1 5599 154 ROLES OF THE NEURON-RESTRICTIVE SILENCER FACTOR IN THE PATHOPHYSIOLOGICAL PROCESS OF THE CENTRAL NERVOUS SYSTEM. THE NEURON-RESTRICTIVE SILENCER FACTOR (NRSF), ALSO KNOWN AS REPRESSOR ELEMENT 1 (RE-1) SILENCING TRANSCRIPTION FACTOR (REST) OR X2 BOX REPRESSOR (XBR), IS A ZINC FINGER TRANSCRIPTION FACTOR THAT IS WIDELY EXPRESSED IN NEURONAL AND NON-NEURONAL CELLS. IT IS A MASTER REGULATOR OF THE NERVOUS SYSTEM, AND THE FUNCTION OF NRSF IS THE BASIS OF NEURONAL DIFFERENTIATION, DIVERSITY, PLASTICITY, AND SURVIVAL. NRSF CAN BIND TO THE NEURON-RESTRICTIVE SILENCER ELEMENT (NRSE), RECRUIT SOME CO-REPRESSORS, AND THEN INHIBIT TRANSCRIPTION OF NRSE DOWNSTREAM GENES THROUGH EPIGENETIC MECHANISMS. IN NEUROGENESIS, NRSF FUNCTIONS NOT ONLY AS A TRANSCRIPTIONAL SILENCER THAT CAN MEDIATE THE TRANSCRIPTIONAL INHIBITION OF NEURON-SPECIFIC GENES IN NON-NEURONAL CELLS AND THUS GIVE NEURON CELLS SPECIFICITY, BUT ALSO AS A TRANSCRIPTIONAL ACTIVATOR TO INDUCE NEURONAL DIFFERENTIATION. MANY STUDIES HAVE CONFIRMED THE ASSOCIATION BETWEEN NRSF AND BRAIN DISORDERS, SUCH AS BRAIN INJURY AND NEURODEGENERATIVE DISEASES. OVEREXPRESSION, UNDEREXPRESSION, OR MUTATION MAY LEAD TO NEUROLOGICAL DISORDERS. IN TUMORIGENESIS, NRSF FUNCTIONS AS AN ONCOGENE IN NEURONAL TUMORS, SUCH AS NEUROBLASTOMAS, MEDULLOBLASTOMAS, AND PHEOCHROMOCYTOMAS, STIMULATING THEIR PROLIFERATION, WHICH RESULTS IN POOR PROGNOSIS. ADDITIONALLY, NRSF-MEDIATED SELECTIVE TARGETS GENE REPRESSION PLAYS AN IMPORTANT ROLE IN THE DEVELOPMENT AND MAINTENANCE OF NEUROPATHIC PAIN CAUSED BY NERVE INJURY, CANCER, AND DIABETES. AT PRESENT, SEVERAL COMPOUNDS THAT TARGET NRSF OR ITS CO-REPRESSORS, SUCH AS REST-VP16 AND X5050, HAVE BEEN SHOWN TO BE CLINICALLY EFFECTIVE AGAINST MANY BRAIN DISEASES, SUCH AS SEIZURES, IMPLYING THAT NRSF AND ITS CO-REPRESSORS MAY BE POTENTIAL AND PROMISING THERAPEUTIC TARGETS FOR NEURAL DISORDERS. IN THE PRESENT REVIEW, WE INTRODUCED THE BIOLOGICAL CHARACTERISTICS OF NRSF; REVIEWED THE PROGRESS TO DATE IN UNDERSTANDING THE ROLES OF NRSF IN THE PATHOPHYSIOLOGICAL PROCESSES OF THE NERVOUS SYSTEM, SUCH AS NEUROGENESIS, BRAIN DISORDERS, NEURAL TUMORIGENESIS, AND NEUROPATHIC PAIN; AND SUGGESTED NEW THERAPEUTIC APPROACHES TO SUCH BRAIN DISEASES. 