1 803 151 CENTRAL CONTROL OF VISCERAL PAIN AND URINARY TRACT FUNCTION. AFFERENT INPUT FROM ADELTA AND C-FIBRES INNERVATING THE URINARY BLADDER ARE PROCESSED DIFFERENTLY BY THE BRAIN, AND HAVE DIFFERENT ROLES IN SIGNALING BLADDER SENSATION. ADELTA FIBRES THAT SIGNAL BLADDER FILLING ACTIVATE A SPINO-BULBO-SPINAL LOOP, WHICH RELAYS IN THE MIDBRAIN PERIAQUEDUCTAL GREY (PAG) AND PONTINE MICTURITION CENTRE (PMC). THE EXCITABILITY OF THIS CIRCUITRY IS REGULATED BY TONIC GABAERGIC INHIBITORY PROCESSES. IN HUMANS AND SOCIALISED ANIMALS MICTURITION IS NORMALLY UNDER VOLITIONAL CONTROL AND INFLUENCED BY A HOST OF PSYCHOSOCIAL FACTORS. HIGHER NERVOUS DECISION-MAKING IN A SOCIAL CONTEXT TO 'GO NOW' OR 'DO NOT GO' PROBABLY RESIDES IN FRONTAL CORTICAL AREAS, WHICH ACT AS A CENTRAL CONTROL SWITCH FOR MICTURITION. EXPOSURE TO PSYCHOSOCIAL STRESS CAN HAVE PROFOUNDLY DISRUPTIVE INFLUENCE ON THE PROCESS AND LEAD TO MALADAPTIVE CHANGES IN THE BLADDER. DURING SLEEPING THE VOIDING REFLEX THRESHOLD APPEARS TO BE RESET TO A HIGHER LEVEL TO PROMOTE URINARY CONTINENCE. UNDER PHYSIOLOGICAL CONDITIONS C-FIBRE BLADDER AFFERENTS ARE NORMALLY SILENT BUT ARE ACTIVATED IN INFLAMMATORY BLADDER STATES AND BY INTENSE DISTENDING PRESSURE. FOLLOWING PROLONGED STIMULATION VISCERAL NOCICEPTORS SENSITISE, LEADING TO A LOWERED THRESHOLD AND HEIGHTENED SENSITIVITY. IN ADDITION, SENSITIZATION MAY OCCUR WITHIN THE CENTRAL PAIN PROCESSING CIRCUITRY, WHICH OUTLASTS THE ORIGINAL NOCICEPTIVE INSULT. VISCERAL NOCICEPTION MAY ALSO BE INFLUENCED BY GENETIC AND ENVIRONMENTAL INFLUENCES. A PERIOD OF CHRONIC STRESS CAN PRODUCE INCREASED SENSITIVITY TO VISCERAL PAIN THAT LASTS FOR MONTHS. ADVERSE EARLY LIFE EVENTS CAN PRODUCE EVEN LONGER LASTING EPIGENETIC CHANGES, WHICH INCREASE THE INDIVIDUAL'S SUSCEPTIBILITY TO DEVELOPING VISCERAL PAIN STATES IN ADULTHOOD. 2016 2 5334 21 QUADRICEPS MUSCLE WEAKNESS AND ATROPHY ARE ASSOCIATED WITH A DIFFERENTIAL EPIGENETIC PROFILE IN ADVANCED COPD. EPIGENETIC MECHANISMS REGULATE MUSCLE MASS AND FUNCTION IN MODELS OF MUSCLE DYSFUNCTION AND ATROPHY. WE ASSESSED WHETHER QUADRICEPS MUSCLE WEAKNESS AND ATROPHY ARE ASSOCIATED WITH A DIFFERENTIAL EXPRESSION PROFILE OF EPIGENETIC EVENTS IN PATIENTS WITH ADVANCED COPD (CHRONIC OBSTRUCTIVE PULMONARY DISEASE). IN VASTUS LATERALIS (VL) OF SEDENTARY SEVERE COPD PATIENTS (N=41), WHO WERE FURTHER SUBDIVIDED INTO THOSE WITH (N=25) AND WITHOUT (N=16) MUSCLE WEAKNESS AND HEALTHY CONTROLS (N=19), EXPRESSION OF MUSCLE-ENRICHED MIRNAS, HISTONE ACETYLTRANSFERASES (HATS) AND DEACETYLASES (HDACS), GROWTH AND ATROPHY SIGNALLING MARKERS, TOTAL PROTEIN AND HISTONE ACETYLATION, TRANSCRIPTION FACTORS, SMALL UBIQUITIN-RELATED MODIFIER (SUMO) LIGASES AND MUSCLE STRUCTURE WERE EXPLORED. ALL SUBJECTS WERE CLINICALLY EVALUATED. COMPARED WITH CONTROLS, IN VL OF ALL COPD TOGETHER AND IN MUSCLE-WEAKNESS PATIENTS, EXPRESSION OF MIR-1, MIR-206 AND MIR-27A, LEVELS OF LYSINE-ACETYLATED PROTEINS AND HISTONES AND ACETYLATED HISTONE 3 WERE INCREASED, WHEREAS EXPRESSION OF HDAC3, HDAC4, SIRTUIN-1 (SIRT-1), IGF-1 (INSULIN-LIKE GROWTH FACTOR-1) WERE DECREASED, AKT (V-AKT MURINE THYMOMA VIRAL ONCOGENE HOMOLOGUE 1) EXPRESSION DID NOT DIFFER, FOLLISTATIN EXPRESSION WAS GREATER, WHEREAS MYOSTATIN EXPRESSION WAS LOWER, SERUM REPONSE FACTOR (SRF) EXPRESSION WAS INCREASED AND FIBRE SIZE OF FAST-TWITCH FIBRES WAS SIGNIFICANTLY REDUCED. IN VL OF SEVERE COPD PATIENTS WITH MUSCLE WEAKNESS AND ATROPHY, EPIGENETIC EVENTS REGULATE MUSCLE DIFFERENTIATION RATHER THAN PROLIFERATION AND MUSCLE GROWTH AND ATROPHY SIGNALLING, PROBABLY AS FEEDBACK MECHANISMS TO PREVENT THOSE MUSCLES FROM UNDERGOING FURTHER ATROPHY. LYSINE-HYPERACETYLATION OF HISTONES MAY DRIVE ENHANCED PROTEIN CATABOLISM IN THOSE MUSCLES. THESE FINDINGS MAY HELP DESIGN NOVEL THERAPEUTIC STRATEGIES (ENHANCERS OF MIRNAS PROMOTING MYOGENESIS AND ACETYLATION INHIBITORS) TO SELECTIVELY TARGET MUSCLE WEAKNESS AND ATROPHY IN SEVERE COPD. 2015 3 5063 30 PHOSPHORYLATED HISTONE 3 AT SERINE 10 IDENTIFIES ACTIVATED SPINAL NEURONS AND CONTRIBUTES TO THE DEVELOPMENT OF TISSUE INJURY-ASSOCIATED PAIN. TRANSCRIPTIONAL CHANGES IN SUPERFICIAL