICATING A TROPHIC ACTION. THESE FINDINGS IDENTIFY ROLES FOR EPIGENETIC MIRNA ALTERATIONS AND ENHANCED GW/P EXPRESSION IN DIABETIC DORSAL ROOT GANGLIA THAT CONTRIBUTE TO THE COMPLEX DPN PHENOTYPE. 2015 2 3141 36 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 3 60 32 A GENOME-WIDE SCREEN REVEALS MICRORNAS IN PERIPHERAL SENSORY NEURONS DRIVING PAINFUL DIABETIC NEUROPATHY. DIABETES IS A LEADING CAUSE OF PERIPHERAL NEUROPATHY (DIABETIC PERIPHERAL NEUROPATHY, DPN), AND UNCONTROLLED LONG-LASTING HYPERGLYCEMIA LEADS TO SEVERE COMPLICATIONS. A MAJOR PROPORTION OF DIABETICS DEVELOP EXCRUCIATING PAIN WITH A VARIABLE COURSE. MECHANISMS LEADING TO PAINFUL DPN ARE NOT COMPLETELY UNDERSTOOD AND TREATMENT OPTIONS LIMITED. WE HYPOTHESIZED THAT EPIGENETIC MODULATION AT THE LEVEL OF MICRORNA (MIRNA) EXPRESSION TRIGGERED BY METABOLIC IMBALANCE AND NERVE DAMAGE REGULATES THE COURSE OF PAIN DEVELOPMENT. WE USED CLINICALLY RELEVANT PRECLINICAL MODELS, GENOME-WIDE SCREENING, IN SILICO ANALYSES, CELLULAR ASSAYS, MIRNA FLUORESCENT IN SITU HYBRIDIZATION, IN VIVO MOLECULAR MANIPULATIONS, AND BEHAVIORAL ANALYSES IN THE CURRENT STUDY. WE IDENTIFIED MIRNAS AND THEIR TARGETS THAT CRITICALLY IMPACT ON NOCICEPTIVE HYPERSENSITIVITY IN PAINFUL DPN. OUR ANALYSES IDENTIFY MIR-33 AND MIR-380 EXPRESSED IN NOCICEPTIVE NEURONS AS CRITICAL DENOMINATORS OF DIABETIC PAIN AND MIR-124-1 AS A MEDIATOR OF PHYSIOLOGICAL NOCICEPTION. OUR COMPREHENSIVE ANALYSES ON THE PUTATIVE MRNA TARGETS FOR MIR-33 OR MIR-124-1 IDENTIFIED A SET OF MRNAS THAT ARE REGULATED AFTER MIR-33 OR MIR-124-1 OVEREXPRESSION IN DORSAL ROOT GANGLIA IN VIVO. OUR RESULTS SHED LIGHT ON THE REGULATION OF DPN PATHOPHYSIOLOGY AND IMPLICATE SPECIFIC MIRNAS AS NOVEL THERAPEUTIC TARGETS FOR TREATING PAINFUL DPN. 2021 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 5 226 31 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 6 345 37 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 7 2442 26 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 8 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 9 4861 27 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 10 710 32 C-TERMINAL DOMAIN SMALL PHOSPHATASE 1 (CTDSP1) REGULATES GROWTH FACTOR EXPRESSION AND AXONAL REGENERATION IN PERIPHERAL NERVE TISSUE. PERIPHERAL NERVE INJURY (PNI) REPRESENTS A MAJOR CLINICAL AND ECONOMIC BURDEN. DESPITE THE ABILITY OF PERIPHERAL NEURONS TO REGENERATE THEIR AXONS AFTER AN INJURY, PATIENTS ARE OFTEN LEFT WITH MOTOR AND/OR SENSORY DISABILITY AND MAY DEVELOP CHRONIC PAIN. SUCCESSFUL REGENERATION AND TARGET ORGAN REINNERVATION