2022 2 4765 62 NRSF AND ITS EPIGENETIC EFFECTORS: NEW TREATMENTS FOR NEUROLOGICAL DISEASE. THE NEURON RESTRICTIVE SILENCER FACTOR (NRSF) IS THE WELL-KNOWN MASTER TRANSCRIPTIONAL REPRESSOR OF THE NEURONAL PHENOTYPE. RESEARCH TO DATE HAS SHOWN THAT IT IS AN IMPORTANT PLAYER IN THE GROWTH AND DEVELOPMENT OF THE NERVOUS SYSTEM. ITS ROLE IN THE MATURATION OF NEURAL PRECURSOR CELLS TO ADULT NEURONS HAS BEEN WELL CHARACTERIZED IN STEM CELL MODELS. WHILE MUCH HAS BEEN CHARACTERIZED FROM A DEVELOPMENTAL PERSPECTIVE, RESEARCH IS REVEALING THAT NRSF PLAYS A ROLE IN VARIOUS NEUROLOGICAL DISEASES, RANGING FROM NEURODEGENERATIVE, NEUROPSYCHIATRIC, TO CANCER. DYSREGULATION OF NRSF ACTIVITY DISRUPTS DOWNSTREAM GENE EXPRESSION THAT IS RESPONSIBLE FOR NEURONAL CELL HOMEOSTASIS IN SEVERAL MODELS THAT CONTRIBUTE TO PATHOLOGIC STATES. INTERESTINGLY, IT IS NOW BECOMING APPARENT THAT THE DYSREGULATION OF NRSF CONTRIBUTES TO NEUROLOGICAL DISEASE THROUGH EPIGENETIC MECHANISMS. ALTHOUGH NRSF ITSELF IS A TRANSCRIPTION FACTOR, ITS MAJOR EFFECTORS ARE CHROMATIN MODIFIERS. AT THE LEVEL OF EPIGENETICS, CHANGES IN NRSF ACTIVITY HAVE BEEN WELL CHARACTERIZED IN MODELS OF NEUROPATHIC PAIN AND EPILEPSY. BETTER UNDERSTANDING OF THE EPIGENETIC BASIS OF BRAIN DISEASES HAS LED TO DESIGN AND USE OF SMALL MOLECULES THAT CAN PREVENT NRSF FROM REPRESSING GENE EXPRESSION BY NEUTRALIZING ITS INTERACTIONS WITH ITS CHROMATIN REMODELERS. THIS REVIEW WILL ADDRESS THE BASIC FUNCTION OF NRSF AND ITS COFACTORS, INVESTIGATE THEIR MECHANISMS, THEN EXPLORE HOW THEIR DYSFUNCTION CAN CAUSE DISEASE STATES. THIS REVIEW WILL ALSO ADDRESS RESEARCH ON NRSF AS A THERAPEUTIC TARGET AND DELVE INTO NEW THERAPEUTIC STRATEGIES THAT FOCUS ON DISRUPTING NRSF'S ABILITY TO RECRUIT CHROMATIN REMODELERS. 2018 3 6226 21 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 4 2176 32 EPIGENETIC MECHANISMS OF CHRONIC PAIN. NEUROPATHIC AND INFLAMMATORY PAIN PROMOTE A LARGE NUMBER OF PERSISTING ADAPTATIONS AT THE CELLULAR AND MOLECULAR LEVEL, ALLOWING EVEN TRANSIENT TISSUE OR NERVE DAMAGE TO ELICIT CHANGES IN CELLS THAT CONTRIBUTE TO THE DEVELOPMENT OF CHRONIC PAIN AND ASSOCIATED SYMPTOMS. THERE IS EVIDENCE THAT INJURY-INDUCED CHANGES IN CHROMATIN STRUCTURE DRIVE STABLE CHANGES IN GENE EXPRESSION AND NEURAL FUNCTION, WHICH MAY CAUSE SEVERAL SYMPTOMS, INCLUDING ALLODYNIA, HYPERALGESIA, ANXIETY, AND DEPRESSION. RECENT FINDINGS ON EPIGENETIC CHANGES IN THE SPINAL CORD AND BRAIN DURING CHRONIC PAIN MAY GUIDE FUNDAMENTAL ADVANCES IN NEW TREATMENTS. HERE, WE PROVIDE A BRIEF OVERVIEW OF EPIGENETIC REGULATION IN THE NERVOUS SYSTEM AND THEN DISCUSS THE STILL-LIMITED LITERATURE THAT DIRECTLY IMPLICATES EPIGENETIC MODIFICATIONS IN CHRONIC PAIN SYNDROMES. 