SPINAL DORSAL HORN NEURONS (SSDHN) ARE ESSENTIAL IN THE DEVELOPMENT AND MAINTENANCE OF PROLONGED PAIN. EPIGENETIC MECHANISMS INCLUDING POST-TRANSLATIONAL MODIFICATIONS IN HISTONES ARE PIVOTAL IN REGULATING TRANSCRIPTION. HERE, WE REPORT THAT PHOSPHORYLATION OF SERINE 10 (S10) IN HISTONE 3 (H3) SPECIFICALLY OCCURS IN A GROUP OF RAT SSDHN FOLLOWING THE ACTIVATION OF NOCICEPTIVE PRIMARY SENSORY NEURONS BY BURN INJURY, CAPSAICIN APPLICATION OR SUSTAINED ELECTRICAL ACTIVATION OF NOCICEPTIVE PRIMARY SENSORY NERVE FIBRES. IN CONTRAST, BRIEF THERMAL OR MECHANICAL NOCICEPTIVE STIMULI, WHICH FAIL TO INDUCE TISSUE INJURY OR INFLAMMATION, DO NOT PRODUCE THE SAME EFFECT. BLOCKING N-METHYL-D-ASPARTATE RECEPTORS OR ACTIVATION OF EXTRACELLULAR SIGNAL-REGULATED KINASES 1 AND 2, OR BLOCKING OR DELETING THE MITOGEN- AND STRESS-ACTIVATED KINASES 1 AND 2 (MSK1/2), WHICH PHOSPHORYLATE S10 IN H3, INHIBIT UP-REGULATION IN PHOSPHORYLATED S10 IN H3 (P-S10H3) AS WELL AS FOS TRANSCRIPTION, A DOWN-STREAM EFFECT OF P-S10H3. DELETING MSK1/2 ALSO INHIBITS THE DEVELOPMENT OF CARRAGEENAN-INDUCED INFLAMMATORY HEAT HYPERALGESIA IN MICE. WE PROPOSE THAT P-S10H3 IS A NOVEL MARKER FOR NOCICEPTIVE PROCESSING IN SSDHN WITH HIGH RELEVANCE TO TRANSCRIPTIONAL CHANGES AND THE DEVELOPMENT OF PROLONGED PAIN. 2017 4 764 29 CBP/P300 ACTIVATION PROMOTES AXON GROWTH, SPROUTING, AND SYNAPTIC PLASTICITY IN CHRONIC EXPERIMENTAL SPINAL CORD INJURY WITH SEVERE DISABILITY. THE INTERRUPTION OF SPINAL CIRCUITRY FOLLOWING SPINAL CORD INJURY (SCI) DISRUPTS NEURAL ACTIVITY AND IS FOLLOWED BY A FAILURE TO MOUNT AN EFFECTIVE REGENERATIVE RESPONSE RESULTING IN PERMANENT NEUROLOGICAL DISABILITY. FUNCTIONAL RECOVERY REQUIRES THE ENHANCEMENT OF AXONAL AND SYNAPTIC PLASTICITY OF SPARED AS WELL AS INJURED FIBRES, WHICH NEED TO SPROUT AND/OR REGENERATE TO FORM NEW CONNECTIONS. HERE, WE HAVE INVESTIGATED WHETHER THE EPIGENETIC STIMULATION OF THE REGENERATIVE GENE EXPRESSION PROGRAM CAN OVERCOME THE CURRENT INABILITY TO PROMOTE NEUROLOGICAL RECOVERY IN CHRONIC SCI WITH SEVERE DISABILITY. WE DELIVERED THE CBP/P300 ACTIVATOR CSP-TTK21 OR VEHICLE CSP WEEKLY BETWEEN WEEK 12 AND 22 FOLLOWING A TRANSECTION MODEL OF SCI IN MICE HOUSED IN AN ENRICHED ENVIRONMENT. DATA ANALYSIS SHOWED THAT CSP-TTK21 ENHANCED CLASSICAL REGENERATIVE SIGNALLING IN DORSAL ROOT GANGLIA SENSORY BUT NOT CORTICAL MOTOR NEURONS, STIMULATED MOTOR AND SENSORY AXON GROWTH, SPROUTING, AND SYNAPTIC PLASTICITY, BUT FAILED TO PROMOTE NEUROLOGICAL SENSORIMOTOR RECOVERY. THIS WORK PROVIDES DIRECT EVIDENCE THAT CLINICALLY SUITABLE PHARMACOLOGICAL CBP/P300 ACTIVATION CAN PROMOTE THE EXPRESSION OF REGENERATION-ASSOCIATED GENES AND AXONAL GROWTH IN A CHRONIC SCI WITH SEVERE NEUROLOGICAL DISABILITY. 2022 5 4201 25 METABOLIC REWIRING AND REDOX ALTERATIONS IN MALIGNANT PLEURAL MESOTHELIOMA. MALIGNANT PLEURAL MESOTHELIOMA (MPM) IS A RARE MALIGNANCY OF MESOTHELIAL CELLS WITH INCREASING INCIDENCE, AND IN MANY CASES, DISMAL PROGNOSIS DUE TO ITS AGGRESSIVENESS AND LACK OF EFFECTIVE THERAPIES. ENVIRONMENTAL AND OCCUPATIONAL EXPOSURE TO ASBESTOS IS CONSIDERED THE MAIN AETIOLOGICAL FACTOR FOR MPM. INHALED ASBESTOS FIBRES ACCUMULATE IN THE LUNGS AND INDUCE THE GENERATION OF REACTIVE OXYGEN SPECIES (ROS) DUE TO THE PRESENCE OF IRON ASSOCIATED WITH THE FIBROUS SILICATES AND TO THE ACTIVATION OF MACROPHAGES AND INFLAMMATION. CHRONIC INFLAMMATION AND A ROS-ENRICHED MICROENVIRONMENT CAN FOSTER THE MALIGNANT TRANSFORMATION OF MESOTHELIAL CELLS. IN ADDITION, MPM CELLS HAVE A HIGHLY GLYCOLYTIC METABOLIC PROFILE AND ARE POSITIVE IN (18)F-FDG PET ANALYSIS. LOSS-OF-FUNCTION MUTATIONS OF BRCA-ASSOCIATED PROTEIN 1 (BAP1) ARE A MAJOR CONTRIBUTOR TO THE METABOLIC REWIRING OF MPM CELLS. A SUBSET OF MPM TUMOURS SHOW LOSS OF THE METHYLADENOSINE PHOSPHORYLASE (MTAP) LOCUS, RESULTING IN PROFOUND ALTERATIONS IN POLYAMINE METABOLISM, ATP AND METHIONINE SALVAGE PATHWAYS, AS WELL AS CHANGES IN EPIGENETIC CONTROL OF GENE EXPRESSION. THIS REVIEW PROVIDES AN OVERVIEW OF THE PERTURBATIONS IN METABOLISM AND ROS HOMOEOSTASIS OF MPM CELLS AND THE ROLE OF THESE ALTERATIONS IN MALIGNANT TRANSFORMATION AND TUMOUR PROGRESSION. 