REQUIRE COMPREHENSIVE TRANSCRIPTIONAL CHANGES IN BOTH INJURED NEURONS AND SUPPORT CELLS LOCATED AT THE SITE OF INJURY. THE EXPRESSION OF MOST OF THE GENES REQUIRED FOR AXON GROWTH AND GUIDANCE AND FOR SYNAPSIS FORMATION IS REPRESSED BY A SINGLE MASTER TRANSCRIPTIONAL REGULATOR, THE REPRESSOR ELEMENT 1 SILENCING TRANSCRIPTION FACTOR (REST). SUSTAINED INCREASE OF REST LEVELS AFTER INJURY INHIBITS AXON REGENERATION AND LEADS TO CHRONIC PAIN. AS TARGETING OF TRANSCRIPTION FACTORS IS CHALLENGING, WE TESTED WHETHER MODULATION OF REST ACTIVITY COULD BE ACHIEVED THROUGH KNOCKDOWN OF CARBOXY-TERMINAL DOMAIN SMALL PHOSPHATASE 1 (CTDSP1), THE ENZYME THAT STABILIZES REST BY PREVENTING ITS TARGETING TO THE PROTEASOME. TO TEST WHETHER KNOCKDOWN OF CTDSP1 PROMOTES NEUROTROPHIC FACTOR EXPRESSION IN BOTH SUPPORT CELLS LOCATED AT THE SITE OF INJURY AND IN PERIPHERAL NEURONS, WE TRANSFECTED MESENCHYMAL PROGENITOR CELLS (MPCS), A TYPE OF SUPPORT CELLS THAT ARE PRESENT AT HIGH CONCENTRATIONS AT THE SITE OF INJURY, AND DORSAL ROOT GANGLION (DRG) NEURONS WITH REST OR CTDSP1 SPECIFIC SIRNA. WE QUANTIFIED NEUROTROPHIC FACTOR EXPRESSION BY RT-QPCR AND WESTERN BLOT, AND BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) RELEASE IN THE CELL CULTURE MEDIUM BY ELISA, AND WE MEASURED NEURITE OUTGROWTH OF DRG NEURONS IN CULTURE. OUR RESULTS SHOW THAT CTDSP1 KNOCKDOWN PROMOTES NEUROTROPHIC FACTOR EXPRESSION IN BOTH DRG NEURONS AND THE SUPPORT CELLS MPCS, AND PROMOTES DRG NEURON REGENERATION. THERAPEUTICS TARGETING CTDSP1 ACTIVITY MAY, THEREFORE, REPRESENT A NOVEL EPIGENETIC STRATEGY TO PROMOTE PERIPHERAL NERVE REGENERATION AFTER PNI BY PROMOTING THE REGENERATIVE PROGRAM REPRESSED BY INJURY-INDUCED INCREASED LEVELS OF REST IN BOTH NEURONS AND SUPPORT CELLS. 2021 11 3076 25 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 12 2297 26 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 13 4742 26 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 14 6461 28 TIME-COURSE PROGRESSION OF WHOLE TRANSCRIPTOME EXPRESSION CHANGES OF TRIGEMINAL GANGLIA COMPARED TO DORSAL ROOT GANGLIA IN RATS EXPOSED TO NERVE INJURY. MECHANISMS UNDERLYING NEUROPATHIC PAIN (NP) ARE COMPLEX WITH MULTIPLE GENES, THEIR INTERACTIONS, ENVIRONMENTAL AND EPIGENETIC FACTORS BEING IMPLICATED. TRANSCRIPTIONAL CHANGES IN THE TRIGEMINAL (TG) AND DORSAL ROOT (DRG) GANGLIA HAVE BEEN IMPLICATED IN THE DEVELOPMENT AND MAINTENANCE OF NP. DESPITE EFFORTS TO UNRAVEL MOLECULAR MECHANISMS OF NP, MANY REMAIN UNKNOWN. ALSO, MOST OF THE STUDIES FOCUSED ON THE SPINAL SYSTEM. ALTHOUGH THE SPINAL AND TRIGEMINAL