2015 5 6895 31 [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 6 6130 33 THE EPIGENETIC REGULATION OF THE OPIOID SYSTEM: NEW INDIVIDUALIZED PROMPT PREVENTION AND TREATMENT STRATEGIES. THE MOST WELL-KNOWN PHYSIOLOGICAL EFFECT ASSOCIATED WITH OPIOD SYSTEM IS THEIR EFFICACY IN PAIN REDUCTION OR ANALGESIA, ALTHOUGH THEIR EFFECT ON A VARIETY OF OTHER PHYSIOLOGICAL AND PHYSIOPHOLOGICAL FUNCTIONS HAS BECOME APPARENT IN RECENT YEARS. THIS REVIEW IS AN ATTEMPT TO CLARIFY IN MORE DETAIL THE EPIGENETIC REGULATION OF OPIOID SYSTEM TO UNDERSTAND WITH MORE PRECISION THEIR TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL REGULATION IN MULTIPLE PYISIOLOGICAL AND PHARMACOLOGICAL CONTEXTS. THE OPIOID RECEPTORS SHOW AN EPIGENETIC REGULATION AND OPIOID PEPTIDE PRECURSORS BY METHYLATION, CHROMATIN REMODELING AND MICRORNA. ALTHOUGH THE OPIOID RECEPTOR PROMOTERS HAVE SIMILARITY BETWEEN THEM, THEY USE DIFFERENT EPIGENETIC REGULATION FORMS AND THEY EXHIBIT DIFFERENT PATTERN OF EXPRESSION DURING THE CELL DIFFERENTIATION. DNA METHYLATION IS ALSO CONFIRMED IN OPIOID PEPTIDE PRECURSORS, BEING IMPORTANT FOR GENE EXPRESSION AND TISSUE SPECIFICITY. UNDERSTANDING THE EPIGENETIC BASIS OF THOSE PHYSIOLOGICAL AND PHYSIOPATHOLOGICAL PROCESESS IS ESSENTIAL FOR THE DEVELOPMENT OF INDIVIDUALIZED PROMPT PREVENTION AND TREATMENT STRATEGIES. 2015 7 2199 31 EPIGENETIC MODIFICATION OF DRG NEURONAL GENE EXPRESSION SUBSEQUENT TO NERVE INJURY: ETIOLOGICAL CONTRIBUTION TO COMPLEX REGIONAL PAIN SYNDROMES (PART II). CUMULATING EVIDENCE INDICATED THAT NERVE INJURY-ASSOCIATED CELLULAR AND MOLECULAR CHANGES PLAY AN ESSENTIAL ROLE IN CONTRIBUTING TO THE DEVELOPMENT OF PATHOLOGICAL PAIN, AND MORE RECENT FINDINGS IMPLICATED THE CRITICAL ROLE OF EPIGENETIC MECHANISMS IN PAIN-RELATED SENSITIZATION IN THE DRG SUBSEQUENT TO NERVE INJURY. IN THIS PART OF THE DYAD REVIEW (PART II), WE REVIEWED AND PAID SPECIAL ATTENTION ON THE ETIOLOGICAL CONTRIBUTION OF DGR GENE EXPRESSION MODULATED BY EPIGENETIC MECHANISMS OF CRPS. AS ESSENTIAL EFFECTORS TO DIFFERENT MOLECULAR ACTIVATION, WE FIRST DISCUSSED THE ACTIVATION OF VARIOUS SIGNALING PATHWAYS THAT SUBSEQUENTLY FROM NERVE INJURY, AND IN FURTHER ILLUSTRATED THE FUNDAMENTAL AND FUNCTIONAL UNDERPINNINGS OF NERVE INJURY-INDUCED PAIN, IN WHICH WE ARGUED FOR THE POTENTIAL EPIGENETIC MECHANISMS IN RESPONSE TO SENSITIZING STIMULI OR INJURY. THEREFORE, UNDERSTANDING THE SPECIFIC MEDIATING FACTORS THAT INFLUENCE INDIVIDUAL EPIGENETIC DIFFERENCES CONTRIBUTING TO PAIN SENSITIVITY AND RESPONSIVENESS TO ANALGESICS POSSESSES CRUCIAL CLINICAL IMPLICATIONS. 