2020 6 2751 26 EXPRESSION OF ACETYL-HISTONE H3 AND ACETYL-HISTONE H4 IN DORSAL ROOT GANGLION AND SPINAL DORSAL HORN IN RAT CHRONIC PAIN MODELS. AIMS: HISTONE ACETYLATION AND DEACETYLATION ARE TWO HISTONE POSTTRANSLATIONAL MODIFICATIONS THAT ARE USUALLY CONTROLLED BY HISTONE ACETYLTRANSFERASES (HATS) AND HISTONE DEACETYLASES (HDACS). ALTHOUGH HATS OR HDACS INHIBITORS COULD RELIEVE PAIN HYPERSENSITIVITIES IN CHRONIC PAIN ANIMAL MODELS, IT IS NOT CLEAR ON THE EXPRESSION OF GLOBAL HISTONE ACETYLATION IN THE DORSAL ROOT GANGLION (DRG) OR SPINAL DORSAL HORN IN CHRONIC PAIN CONDITIONS. MAIN METHODS: A SPINAL NERVE LIGATION (SNL)-INDUCED NEUROPATHIC PAIN MODEL AND A COMPLETE FREUND'S ADJUVANT (CFA)-INDUCED INFLAMMATORY PAIN MODEL IN RATS WERE USED TO EXAMINE THE EXPRESSION OF TOTAL ACETYL-HISTONE H3 (ACH3) AND TOTAL ACETYL-HISTONE H4 (ACH4) BY IMMUNOFLUORESCENCE OR WESTERN BLOT. KEY FINDINGS: ACH3 AND ACH4 NOT ONLY LOCALIZED IN NEURONAL NUCLEI, BUT ALSO IN NUCLEI OF GLIAL CELLS IN THE DRG. UNILATERAL SNL INDUCED THE INCREASE OF ACH3 AND ACH4 EXPRESSION IN THE INJURED LUMBAR 5 (L5) DRG, BUT NOT IN THE UNINJURED L5 DRG OR THE SPINAL DORSAL HORN, WHILE UNILATERAL INTRAPLANTAR INJECTION OF CFA INCREASED ACH3 AND ACH4 EXPRESSION IN THE IPSILATERAL L4/5 SPINAL DORSAL HORN, BUT NOT IN THE L4/5 DRG. SIGNIFICANCE: THESE RESULTS PROVIDE MORPHOLOGICAL EVIDENCE FOR GLOBAL HISTONE ACETYLATION EXPRESSION IN THE DRG AND SPINAL CORD AND INDICATE THE DIFFERENTIAL EXPRESSION IN THE DRG AND SPINAL DORSAL HORN IN DIFFERENT CHRONIC PAIN MODELS. MORE PRECISE EPIGENETIC MECHANISMS OF HISTONE ACETYLATION ON THE TARGET GENES NEED TO BE REVEALED. 2018 7 3657 27 INDUCTION AND RECOVERY OF CPG SITE SPECIFIC METHYLATION CHANGES IN HUMAN BRONCHIAL CELLS AFTER LONG-TERM EXPOSURE TO CARBON NANOTUBES AND ASBESTOS. INTRODUCTION: INHALATION OF ASBESTOS INDUCES LUNG CANCER VIA DIFFERENT CELLULAR MECHANISMS. TOGETHER WITH THE INCREASED PRODUCTION OF CARBON NANOTUBES (CNTS) GROWS THE CONCERN ABOUT ADVERSE EFFECTS ON THE LUNGS GIVEN THE SIMILARITIES WITH ASBESTOS. WHILE IT HAS BEEN ESTABLISHED THAT CNT AND ASBESTOS INDUCE EPIGENETIC ALTERATIONS, IT IS CURRENTLY NOT KNOWN WHETHER ALTERATIONS AT EPIGENETIC LEVEL REMAIN STABLE AFTER WITHDRAWAL OF THE EXPOSURE. IDENTIFICATION OF DNA METHYLATION CHANGES AFTER A LOW DOSE OF CNT AND ASBESTOS EXPOSURE AND RECOVERY CAN BE USEFUL TO DETERMINE THE FIBRE/PARTICLE TOXICITY AND ADVERSE OUTCOME. METHODS: HUMAN BRONCHIAL EPITHELIAL CELLS (16HBE) WERE TREATED WITH A LOW AND NON-CYTOTOXIC DOSE (0.25 MICROG/ML) OF MULTI-WALLED CARBON NANOTUBES (MWCNTS-NM400) OR SINGLE-WALLED CARBON NANOTUBES (SWCNTS-SRM2483) AND 0.05 MICROG/ML AMOSITE (BROWN) ASBESTOS FOR THE COURSE OF FOUR WEEKS (SUB-CHRONIC EXPOSURE). AFTER THIS TREATMENT, THE CELLS WERE FURTHER INCUBATED (WITHOUT PARTICLE/FIBRE) FOR TWO WEEKS, ALLOWING RECOVERY FROM THE EXPOSURE (RECOVERY PERIOD). NUCLEAR DEPOSITIONS OF THE CNTS WERE ASSESSED USING FEMTOSECOND PULSED LASER MICROSCOPY IN A LABEL-FREE MANNER. DNA METHYLATION ALTERATIONS WERE ANALYSED USING MICROARRAYS THAT ASSESS MORE THAN 850 THOUSAND CPG SITES IN THE WHOLE GENOME. RESULTS: AT NON-CYTOTOXIC DOSES, CNTS WERE NOTED TO BE INCORPORATED WITH IN THE NUCLEUS AFTER A FOUR WEEKS PERIOD. EXPOSURE TO MWCNTS INDUCED A SINGLE HYPOMETHYLATION AT A CPG SITE AND GENE PROMOTER REGION. NO CHANGE IN DNA METHYLATION WAS OBSERVED AFTER THE RECOVERY PERIOD FOR MWCNTS. EXPOSURE TO SWCNTS OR AMOSITE INDUCED HYPERMETHYLATION AT CPG SITES AFTER SUB-CHRONIC EXPOSURE WHICH MAY INVOLVE IN 'TRANSCRIPTION FACTOR ACTIVITY' AND 'SEQUENCE-SPECIFIC DNA BINDING' GENE ONTOLOGIES. AFTER THE RECOVERY PERIOD, HYPERMETHYLATION AND HYPOMETHYLATION WERE NOTED FOR BOTH SWCNTS AND AMOSITE. HIPPOCALCINLIKE 1 (HPCAL1), PROTEASE SERINE 3 (PRSS3), KALLIKREIN-RELATED PEPTIDASE 3 (KLK3), KRUPPEL LIKE FACTOR 3 (KLF3) GENES WERE HYPERMETHYLATED AT DIFFERENT TIME POINTS IN EITHER SWCNT-EXPOSED OR AMOSITE-EXPOSED CELLS. CONCLUSION: THESE RESULTS SUGGEST THAT THE SPECIFIC SWCNT (SRM2483) AND AMOSITE FIBRES STUDIED INDUCE HYPO- OR HYPERMETHYLATION ON CPG SITES IN DNA AFTER VERY LOW-DOSE EXPOSURE AND RECOVERY PERIOD. THIS EFFECT WAS NOT SEEN FOR THE STUDIED MWCNT (NM400). 