SYSTEMS SHARE SOME OF THE MOLECULAR MECHANISMS, DIFFERENCES EXIST. WE USED RNA-SEQUENCING TECHNOLOGY TO IDENTIFY DIFFERENTIALLY EXPRESSED GENES (DEGS) IN THE TG AND DRG AT BASELINE AND 3 TIME-POINTS FOLLOWING THE INFRAORBITAL OR SCIATIC NERVE INJURIES, RESPECTIVELY. PATHWAY ANALYSIS AND COMPARISON ANALYSIS WERE PERFORMED TO IDENTIFY DIFFERENTIALLY EXPRESSED PATHWAYS. ADDITIONALLY, UPSTREAM REGULATOR EFFECTS WERE INVESTIGATED IN THE TWO SYSTEMS. DEG (DIFFERENTIALLY EXPRESSED GENES) ANALYSES IDENTIFIED 3,225 GENES TO BE DIFFERENTIALLY EXPRESSED BETWEEN TG AND DRG IN NAIVE ANIMALS, 1,828 GENES FOUR DAYS POST INJURY, 5,644 AT DAY 8 AND 9,777 DEGS AT 21 DAYS POST INJURY. COMPARISON OF TOP ENRICHED CANONICAL PATHWAYS REVEALED THAT A NUMBER OF SIGNALING PATHWAY WAS SIGNIFICANTLY INHIBITED IN THE TG AND ACTIVATED IN THE DRG AT 21 DAYS POST INJURY. FINALLY, CORT UPSTREAM REGULATOR WAS PREDICTED TO BE INHIBITED IN THE TG WHILE EXPRESSION LEVELS OF CSF1 UPSTREAM REGULATOR WERE SIGNIFICANTLY ELEVATED IN THE DRG AT 21 DAYS POST INJURY. THIS STUDY PROVIDES A BASIS FOR FURTHER IN-DEPTH STUDIES INVESTIGATING TRANSCRIPTIONAL CHANGES, PATHWAYS, AND UPSTREAM REGULATION IN TG AND DRG IN RATS EXPOSED TO PERIPHERAL NERVE INJURIES. 2023 15 3194 24 HDAC INHIBITORS ATTENUATE THE DEVELOPMENT OF HYPERSENSITIVITY IN MODELS OF NEUROPATHIC PAIN. HISTONE DEACETYLASE INHIBITORS (HDACIS) INTERFERE WITH THE EPIGENETIC PROCESS OF HISTONE ACETYLATION AND ARE KNOWN TO HAVE ANALGESIC PROPERTIES IN MODELS OF CHRONIC INFLAMMATORY PAIN. THE AIM OF THIS STUDY WAS TO DETERMINE WHETHER THESE COMPOUNDS COULD ALSO AFFECT NEUROPATHIC PAIN. DIFFERENT CLASS I HDACIS WERE DELIVERED INTRATHECALLY INTO RAT SPINAL CORD IN MODELS OF TRAUMATIC NERVE INJURY AND ANTIRETROVIRAL DRUG-INDUCED PERIPHERAL NEUROPATHY (STAVUDINE, D4T). MECHANICAL AND THERMAL HYPERSENSITIVITY WAS ATTENUATED BY 40% TO 50% AS A RESULT OF HDACI TREATMENT, BUT ONLY IF STARTED BEFORE ANY INSULT. THE DRUGS GLOBALLY INCREASED HISTONE ACETYLATION IN THE SPINAL CORD, BUT APPEARED TO HAVE NO MEASURABLE EFFECTS IN RELEVANT DORSAL ROOT GANGLIA IN THIS TREATMENT PARADIGM, SUGGESTING THAT ANY POTENTIAL MECHANISM SHOULD BE SOUGHT IN THE CENTRAL NERVOUS SYSTEM. MICROARRAY ANALYSIS OF DORSAL CORD RNA REVEALED THE SIGNATURE OF THE SPECIFIC COMPOUND USED (MS-275) AND SUGGESTED THAT ITS MAIN EFFECT WAS MEDIATED THROUGH HDAC1. TAKEN TOGETHER, THESE DATA SUPPORT A ROLE FOR HISTONE ACETYLATION IN THE EMERGENCE OF NEUROPATHIC PAIN. 2013 16 6804 36 [EPIGENETIC REGULATION IN DEPRESSION]. RECENT RESEARCH HAS RAISED THE NOTION THAT EPIGENETIC