2014 8 4861 36 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 9 5626 42 SELECTIVE REPRESSION OF GENE EXPRESSION IN NEUROPATHIC PAIN BY THE NEURON-RESTRICTIVE SILENCING FACTOR/REPRESSOR ELEMENT-1 SILENCING TRANSCRIPTION (NRSF/REST). NEUROPATHIC PAIN OFTEN DEVELOPS FOLLOWING NERVE INJURY AS A RESULT OF MALADAPTIVE CHANGES THAT OCCUR IN THE INJURED NERVE AND ALONG THE NOCICEPTIVE PATHWAYS OF THE PERIPHERAL AND CENTRAL NERVOUS SYSTEMS. MULTIPLE CELLULAR AND MOLECULAR MECHANISMS LIKELY ACCOUNT FOR THESE CHANGES; HOWEVER, THE EXACT NATURE OF THESE MECHANISMS REMAIN LARGELY UNKNOWN. A GROWING NUMBER OF STUDIES SUGGEST THAT ALTERATION IN GENE EXPRESSION IS AN IMPORTANT STEP IN THE PROGRESSION FROM ACUTE TO CHRONIC PAIN STATES AND EPIGENETIC REGULATION HAS BEEN PROPOSED TO DRIVE THIS CHANGE IN GENE EXPRESSION. IN THIS REVIEW, WE DISCUSS RECENT EVIDENCE THAT THE DNA-BINDING PROTEIN NEURON-RESTRICTIVE SILENCING FACTOR/REPRESSOR ELEMENT-1 SILENCING TRANSCRIPTION FACTOR (NRSF/REST) IS AN IMPORTANT COMPONENT IN THE DEVELOPMENT AND MAINTENANCE OF NEUROPATHIC PAIN THROUGH ITS ROLE AS A TRANSCRIPTIONAL REGULATOR FOR A SELECT SUBSET OF GENES THAT IT NORMALLY REPRESSES DURING DEVELOPMENT. 2016 10 980 29 CHRONIC PAIN: EMERGING EVIDENCE FOR THE INVOLVEMENT OF EPIGENETICS. EPIGENETIC PROCESSES, SUCH AS HISTONE MODIFICATIONS AND DNA METHYLATION, HAVE BEEN ASSOCIATED WITH MANY NEURAL FUNCTIONS INCLUDING SYNAPTIC PLASTICITY, LEARNING, AND MEMORY. HERE, WE CRITICALLY EXAMINE EMERGING EVIDENCE LINKING EPIGENETIC MECHANISMS TO THE DEVELOPMENT OR MAINTENANCE OF CHRONIC PAIN STATES. ALTHOUGH IN ITS INFANCY, RESEARCH IN THIS AREA POTENTIALLY UNIFIES SEVERAL PATHOPHYSIOLOGICAL PROCESSES UNDERPINNING ABNORMAL PAIN PROCESSING AND OPENS UP A DIFFERENT AVENUE FOR THE DEVELOPMENT OF NOVEL ANALGESICS. 2012 11 5347 35 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 12 405 31 ANALYSIS OF EPIGENETIC MECHANISMS REGULATING OPIOID RECEPTOR GENE TRANSCRIPTION. OPIOID DRUGS ARE GENERALLY USED FOR MODERATE AND SEVERE PAIN REDUCTIONS WHICH ACT THROUGH OPIOID RECEPTORS. STUDIES ON TRANSCRIPTIONAL REGULATION OF OPIOID RECEPTORS ARE STILL INVALUABLE BECAUSE NOT ONLY TRANSCRIPTION IS THE FIRST STEP TO PRODUCE PROTEIN PRODUCTS IN CELLS, BUT THE RECEPTOR TRANSCRIPTION LEVELS ALSO AFFECT THE PAIN REDUCTION BY OPIOIDS, AS OBSERVED IN STUDIES OF HETEROZYGOUS OPIOID RECEPTOR KNOCKOUT MICE.THERE ARE GROWING EVIDENCES THAT EPIGENETIC REGULATION HAS PLAYED SIGNIFICANT ROLES IN TRANSCRIPTIONAL REGULATION OF GENES, INCLUDING OPIOID RECEPTORS. IN GENERAL, EPIGENETIC MECHANISMS