2020 8 742 33 CANNABINOID CB2 RECEPTORS ARE UPREGULATED VIA BIVALENT HISTONE MODIFICATIONS AND CONTROL PRIMARY AFFERENT INPUT TO THE SPINAL CORD IN NEUROPATHIC PAIN. TYPE-2 CANNABINOID RECEPTORS (CB2, ENCODED BY THE CNR2 GENE) ARE MAINLY EXPRESSED IN IMMUNE CELLS, AND CB2 AGONISTS NORMALLY HAVE NO ANALGESIC EFFECT. HOWEVER, NERVE INJURY UPREGULATES CB2 IN THE DORSAL ROOT GANGLION (DRG), FOLLOWING WHICH CB2 STIMULATION REDUCES NEUROPATHIC PAIN. IT IS UNCLEAR HOW NERVE INJURY INCREASES CB2 EXPRESSION OR HOW CB2 ACTIVITY IS TRANSFORMED IN NEUROPATHIC PAIN. IN THIS STUDY, IMMUNOBLOTTING SHOWED THAT SPINAL NERVE LIGATION (SNL) INDUCED A DELAYED AND SUSTAINED INCREASE IN CB2 EXPRESSION IN THE DRG AND DORSAL SPINAL CORD SYNAPTOSOMES. RNASCOPE IN SITU HYBRIDIZATION ALSO SHOWED THAT SNL SUBSTANTIALLY INCREASED CB2 MRNA LEVELS, MOSTLY IN MEDIUM AND LARGE DRG NEURONS. FURTHERMORE, WE FOUND THAT THE SPECIFIC CB2 AGONIST JWH-133 SIGNIFICANTLY INHIBITS THE AMPLITUDE OF DORSAL ROOT-EVOKED GLUTAMATERGIC EXCITATORY POSTSYNAPTIC CURRENTS IN SPINAL DORSAL HORN NEURONS IN SNL RATS, BUT NOT IN SHAM CONTROL RATS; INTRATHECAL INJECTION OF JWH-133 REVERSED PAIN HYPERSENSITIVITY IN SNL RATS, BUT HAD NO EFFECT IN SHAM CONTROL RATS. IN ADDITION, CHROMATIN IMMUNOPRECIPITATION-QPCR ANALYSIS SHOWED THAT SNL INCREASED ENRICHMENT OF TWO ACTIVATING HISTONE MARKS (H3K4ME3 AND H3K9AC) AND DIMINISHED OCCUPANCY OF TWO REPRESSIVE HISTONE MARKS (H3K9ME2 AND H3K27ME3) AT THE CNR2 PROMOTER IN THE DRG. IN CONTRAST, SNL HAD NO EFFECT ON DNA METHYLATION LEVELS AROUND THE CNR2 PROMOTER. OUR FINDINGS SUGGEST THAT PERIPHERAL NERVE INJURY PROMOTES CB2 EXPRESSION IN PRIMARY SENSORY NEURONS VIA EPIGENETIC BIVALENT HISTONE MODIFICATIONS AND THAT CB2 ACTIVATION REDUCES NEUROPATHIC PAIN BY ATTENUATING NOCICEPTIVE TRANSMISSION FROM PRIMARY AFFERENT NERVES TO THE SPINAL CORD. 2022 9 3196 20 HDAC INHIBITORS RESTORE C-FIBRE SENSITIVITY IN EXPERIMENTAL NEUROPATHIC PAIN MODEL. BACKGROUND AND PURPOSE: HYPOESTHESIA IS A CLINICAL FEATURE OF NEUROPATHIC PAIN. THE FEATURE IS PARTLY EXPLAINED BY THE EVIDENCE OF EPIGENETIC REPRESSION OF NAV 1.8 SODIUM CHANNEL IN THE DORSAL ROOT GANGLION (DRG). EXPERIMENTAL APPROACH: WE INVESTIGATED THE POSSIBILITY OF TRICHOSTATIN A (TSA), VALPROIC ACID (VPA) AND SUBEROYLANILIDE HYDROXAMIC ACID (SAHA) TO REVERSE THE UNIQUE C-FIBRE SENSITIVITY OBSERVED FOLLOWING PARTIAL LIGATION OF SCIATIC NERVE IN MICE. KEY RESULTS: NERVE INJURY-INDUCED DOWN-REGULATION OF DRG NAV 1.8 SODIUM CHANNEL AND C-FIBRE-RELATED HYPOESTHESIA WERE REVERSED BY TSA, VPA AND SAHA TREATMENTS, WHICH INHIBIT HISTONE DEACETYLASE (HDAC), AND INCREASE HISTONE ACETYLATION AT THE REGULATORY SEQUENCE OF NAV 1.8. CONCLUSIONS AND IMPLICATIONS: TAKEN TOGETHER, THESE STUDIES PROVIDE THE EVIDENCE THAT HYPOESTHESIA AND UNDERLYING DOWN-REGULATION OF NAV 1.8, NEGATIVE SYMPTOMS OBSERVED IN NERVE INJURY-INDUCED NEUROPATHIC PAIN MODELS ARE REGULATED BY AN EPIGENETIC CHROMATIN REMODELLING THROUGH HDAC-RELATED MACHINERIES. 2013 10 1630 27 DNMT3A CONTRIBUTES TO THE DEVELOPMENT AND MAINTENANCE OF BONE CANCER PAIN BY SILENCING KV1.2 EXPRESSION IN SPINAL CORD DORSAL HORN. METASTATIC BONE TUMOR-INDUCED CHANGES IN GENE TRANSCRIPTION AND TRANSLATION IN PAIN-RELATED REGIONS OF THE NERVOUS SYSTEM MAY PARTICIPATE IN THE DEVELOPMENT AND MAINTENANCE OF BONE CANCER PAIN. EPIGENETIC MODIFICATIONS INCLUDING DNA METHYLATION REGULATE GENE TRANSCRIPTION. HERE, WE REPORT THAT INTRATHECAL INJECTION OF DECITABINE, A DNA METHYLTRANSFERASE (DNMT) INHIBITOR, DOSE DEPENDENTLY ATTENUATED THE DEVELOPMENT AND MAINTENANCE OF BONE CANCER PAIN INDUCED BY INJECTING PROSTATE CANCER CELLS INTO THE TIBIA. THE LEVEL OF THE DE NOVO DNMT3A, BUT NOT DNMT3B, TIME DEPENDENTLY INCREASED IN THE IPSILATERAL L4/5 DORSAL HORN (NOT L4/5 DORSAL ROOT GANGLION) AFTER PROSTATE CANCER CELLS INJECTION. BLOCKING THIS INCREASE THROUGH MICROINJECTION OF RECOMBINANT ADENO-ASSOCIATED VIRUS 5 (AAV5) EXPRESSING DNMT3A SHRNA INTO DORSAL HORN RESCUED PROSTATE CANCER CELLS-INDUCED DOWNREGULATION OF DORSAL HORN KV1.2 