MECHANISMS (E.G., DNA METHYLATION AND HISTONE MODIFICATIONS), WHICH EXERT LASTING CONTROL OVER GENE EXPRESSION WITHOUT ALTERING THE GENETIC CODE, COULD MEDIATE STABLE CHANGES IN BRAIN FUNCTION. HOWEVER, THE ROLE OF ENVIRONMENTAL FACTORS ALONG WITH GENETIC FACTORS IN THE EPIGENETIC REGULATION OF THE PATHOGENESIS OF DEPRESSION IS LARGELY UNKNOWN. TWO GENETICALLY DISTINCT MICE STRAINS, BALB/C (BALB) AND C57BL/6 (B6), EXHIBIT DIFFERENT BEHAVIORAL RESPONSES TO CHRONIC STRESS. WITH CHRONIC STRESS, BALB MICE SHOWED DEPRESSIVE-LIKE BEHAVIORS, BUT NOT B6 MICE, AND GLIAL CELL-DERIVED NEUROTROPHIC FACTOR (GDNF) EXPRESSION LEVEL WAS DECREASED IN THE VENTRAL STRIATUM OF BALB MICE BUT INCREASED IN B6 MICE. IN BALB MICE, DEPRESSIVE-LIKE BEHAVIORS AND DECREASED GDNF EXPRESSION WERE RECOVERED BY CHRONIC ANTIDEPRESSANT TREATMENT. THEREFORE, WE USED THESE TWO MICE STRAINS TO INVESTIGATE HOW THE EPIGENETIC STATUS OF THE GDNF GENE IN THE VENTRAL STRIATUM MODULATES STRESS VULNERABILITY. BOTH MICE STRAINS SHOWED INCREASED DNA METHYLATION LEVELS AND MECP2 RECRUITMENT IN THE GDNF PROMOTER REGION. HOWEVER, HISTONE H3 ACETYLATION LEVEL WAS DECREASED IN BALB MICE, BUT INCREASED IN B6 MICE. FURTHERMORE, BALB MICE SHOWED INCREASED HISTONE DEACETYLASE2 (HDAC2) EXPRESSION LEVEL AND RE-CHIP ASSAY REVEALED HDAC2-MECP2 COMPLEX IN BALB MICE. OUR RESULTS INDICATE THE CRUCIAL ROLE OF HISTONE MODIFICATION BY HDAC2 AND MECP2 COMPLEX FOR THE CONTROL OF GDNF EXPRESSION AND SUBSEQUENT BEHAVIORAL RESPONSES TO CHRONIC STRESS, IN OTHER WORDS, THE SUSCEPTIBILITY TO STRESS. IN ADDITION, WE INVESTIGATED THE EFFECT OF ANTIDEPRESSANTS ON THE EPIGENETIC REGULATION OF GDNF EXPRESSION. WE FOUND A REDUCED LEVEL OF HDAC4 RECRUITMENT AT THE GDNF PROMOTER REGION WITH ANTIDEPRESSANTS. THUS, OUR DATA SUGGEST THAT ANTIDEPRESSANTS INCREASE TRANSCRIPTIONAL ACTIVITY OF THE GDNF GENE THROUGH THE MODULATION OF HISTONE ACETYLATION BY HDAC4. FINALLY, WE EXAMINED THE EXPRESSIONS OF GDNF AND EPIGENETIC-RELATED MOLECULES MRNAS WITH MAJOR DEPRESSIVE AND BIPOLAR DISORDER PATIENTS BY USING QUANTITATIVE REAL-TIME PCR. WE FOUND THE ABERRANT EXPRESSION OF GDNF AND EPIGENETIC-RELATED GENES INCLUDING HDAC2 AND HDAC4 IN MOOD DISORDER PATIENTS. THUS, OUR DATA PROVIDE NOVEL INSIGHTS SUGGESTING THAT EPIGENETIC MECHANISMS OF GDNF EXPRESSION ARE INVOLVED IN THE PATHOGENESIS OR PATHOPHYSIOLOGY OF DEPRESSION. 