INCLUDE THREE MAIN REGULATORY FACTORS: DNA METHYLATION, CHROMATIN MODIFICATION, AND NONCODING RNAS (SUCH AS MICRORNA). FROM PREVIOUS STUDIES OF OURS AND OTHERS ON OPIOID RECEPTORS, THOSE EPIGENETIC FACTORS WERE CLEARLY INVOLVED IN REGULATING OPIOID RECEPTOR EXPRESSION IN VIVO AND IN VITRO. IN THIS CHAPTER, AMONG THOSE THREE TECHNIQUES WE DESCRIBE MORE DETAILS OF DNA METHYLATION METHODS BECAUSE OF EMERGING CONCEPTS OF DNA METHYLATION WITH THE RECENT DISCOVERY OF 5-HYDROXYMETHYLCYTOSINE CONVERTING ENZYME, TET1. ANOTHER ANALYTICAL METHOD OF THE EPIGENETIC FACTORS, CHROMATIN MODIFICATION, WILL BE DESCRIBED BRIEFLY AND INFORMATION OF ANALYZING NONCODING RNAS IS BRIEFLY MENTIONED IN SUBHEADING 1. 2015 13 656 32 BLOCKADE OF THE IL-1R1/TLR4 PATHWAY MEDIATES DISEASE-MODIFICATION THERAPEUTIC EFFECTS IN A MODEL OF ACQUIRED EPILEPSY. WE RECENTLY DISCOVERED THAT FOREBRAIN ACTIVATION OF THE IL-1 RECEPTOR/TOLL-LIKE RECEPTOR (IL-1R1/TLR4) INNATE IMMUNITY SIGNAL PLAYS A PIVOTAL ROLE IN NEURONAL HYPEREXCITABILITY UNDERLYING SEIZURES IN RODENTS. SINCE THIS PATHWAY IS ACTIVATED IN NEURONS AND GLIA IN HUMAN EPILEPTOGENIC FOCI, IT REPRESENTS A POTENTIAL TARGET FOR DEVELOPING DRUGS INTERFERING WITH THE MECHANISMS OF EPILEPTOGENESIS THAT LEAD TO SPONTANEOUS SEIZURES. THE LACK OF SUCH DRUGS REPRESENTS A MAJOR UNMET CLINICAL NEED. WE TESTED THEREFORE NOVEL THERAPIES INHIBITING THE IL-1R1/TLR4 SIGNALING IN AN ESTABLISHED MURINE MODEL OF ACQUIRED EPILEPSY. WE USED AN EPIGENETIC APPROACH BY INJECTING A SYNTHETIC MIMIC OF MICRO(MI)RNA-146A THAT IMPAIRS IL1R1/TLR4 SIGNAL TRANSDUCTION, OR WE BLOCKED RECEPTOR ACTIVATION WITH ANTIINFLAMMATORY DRUGS. BOTH INTERVENTIONS WHEN TRANSIENTLY APPLIED TO MICE AFTER EPILEPSY ONSET, PREVENTED DISEASE PROGRESSION AND DRAMATICALLY REDUCED CHRONIC SEIZURE RECURRENCE, WHILE THE ANTICONVULSANT DRUG CARBAMAZEPINE WAS INEFFECTIVE. WE CONCLUDE THAT IL-1R1/TLR4 IS A NOVEL POTENTIAL THERAPEUTIC TARGET FOR ATTAINING DISEASE-MODIFICATIONS IN PATIENTS WITH DIAGNOSED EPILEPSY. 2017 14 789 39 CELLULAR AND MOLECULAR MECHANISMS DRIVING NEUROPATHIC PAIN: RECENT ADVANCEMENTS AND CHALLENGES. CURRENT PHARMACOTHERAPEUTICS FOR NEUROPATHIC PAIN OFFER ONLY SYMPTOMATIC RELIEF WITHOUT TREATING THE UNDERLYING PATHOPHYSIOLOGY. ADDITIONALLY, THEY ARE ASSOCIATED WITH VARIOUS DOSE-LIMITING SIDE EFFECTS. PAIN RESEARCH IN THE PAST FEW DECADES HAS REVOLVED AROUND THE ROLE OF OXIDATIVE-NITROSATIVE STRESS, PROTEIN KINASES, GLIAL CELL ACTIVATION, AND INFLAMMATORY SIGNALING CASCADES BUT HAS FAILED TO PRODUCE