EXPRESSION AND IMPAIRED PROSTATE CANCER CELLS-INDUCED PAIN HYPERSENSITIVITY. IN TURN, MIMICKING THIS INCREASE THROUGH MICROINJECTION OF AAV5 EXPRESSING FULL-LENGTH DNMT3A INTO DORSAL HORN REDUCED DORSAL HORN KV1.2 EXPRESSION AND PRODUCED PAIN HYPERSENSITIVITY IN THE ABSENCE OF PROSTATE CANCER CELLS INJECTION. ADMINISTRATION OF NEITHER DECITABINE NOR VIRUS AFFECTED LOCOMOTOR FUNCTION AND ACUTE RESPONSES TO MECHANICAL, THERMAL, OR COLD STIMULI. GIVEN THAT DNMT3A MRNA IS CO-EXPRESSED WITH KCNA2 MRNA (ENCODING KV1.2) IN INDIVIDUAL DORSAL HORN NEURONS, OUR FINDINGS SUGGEST THAT INCREASED DORSAL HORN DNMT3A CONTRIBUTES TO BONE CANCER PAIN THROUGH SILENCING DORSAL HORN KV1.2 EXPRESSION. DNMT3A MAY REPRESENT A POTENTIAL NEW TARGET FOR CANCER PAIN MANAGEMENT. 2017 11 1654 22 DORSAL ROOT GANGLIA COACTIVATOR-ASSOCIATED ARGININE METHYLTRANSFERASE 1 CONTRIBUTES TO PERIPHERAL NERVE INJURY-INDUCED PAIN HYPERSENSITIVITIES. NEUROPATHIC PAIN IS ASSOCIATED WITH GENE EXPRESSION CHANGES WITHIN THE DORSAL ROOT GANGLION (DRG) AFTER PERIPHERAL NERVE INJURY, WHICH INVOLVES EPIGENETIC MECHANISMS. COACTIVATOR-ASSOCIATED ARGININE METHYLTRANSFERASE 1 (CARM1), AN EPIGENETIC ACTIVATOR, REGULATES GENE TRANSCRIPTIONAL ACTIVITY BY PROTEIN POSTTRANSLATIONAL MODIFICATIONS. HOWEVER, WHETHER CARM1 PLAYS AN ESSENTIAL ROLE IN THE DEVELOPMENT AND MAINTENANCE OF NEUROPATHIC PAIN IS UNKNOWN. WE REPORT HERE THAT PERIPHERAL NERVE INJURY INDUCED THE UPREGULATION OF THE MRNA AND PROTEIN EXPRESSION OF CARM1 IN THE INJURED DRG, AND BLOCKING ITS EXPRESSION THROUGH SMALL INTERFERING RNA (SIRNA) IN THE INJURED DRG ATTENUATED THE DEVELOPMENT AND MAINTENANCE OF NEUROPATHIC PAIN. FURTHERMORE, PHARMACOLOGICAL INHIBITION OF CARM1 MITIGATED PERIPHERAL NERVE INJURY-INDUCED MECHANICAL ALLODYNIA AND THERMAL HYPERALGESIA. GIVEN THAT CARM1 INHIBITION OR KNOCKDOWN ATTENUATED THE INDUCTION AND MAINTENANCE OF NEUROPATHIC PAIN AFTER PERIPHERAL NERVE INJURY, OUR FINDINGS SUGGEST THAT CARM1 MAY SERVE AS A PROMISING THERAPEUTIC TARGET FOR NEUROPATHIC PAIN TREATMENT IN CLINICAL APPLICATIONS. 2018 12 1220 22 CRISPR/CAS9-BASED MUTAGENESIS OF HISTONE H3.1 IN SPINAL DYNORPHINERGIC NEURONS ATTENUATES THERMAL SENSITIVITY IN MICE. BURN INJURY IS A TRAUMA RESULTING IN TISSUE DEGRADATION AND SEVERE PAIN, WHICH IS PROCESSED FIRST BY NEURONAL CIRCUITS IN THE SPINAL DORSAL HORN. WE HAVE RECENTLY SHOWN THAT IN MICE, EXCITATORY DYNORPHINERGIC (PDYN) NEURONS PLAY A PIVOTAL ROLE IN THE RESPONSE TO BURN-INJURY-ASSOCIATED TISSUE DAMAGE VIA HISTONE H3.1 PHOSPHORYLATION-DEPENDENT SIGNALING. AS PDYN NEURONS WERE MOSTLY ASSOCIATED WITH MECHANICAL ALLODYNIA, THEIR INVOLVEMENT IN THERMONOCICEPTION HAD TO BE FURTHER ELUCIDATED. USING A CUSTOM-MADE AAV9_MUTH3.1 VIRUS COMBINED WITH THE CRISPR/CAS9 SYSTEM, HERE WE PROVIDE EVIDENCE THAT BLOCKING HISTONE H3.1 PHOSPHORYLATION AT POSITION SERINE 10 (S10) IN SPINAL PDYN NEURONS SIGNIFICANTLY INCREASES THE THERMAL NOCICEPTIVE THRESHOLD IN MICE. IN CONTRAST, NEITHER MECHANOSENSATION NOR ACUTE CHEMONOCICEPTION WAS AFFECTED BY THE TRANSGENIC MANIPULATION OF HISTONE H3.1. THESE RESULTS SUGGEST THAT BLOCKING RAPID EPIGENETIC TAGGING OF S10H3 IN SPINAL PDYN NEURONS ALTERS ACUTE THERMOSENSATION AND THUS EXPLAINS THE INVOLVEMENT OF PDYN CELLS IN THE IMMEDIATE RESPONSE TO BURN-INJURY-ASSOCIATED TISSUE DAMAGE. 2022 13 4098 24 MBD1 CONTRIBUTES TO THE GENESIS OF ACUTE PAIN AND NEUROPATHIC PAIN BY EPIGENETIC SILENCING OF OPRM1 AND KCNA2 GENES IN PRIMARY SENSORY NEURONS. THE TRANSMISSION OF NORMAL SENSORY AND/OR ACUTE NOXIOUS INFORMATION REQUIRES INTACT EXPRESSION OF PAIN-ASSOCIATED GENES WITHIN THE PAIN PATHWAYS OF NERVOUS SYSTEM. EXPRESSIONAL CHANGES OF THESE GENES AFTER PERIPHERAL NERVE INJURY ARE ALSO CRITICAL FOR NEUROPATHIC PAIN INDUCTION AND MAINTENANCE. METHYL-CPG-BINDING DOMAIN PROTEIN 1 (MBD1), AN EPIGENETIC REPRESSOR, REGULATES GENE TRANSCRIPTIONAL ACTIVITY. WE REPORT HERE THAT MBD1 IN THE PRIMARY SENSORY NEURONS OF DRG IS CRITICAL FOR THE GENESIS OF ACUTE PAIN AND NEUROPATHIC PAIN AS DRG MBD1-DEFICIENT MICE EXHIBIT THE REDUCED RESPONSES TO ACUTE MECHANICAL, HEAT, COLD, AND CAPSAICIN STIMULI AND THE BLUNTED