2012 17 6895 20 [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 18 5065 35 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 19 885 38 CHRONIC CONSTRICTION INJURY-INDUCED CHANGES IN CIRCULAR RNA EXPRESSION PROFILING OF THE DORSAL ROOT GANGLION IN A RAT MODEL OF NEUROPATHIC PAIN. BACKGROUND: THE PATHOGENESIS OF NEUROPATHIC PAIN (NP) HAS NOT BEEN FULLY ELUCIDATED. GENE CHANGES IN DORSAL ROOT GANGLIA (DRG) MAY CONTRIBUTE TO THE DEVELOPMENT OF NP. CIRCULAR RNAS (CIRCRNAS) ARE A CLASS OF ENDOGENOUS NONCODING RNAS THAT FORM COVALENTLY CLOSED LOOP STRUCTURES AND ARE CRUCIAL FOR GENETIC AND EPIGENETIC REGULATION. HOWEVER, LITTLE IS KNOWN ABOUT CIRCRNA CHANGES IN DRG NEURONS AFTER PERIPHERAL NERVE INJURY. METHODS: A SCIATIC NERVE CHRONIC CONSTRICTION INJURY (CCI) MODEL WAS ESTABLISHED TO INDUCE NEUROPATHIC PAIN. WE PERFORMED GENOME-WIDE CIRCRNA ANALYSIS OF FOUR PAIRED DORSAL ROOT GANGLION (DRG) SAMPLES (L4-L5) FROM CCI AND NEGATIVE CONTROL (NC) RATS USING NEXT-GENERATION SEQUENCING TECHNOLOGY. THE DIFFERENTIALLY EXPRESSED CIRCRNAS (DECIRCRNAS) WERE IDENTIFIED BY DIFFERENTIAL EXPRESSION ANALYSIS, AND THE EXPRESSION PROFILE OF CIRCRNAS WAS VALIDATED BY QUANTITATIVE PCR. GENE ONTOLOGY AND KYOTO ENCYCLOPEDIA OF GENES AND GENOMES ANALYSES WERE PERFORMED TO PREDICT THE FUNCTION OF DECIRCRNAS. RESULTS: A TOTAL OF 374 DECIRCRNAS WERE IDENTIFIED BETWEEN CCI AND NC RATS USING CIRCRNA HIGH-THROUGHPUT SEQUENCING. AMONG THEM, 290 WERE UPREGULATED AND 84 WERE DOWNREGULATED IN THE CCI GROUP. THE EXPRESSION LEVELS OF NINE DECIRCRNAS WERE VALIDATED BY QPCR. FUNCTIONAL ANNOTATION ANALYSIS SHOWED THAT THE DECIRCRNAS WERE MAINLY ENRICHED IN PATHWAYS AND FUNCTIONS, INCLUDING 'DOPAMINERGIC SYNAPSE,' 'RENIN SECRETION,' 'MITOGEN-ACTIVATED PROTEIN KINASE SIGNALING PATHWAY,' AND 'NEUROGENESIS.' COMPETING ENDOGENOUS RNA ANALYSIS SHOWED THAT THE TOP 50 CIRCRNAS EXHIBITED INTERACTIONS WITH FOUR PAIN-RELATED MICRORNAS (MIRNAS). CIRC:CHR2:33950934-33955969 WAS THE LARGEST NODE IN THE CIRCRNA-MIRNA INTERACTION NETWORK. CONCLUSIONS: PERIPHERAL NERVE INJURY-INDUCED NEUROPATHIC PAIN LED TO CHANGES IN THE COMPREHENSIVE EXPRESSION PROFILE OF CIRCRNAS IN THE DRG OF RATS. DECIRCRNAS MAY ADVANCE OUR UNDERSTANDING OF THE MOLECULAR MECHANISMS UNDERLYING NEUROPATHIC PAIN. 2022 20 6226 14 THE LINK BETWEEN EPIGENETICS, PAIN SENSITIVITY AND CHRONIC PAIN. INCREASING EVIDENCE SUGGESTS AN ASSOCIATION BETWEEN GENE EXPRESSION AND CLINICAL PAIN. EPIGENETIC MODIFICATIONS ARE THE MAIN MODULATORS OF GENE EXPRESSION OR PROTEIN TRANSLATION IN RESPONSE TO ENVIRONMENTAL STIMULI AND PATHOPHYSIOLOGICAL CONDITIONS. PRECLINICAL AND CLINICAL STUDIES INDICATE THAT EPIGENETIC MODIFICATIONS COULD ALSO IMPACT THE DEVELOPMENT OF PAIN, THE TRANSITION FROM ACUTE TO CHRONIC PAIN, AND THE MAINTENANCE HEREOF. 2022