SPECIFIC AND EFFECTIVE THERAPIES. AREAS COVERED: THIS REVIEW FOCUSES ON RECENT ADVANCES IN CELLULAR AND MOLECULAR MECHANISMS OF NEUROPATHIC PAIN THAT MAY BE TRANSLATED INTO FUTURE THERAPIES. WE DISCUSS EMERGING TARGETS SUCH AS WNT SIGNALING MECHANISMS, THE TETRAHYDROBIOPTERIN PATHWAY, MRG RECEPTORS, ENDOGENOUS LIPID MEDIATORS, MICRO-RNAS AND THEIR ROLES IN PAIN REGULATION. RECENT EVIDENCE IS ALSO PRESENTED REGARDING GENETIC AND EPIGENETIC MECHANISMS OF PAIN MODULATION. EXPERT OPINION: DURING CHRONIC NEUROPATHIC PAIN, MALADAPTATION OCCURS IN THE PERIPHERAL AND CENTRAL NERVOUS SYSTEMS, INCLUDING A SHIFT IN MICROGLIAL PHENOTYPE FROM A SURVEILLANCE STATE TO AN ACTIVATED STATE. MICROGLIAL ACTIVATION LEADS TO AN ALTERED EXPRESSION OF CELL SURFACE PROTEINS, GROWTH FACTORS, AND INTRACELLULAR SIGNALING MOLECULES THAT CONTRIBUTE TO DEVELOPMENT OF A NEUROINFLAMMATORY CASCADE AND CHRONIC PAIN SENSITIZATION. SPECIFIC TARGETING OF THESE CELLULAR AND MOLECULAR MECHANISMS MAY PROVIDE THE KEY TO DEVELOPMENT OF EFFECTIVE NEUROPATHIC PAIN THERAPIES THAT HAVE MINIMAL SIDE EFFECTS. 2018 15 5288 27 PROSPECTS FOR EPIGENETIC COMPOUNDS IN THE TREATMENT OF AUTOIMMUNE DISEASE. THERE IS GROWING EVIDENCE FOR A ROLE FOR EPIGENETIC MECHANISMS IN THE DEVELOPMENT OF AUTOIMMUNE DISEASES. IN MOST CASES OFAUTOIMMUNE DISEASE THE PRECISE EPIGENETIC MECHANISM INVOLVED REMAINS TO BE RESOLVED, HOWEVER DNA HYPOMETHYLATION ACCOMPANIED BY HYPOACETYLATION OFHISTONE H3/H4 IS COMMONLY OBSERVED. DUE TO THE REVERSIBLE NATURE OF EPIGENETIC MARKS THEIR MAINTENANCE ENZYMES SUCH AS DNA METHYLTRANSFERASES (DNMTS), HISTONE DEACETYLASES (HDACS) AND HISTONE LYSINE METHYLTRANSFERASES (HKMT) ARE ATTRACTIVE DRUG TARGETS. SMALL MOLECULE INHIBITORS OF HISTONE MODIFICATION AND DNA METHYLATION MAINTENANCE ARE INCREASINGLY BECOMING AVAILABLE AND WILL BE USEFUL CHEMICAL BIOLOGICAL TOOLS TO DISSECT EPIGENETIC MECHANISMS IN THESE DISEASES. HOWEVER, ALTHOUGH EPIGENETIC THERAPIES USED IN CANCER TREATMENT ARE A PROMISING STARTING POINT FOR THE EXPLORATION OF AUTOIMMUNE DISEASE TREATMENT, THERE IS A REQUIREMENT FOR MORE SPECIFIC AND LESS TOXIC AGENTS FOR THESE CHRONIC DISEASES OR FOR USE AS CHEMOPREVENTATIVE AGENTS. 