NERVE INJURY-INDUCED PAIN HYPERSENSITIVITIES. FURTHERMORE, DRG OVEREXPRESSION OF MBD1 LEADS TO SPONTANEOUS PAIN AND EVOKED PAIN HYPERSENSITIVITIES IN THE WT MICE AND RESTORES ACUTE PAIN SENSITIVITIES IN THE MBD1-DEFICIENT MICE. MECHANISTICALLY, MDB1 REPRESSES OPRM1 AND KCNA2 GENE EXPRESSION BY RECRUITING DNA METHYLTRANSFERASE DNMT3A INTO THESE TWO GENE PROMOTERS IN THE DRG NEURONS. DRG MBD1 IS LIKELY A KEY PLAYER UNDER THE CONDITIONS OF ACUTE PAIN AND NEUROPATHIC PAIN.SIGNIFICANCE STATEMENT IN THE PRESENT STUDY, WE REVEALED THAT THE MICE WITH DEFICIENCY OF METHYL-CPG-BINDING DOMAIN PROTEIN 1 (MBD1), AN EPIGENETIC REPRESSOR, IN THE DRG DISPLAYED THE REDUCED RESPONSES TO ACUTE NOXIOUS STIMULI AND THE BLUNTED NEUROPATHIC PAIN. WE ALSO SHOWED THAT DRG OVEREXPRESSION OF MBD1 PRODUCED THE HYPERSENSITIVITIES TO NOXIOUS STIMULI IN THE WT MICE AND RESCUED ACUTE PAIN SENSITIVITIES IN THE MBD1-DEFICIENT MICE. WE HAVE ALSO PROVIDED THE EVIDENCE THAT MDB1 REPRESSES OPRM1 AND KCNA2 GENE EXPRESSION BY RECRUITING DNA METHYLTRANSFERASE DNMT3A INTO THESE TWO GENE PROMOTERS IN THE DRG NEURONS. DRG MBD1 MAY PARTICIPATE IN THE GENESIS OF ACUTE PAIN AND NEUROPATHIC PAIN LIKELY THROUGH REGULATING DNMT3A-CONTROLLED OPRM1 AND KCNA2 GENE EXPRESSION IN THE DRG NEURONS. 2018 14 4615 28 NERVE INJURY DIMINISHES OPIOID ANALGESIA THROUGH LYSINE METHYLTRANSFERASE-MEDIATED TRANSCRIPTIONAL REPRESSION OF MU-OPIOID RECEPTORS IN PRIMARY SENSORY NEURONS. THE MU-OPIOID RECEPTOR (MOR, ENCODED BY OPRM1) AGONISTS ARE THE MAINSTAY ANALGESICS FOR TREATING MODERATE TO SEVERE PAIN. NERVE INJURY CAUSES DOWN-REGULATION OF MORS IN THE DORSAL ROOT GANGLION (DRG) AND DIMINISHES THE OPIOID EFFECT ON NEUROPATHIC PAIN. HOWEVER, THE EPIGENETIC MECHANISMS UNDERLYING THE DIMINISHED MOR EXPRESSION CAUSED BY NERVE INJURY ARE NOT CLEAR. G9A (ENCODED BY EHMT2), A HISTONE 3 AT LYSINE 9 METHYLTRANSFERASE, IS A KEY CHROMATIN REGULATOR RESPONSIBLE FOR GENE SILENCING. IN THIS STUDY, WE DETERMINED THE ROLE OF G9A IN DIMINISHED MOR EXPRESSION AND OPIOID ANALGESIC EFFECTS IN ANIMAL MODELS OF NEUROPATHIC PAIN. WE FOUND THAT NERVE INJURY IN RATS INDUCED A LONG-LASTING REDUCTION IN THE EXPRESSION LEVEL OF MORS IN THE DRG BUT NOT IN THE SPINAL CORD. NERVE INJURY CONSISTENTLY INCREASED THE ENRICHMENT OF THE G9A PRODUCT HISTONE 3 AT LYSINE 9 DIMETHYLATION IN THE PROMOTER OF OPRM1 IN THE DRG. G9A INHIBITION OR SIRNA KNOCKDOWN FULLY REVERSED MOR EXPRESSION IN THE INJURED DRG AND POTENTIATED THE MORPHINE EFFECT ON PAIN HYPERSENSITIVITY INDUCED BY NERVE INJURY. IN MICE LACKING EHMT2 IN DRG NEURONS, NERVE INJURY FAILED TO REDUCE THE EXPRESSION LEVEL OF MORS AND THE MORPHINE EFFECT. IN ADDITION, G9A INHIBITION OR EHMT2 KNOCKOUT IN DRG NEURONS NORMALIZED NERVE INJURY-INDUCED REDUCTION IN THE INHIBITORY EFFECT OF THE OPIOID ON SYNAPTIC GLUTAMATE RELEASE FROM PRIMARY AFFERENT NERVES. OUR FINDINGS INDICATE THAT G9A CONTRIBUTES CRITICALLY TO TRANSCRIPTIONAL REPRESSION OF MORS IN PRIMARY SENSORY NEURONS IN NEUROPATHIC PAIN. G9A INHIBITORS MAY BE USED TO ENHANCE THE OPIOID ANALGESIC EFFECT IN THE TREATMENT OF CHRONIC NEUROPATHIC PAIN. 2016 15 1167 25 CONTRIBUTION OF DORSAL ROOT GANGLION OCTAMER TRANSCRIPTION FACTOR 1 TO NEUROPATHIC PAIN AFTER PERIPHERAL NERVE INJURY. NEUROPATHIC PAIN GENESIS IS RELATED TO GENE ALTERATIONS IN THE DORSAL ROOT GANGLION (DRG) AFTER PERIPHERAL NERVE INJURY. TRANSCRIPTION FACTORS CONTROL GENE EXPRESSION. IN THIS STUDY, WE INVESTIGATED WHETHER OCTAMER TRANSCRIPTION FACTOR 1 (OCT1), A TRANSCRIPTION FACTOR, CONTRIBUTED TO NEUROPATHIC PAIN CAUSED BY CHRONIC CONSTRICTION INJURY (CCI) OF THE SCIATIC NERVE. CHRONIC CONSTRICTION INJURY PRODUCED A TIME-DEPENDENT INCREASE IN THE LEVEL OF OCT1 PROTEIN IN THE IPSILATERAL L4/5 DRG, BUT NOT IN THE SPINAL CORD. BLOCKING THIS INCREASE THROUGH MICROINJECTION OF OCT1 SIRNA INTO THE IPSILATERAL L4/5 DRG ATTENUATED THE INITIATION AND MAINTENANCE OF CCI-INDUCED MECHANICAL ALLODYNIA, HEAT HYPERALGESIA, AND COLD ALLODYNIA AND IMPROVED MORPHINE ANALGESIA AFTER CCI, WITHOUT AFFECTING BASAL RESPONSES TO ACUTE MECHANICAL, HEAT, AND COLD STIMULI AS WELL AS LOCOMOTOR FUNCTIONS. MIMICKING