2011 16 4619 33 NERVE TRAUMA-CAUSED DOWNREGULATION OF OPIOID RECEPTORS IN PRIMARY AFFERENT NEURONS: MOLECULAR MECHANISMS AND POTENTIAL MANAGEMENTS. NEUROPATHIC PAIN IS THE MOST COMMON CLINICAL DISORDER DESTROYING THE QUALITY OF PATIENT LIFE AND LEADING TO A MARKED ECONOMIC AND SOCIAL BURDEN. OPIOIDS ARE STILL LAST OPTION FOR PHARMACOLOGICAL TREATMENT OF THIS DISORDER, BUT THEIR ANTINOCICEPTIVE EFFECTS ARE LIMITED IN PART DUE TO THE DOWNREGULATION OF OPIOID RECEPTORS IN THE PRIMARY AFFERENT NEURONS AFTER PERIPHERAL NERVE TRAUMA. HOW THIS DOWNREGULATION OCCURS IS NOT COMPLETELY UNDERSTOOD, BUT RECENT STUDIES HAVE DEMONSTRATED THAT PERIPHERAL NERVE TRAUMA DRIVES THE ALTERATIONS IN EPIGENETIC MODIFICATIONS (INCLUDING DNA METHYLATION, HISTONE METHYLATION AND MCIRORNAS), EXPRESSION OF TRANSCRIPTION FACTORS, POST-TRANSCRIPTIONAL MODIFICATIONS (E.G., RNA METHYLATION) AND PROTEIN TRANSLATION INITIATION IN THE NEURONS OF NERVE TRAUMA-RELATED DORSAL ROOT GANGLION (DRG) AND THAT THESE ALTERNATIONS MAY BE ASSOCIATED WITH NERVE TRAUMA-CAUSED DOWNREGULATION OF DRG OPIOID RECEPTORS. THIS REVIEW PRESENTS HOW OPIOID RECEPTORS ARE DOWNREGULATED IN THE DRG AFTER PERIPHERAL NERVE TRAUMA, SPECIFICALLY FOCUSING ON DISTINCT MOLECULAR MECHANISMS UNDERLYING TRANSCRIPTIONAL AND TRANSLATIONAL PROCESSES. THIS REVIEW ALSO DISCUSSES HOW THIS DOWNREGULATION CONTRIBUTES TO THE INDUCTION AND MAINTENANCE OF NEUROPATHIC PAIN. A DEEPER UNDERSTANDING OF THESE MOLECULAR MECHANISMS LIKELY PROVIDES A NOVEL AVENUE FOR PREVENTION AND/OR TREATMENT OF NEUROPATHIC PAIN. 2021 17 2993 35 GENETIC PAIN LOSS DISORDERS. GENETIC PAIN LOSS INCLUDES CONGENITAL INSENSITIVITY TO PAIN (CIP), HEREDITARY SENSORY NEUROPATHIES AND, IF AUTONOMIC NERVES ARE INVOLVED, HEREDITARY SENSORY AND AUTONOMIC NEUROPATHY (HSAN). THIS HETEROGENEOUS GROUP OF DISORDERS HIGHLIGHTS THE ESSENTIAL ROLE OF NOCICEPTION IN PROTECTING AGAINST TISSUE DAMAGE. PATIENTS WITH GENETIC PAIN LOSS HAVE RECURRENT INJURIES, BURNS AND POORLY HEALING WOUNDS AS DISEASE HALLMARKS. CIP AND HSAN ARE CAUSED BY PATHOGENIC GENETIC VARIANTS IN >20 GENES THAT LEAD TO DEVELOPMENTAL DEFECTS, NEURODEGENERATION OR ALTERED NEURONAL EXCITABILITY OF PERIPHERAL DAMAGE-SENSING NEURONS. THESE GENETIC VARIANTS LEAD TO HYPERACTIVITY OF SODIUM CHANNELS, DISTURBED HAEM METABOLISM, ALTERED CLATHRIN-MEDIATED TRANSPORT AND IMPAIRED GENE REGULATORY MECHANISMS AFFECTING EPIGENETIC MARKS, LONG NON-CODING RNAS AND REPETITIVE ELEMENTS. THERAPIES FOR PAIN LOSS DISORDERS ARE MAINLY SYMPTOMATIC BUT THE FIRST TARGETED THERAPIES ARE BEING TESTED. CONVERSELY, CHRONIC PAIN REMAINS ONE OF THE GREATEST UNRESOLVED MEDICAL CHALLENGES, AND THE GENES AND MECHANISMS ASSOCIATED WITH PAIN LOSS OFFER NEW TARGETS FOR ANALGESICS. GIVEN THE PROGRESS THAT HAS BEEN MADE, THE COMING YEARS ARE PROMISING BOTH IN TERMS OF TARGETED TREATMENTS FOR PAIN LOSS DISORDERS AND THE DEVELOPMENT OF INNOVATIVE PAIN MEDICINES BASED ON KNOWLEDGE OF THESE GENETIC DISEASES. 