THIS INCREASE THROUGH MICROINJECTION OF RECOMBINANT ADENO-ASSOCIATED VIRUS 5 HARBORING FULL-LENGTH OCT1 INTO THE UNILATERAL L4/5 DRG LED TO MARKED MECHANICAL ALLODYNIA, HEAT HYPERALGESIA, AND COLD ALLODYNIA IN NAIVE RATS. MECHANISTICALLY, OCT1 PARTICIPATED IN CCI-INDUCED INCREASES IN DNMT3A MRNA AND ITS PROTEIN AND DNMT3A-MEDIATED DECREASES IN OPRM1 AND KCNA2 MRNAS AND THEIR PROTEINS IN THE INJURED DRG. THESE FINDINGS INDICATE THAT OCT1 MAY PARTICIPATE IN NEUROPATHIC PAIN AT LEAST IN PART BY TRANSCRIPTIONALLY ACTIVATING DNMT3A AND SUBSEQUENTLY EPIGENETIC SILENCING OF OPRM1 AND KCAN2 IN THE DRG. OCT1 MAY SERVE AS A POTENTIAL TARGET FOR THERAPEUTIC TREATMENTS AGAINST NEUROPATHIC PAIN. 2019 16 3154 19 GLUN2B/CAMKII MEDIATES CFA-INDUCED HYPERALGESIA VIA HDAC4-MODIFIED SPINAL COX2 TRANSCRIPTION. HISTONE DEACETYLASE 4 (HDAC4), WHICH ACTIVELY SHUTTLES BETWEEN THE NUCLEUS AND CYTOPLASM, IS AN ATTRACTIVE CANDIDATE FOR A REPRESSOR MECHANISM IN EPIGENETIC MODIFICATION. HOWEVER, THE POTENTIAL ROLE OF HDAC4-DEPENDENT EPIGENETICS IN THE NEURAL PLASTICITY UNDERLYING THE DEVELOPMENT OF INFLAMMATORY PAIN HAS NOT BEEN WELL ESTABLISHED. BY INJECTING COMPLETE FREUND'S ADJUVANT (CFA) INTO THE HIND-PAW OF SPRAGUE-DAWLEY RATS (200-250 G), WE FOUND ANIMALS DISPLAYED BEHAVIORAL HYPERALGESIA WAS ACCOMPANIED WITH HDAC4 PHOSPHORYLATION AND CYTOPLASMIC REDISTRIBUTION IN THE DORSAL HORN NEURONS. CYTOPLASMIC HDAC4 RETENTION LED TO ITS UNCOUPLING WITH THE COX2 PROMOTER, HENCE PROMPTING SPINAL COX2 TRANSCRIPTION AND EXPRESSION IN THE DORSAL HORN. MOREOVER, THE GLUN2B-BEARING N-METHYL-D-ASPARTATE RECEPTOR (GLUN2B-NMDAR)/CALMODULIN-DEPENDENT PROTEIN KINASE II (CAMKII) ACTED AS AN UPSTREAM CASCADE TO FACILITATE HDAC4 PHOSPHORYLATION/REDISTRIBUTION-ASSOCIATED SPINAL COX2 EXPRESSION AFTER INFLAMMATORY INSULTS. THE RESULTS OF THIS PILOT STUDY DEMONSTRATED THAT THE DEVELOPMENT AND/OR MAINTENANCE OF INFLAMMATORY PAIN INVOLVED THE SPINAL HDAC4-DEPENDENT EPIGENETIC MECHANISMS. OUR FINDINGS OPEN UP A NEW AVENUE FOR THE DEVELOPMENT OF A NOVEL MEDICAL STRATEGY FOR THE RELIEF OF INFLAMMATORY PAIN. 2018 17 4577 24 MYOSTATIN: BASIC BIOLOGY TO CLINICAL APPLICATION. MYOSTATIN IS A MEMBER OF THE TRANSFORMING GROWTH FACTOR (TGF)-BETA SUPERFAMILY. IT IS EXPRESSED BY ANIMAL AND HUMAN SKELETAL MUSCLE CELLS WHERE IT LIMITS MUSCLE GROWTH AND PROMOTES PROTEIN BREAKDOWN. ITS EFFECTS ARE INFLUENCED BY COMPLEX MECHANISMS INCLUDING TRANSCRIPTIONAL AND EPIGENETIC REGULATION AND MODULATION BY EXTRACELLULAR BINDING PROTEINS. DUE TO ITS ACTIONS IN PROMOTING MUSCLE ATROPHY AND CACHEXIA, MYOSTATIN HAS BEEN INVESTIGATED AS A PROMISING THERAPEUTIC TARGET TO COUNTERACT MUSCLE MASS LOSS IN EXPERIMENTAL MODELS AND PATIENTS AFFECTED BY DIFFERENT MUSCLE-WASTING CONDITIONS. MOREOVER, GROWING EVIDENCE INDICATES THAT MYOSTATIN, BEYOND TO REGULATE SKELETAL MUSCLE GROWTH, MAY HAVE A ROLE IN MANY PHYSIOLOGIC AND PATHOLOGIC PROCESSES, SUCH AS OBESITY, INSULIN RESISTANCE, CARDIOVASCULAR AND CHRONIC KIDNEY DISEASE. IN THIS CHAPTER, WE REVIEW MYOSTATIN BIOLOGY, INCLUDING INTRACELLULAR AND EXTRACELLULAR REGULATORY PATHWAYS, AND THE ROLE OF MYOSTATIN IN MODULATING PHYSIOLOGIC PROCESSES, SUCH AS MUSCLE GROWTH AND AGING. MOREOVER, WE DISCUSS THE MOST RELEVANT EXPERIMENTAL AND CLINICAL EVIDENCE SUPPORTING THE EXTRA-MUSCLE EFFECTS OF MYOSTATIN. FINALLY, WE CONSIDER THE MAIN STRATEGIES DEVELOPED AND TESTED TO INHIBIT MYOSTATIN IN CLINICAL TRIALS AND DISCUSS THE LIMITS AND FUTURE PERSPECTIVES OF THE RESEARCH ON MYOSTATIN. 2022 18 1166 25 CONTRIBUTION OF DNMT1 TO NEUROPATHIC PAIN GENESIS PARTIALLY THROUGH EPIGENETICALLY REPRESSING KCNA2 IN PRIMARY AFFERENT NEURONS. EXPRESSIONAL CHANGES OF PAIN-ASSOCIATED GENES IN PRIMARY SENSORY NEURONS OF DRG ARE CRITICAL FOR NEUROPATHIC PAIN GENESIS. DNA METHYLTRANSFERASE (DNMT)-TRIGGERED DNA METHYLATION SILENCES GENE EXPRESSION. WE SHOW HERE THAT DNMT1, A CANONICAL MAINTENANCE METHYLTRANSFERASE, ACTS AS THE DE NOVO DNMT AND IS REQUIRED FOR NEUROPATHIC PAIN GENESIS LIKELY THROUGH REPRESSING AT LEAST DRG KCNA2 GENE EXPRESSION IN MALE MICE. PERIPHERAL NERVE INJURY UPREGULATED DNMT1 EXPRESSION IN THE INJURED DRG THROUGH THE TRANSCRIPTION FACTOR CAMP RESPONSE ELEMENT BINDING PROTEIN-TRIGGERED TRANSCRIPTIONAL ACTIVATION OF DNMT1 GENE. BLOCKING THIS UPREGULATION PREVENTED NERVE INJURY-INDUCED DNA METHYLATION WITHIN THE PROMOTER AND 5'-UNTRANSLATED REGION OF KCNA2 GENE, RESCUED KCNA2 EXPRESSION AND TOTAL KV CURRENT, ATTENUATED HYPEREXCITABILITY IN THE INJURED DRG NEURONS, AND ALLEVIATED NERVE INJURY-INDUCED PAIN HYPERSENSITIVITIES. GIVEN THAT KCNA2 IS A KEY PLAYER IN NEUROPATHIC PAIN, OUR FINDINGS SUGGEST THAT DRG DNMT1 MAY BE A POTENTIAL TARGET FOR NEUROPATHIC PAIN MANAGEMENT.SIGNIFICANCE STATEMENT IN THE PRESENT STUDY, WE REPORTED THAT DNMT1, A CANONICAL DNA MAINTENANCE METHYLTRANSFERASE, IS UPREGULATED VIA THE ACTIVATION OF THE TRANSCRIPTION FACTOR CREB IN THE INJURED DRG AFTER PERIPHERAL NERVE INJURY. THIS UPREGULATION WAS RESPONSIBLE FOR NERVE INJURY-INDUCED DE NOVO DNA METHYLATION WITHIN THE PROMOTER AND 5'-UNTRANSLATED REGION OF THE KCNA2 GENE, REDUCTIONS IN KCNA2 EXPRESSION AND KV CURRENT AND INCREASES IN NEURONAL EXCITABILITY IN THE INJURED DRG. SINCE PHARMACOLOGICAL INHIBITION OR GENETIC KNOCKDOWN OF DRG DNMT1 ALLEVIATED NERVE INJURY-INDUCED PAIN HYPERSENSITIVITIES, DRG DNMT1 CONTRIBUTES TO NEUROPATHIC PAIN GENESIS PARTIALLY THROUGH REPRESSION OF DRG KCNA2 GENE EXPRESSION. 2019 19 2885 22 G9A PARTICIPATES IN NERVE INJURY-INDUCED KCNA2 DOWNREGULATION IN PRIMARY SENSORY NEURONS. NERVE INJURY-INDUCED DOWNREGULATION OF VOLTAGE-GATED POTASSIUM CHANNEL SUBUNIT KCNA2 IN THE DORSAL ROOT GANGLION (DRG) IS CRITICAL FOR DRG NEURONAL EXCITABILITY AND NEUROPATHIC PAIN GENESIS. HOWEVER, HOW NERVE INJURY CAUSES THIS DOWNREGULATION IS STILL ELUSIVE. EUCHROMATIC HISTONE-LYSINE N-METHYLTRANSFERASE 2, ALSO KNOWN AS G9A, METHYLATES HISTONE H3 ON LYSINE RESIDUE 9 TO PREDOMINANTLY PRODUCE A DYNAMIC HISTONE DIMETHYLATION, RESULTING IN CONDENSED CHROMATIN AND GENE TRANSCRIPTIONAL REPRESSION. WE SHOWED HERE THAT BLOCKING NERVE INJURY-INDUCED INCREASE IN G9A RESCUED KCNA2 MRNA AND PROTEIN EXPRESSION IN THE AXOTOMIZED DRG AND ATTENUATED THE DEVELOPMENT OF NERVE INJURY-INDUCED PAIN HYPERSENSITIVITY. MIMICKING THIS INCREASE DECREASED KCNA2 MRNA AND PROTEIN EXPRESSION, REDUCED KV CURRENT, AND INCREASED EXCITABILITY IN THE DRG NEURONS AND LED TO SPINAL CORD CENTRAL SENSITIZATION AND NEUROPATHIC PAIN-LIKE SYMPTOMS. G9A MRNA IS CO-LOCALIZED WITH KCNA2 MRNA IN THE DRG NEURONS. THESE FINDINGS INDICATE THAT G9A CONTRIBUTES TO NEUROPATHIC PAIN DEVELOPMENT THROUGH EPIGENETIC SILENCING OF KCNA2 IN THE AXOTOMIZED DRG. 2016 20 5574 24 ROLE OF MICRORNA-143 IN NERVE INJURY-INDUCED UPREGULATION OF DNMT3A EXPRESSION IN PRIMARY SENSORY NEURONS. PERIPHERAL NERVE INJURY INCREASED THE EXPRESSION OF THE DNA METHYLTRANSFERASE 3A (DNMT3A) MRNA AND ITS ENCODING DNMT3A PROTEIN IN INJURED DORSAL ROOT GANGLIA (DRG). THIS INCREASE IS CONSIDERED AS AN ENDOGENOUS INSTIGATOR IN NEUROPATHIC PAIN GENESIS THROUGH EPIGENETIC SILENCING OF PAIN-ASSOCIATED GENES (SUCH AS OPRM1) IN INJURED DRG. HOWEVER, HOW DRG DNMT3A IS INCREASED FOLLOWING PERIPHERAL NERVE INJURY IS STILL ELUSIVE. WE REPORTED HERE THAT PERIPHERAL NERVE INJURY CAUSED BY THE FIFTH SPINAL NERVE LIGATION (SNL) DOWNREGULATED MICRORNA (MIR)-143 EXPRESSION IN INJURED DRG. THIS DOWNREGULATION WAS REQUIRED FOR SNL-INDUCED DRG DNMT3A INCREASE AS RESCUING MIR-143 DOWNREGULATION THROUGH MICROINJECTION OF MIR-143 MIMICS INTO INJURED DRG BLOCKED THE SNL-INDUCED INCREASE IN DNMT3A AND RESTORED THE SNL-INDUCED DECREASES IN OPRM1 MRNA AND ITS ENCODING MU OPIOID RECEPTOR (MOR) IN INJURED DRG, IMPAIRED SPINAL CORD CENTRAL SENSITIZATION AND NEUROPATHIC PAIN, AND IMPROVED MORPHINE ANALGESIC EFFECTS FOLLOWING SNL. MIMICKING SNL-INDUCED DRG MIR-143 DOWNREGULATION THROUGH DRG MICROINJECTION OF MIR143 INHIBITORS IN NAIVE RATS INCREASED THE EXPRESSION OF DNMT3A AND REDUCED THE EXPRESSION OF OPRM1 MRNA AND MOR IN INJECTED DRG AND PRODUCED NEUROPATHIC PAIN-LIKE SYMPTOMS. THESE FINDINGS SUGGEST THAT MIR-143 IS A NEGATIVE REGULATOR IN DNMT3A EXPRESSION IN THE DRG UNDER NEUROPATHIC PAIN CONDITIONS AND MAY BE A POTENTIAL TARGET FOR THERAPEUTIC MANAGEMENT OF NEUROPATHIC PAIN. 2017