2022 18 2442 33 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 19 6136 51 THE EPIGENETICS OF MULTIPLE SCLEROSIS AND OTHER RELATED DISORDERS. MULTIPLE SCLEROSIS (MS) IS A DEMYELINATING DISEASE CHARACTERIZED BY CHRONIC INFLAMMATION OF THE CENTRAL NERVOUS SYSTEM (CNS) GRAY AND WHITE MATTER. ALTHOUGH THE CAUSE OF MS IS UNKNOWN, IT IS WIDELY APPRECIATED THAT INNATE AND ADAPTIVE IMMUNE PROCESSES CONTRIBUTE TO ITS PATHOGENESIS. THESE INCLUDE MICROGLIA/MACROPHAGE ACTIVATION, PRO-INFLAMMATORY T-CELL (TH1) RESPONSES AND HUMORAL RESPONSES. ADDITIONALLY, THERE IS EVIDENCE INDICATING THAT MS HAS A NEURODEGENERATIVE COMPONENT SINCE NEURONAL AND AXONAL LOSS OCCURS EVEN IN THE ABSENCE OF OVERT INFLAMMATION. THESE ASPECTS ALSO FORM THE RATIONALE FOR CLINICAL MANAGEMENT OF THE DISEASE. HOWEVER, THE CURRENTLY AVAILABLE THERAPIES TO CONTROL THE DISEASE ARE ONLY PARTIALLY EFFECTIVE AT BEST INDICATING THAT MORE EFFECTIVE THERAPEUTIC SOLUTIONS ARE URGENTLY NEEDED. IT IS APPRECIATED THAT IN THE IMMUNE-DRIVEN AND NEURODEGENERATIVE PROCESSES MS-SPECIFIC DEREGULATION OF GENE EXPRESSIONS AND RESULTING PROTEIN DYSFUNCTION ARE THOUGHT TO PLAY A CENTRAL ROLE. THESE DEVIATIONS IN GENE EXPRESSION PATTERNS CONTRIBUTE TO THE INFLAMMATORY RESPONSE IN THE CNS, AND TO NEURONAL OR AXONAL LOSS. EPIGENETIC MECHANISMS CONTROL TRANSCRIPTION OF MOST, IF NOT ALL GENES, IN NUCLEATED CELLS INCLUDING CELLS OF THE CNS AND IN HAEMATOPOIETIC CELLS. MS-SPECIFIC ALTERATIONS IN EPIGENETIC REGULATION OF GENE EXPRESSION MAY THEREFORE LIE AT THE HEART OF THE DEREGULATION OF GENE EXPRESSION IN MS. AS SUCH, EPIGENETIC MECHANISMS MOST LIKELY PLAY AN IMPORTANT ROLE IN DISEASE PATHOGENESIS. IN THIS REVIEW WE DISCUSS A ROLE FOR MS-SPECIFIC DEREGULATION OF EPIGENETIC FEATURES THAT CONTROL GENE EXPRESSION IN THE CNS AND IN THE PERIPHERY. FURTHERMORE, WE DISCUSS THE APPLICATION OF SMALL MOLECULE INHIBITORS THAT TARGET THE EPIGENETIC MACHINERY TO AMELIORATE DISEASE IN EXPERIMENTAL ANIMAL MODELS, INDICATING THAT SUCH APPROACHES MAY BE APPLICABLE TO MS PATIENTS. 2014 20 2354 29 EPIGENETIC REGULATION OF PERSISTENT PAIN. PERSISTENT OR CHRONIC PAIN IS TIGHTLY ASSOCIATED WITH VARIOUS ENVIRONMENTAL CHANGES AND LINKED TO ABNORMAL GENE EXPRESSION WITHIN CELLS PROCESSING NOCICEPTIVE SIGNALING. EPIGENETIC REGULATION GOVERNS GENE EXPRESSION IN RESPONSE TO ENVIRONMENTAL CUES. RECENT ANIMAL MODEL AND CLINICAL STUDIES INDICATE THAT EPIGENETIC REGULATION PLAYS AN IMPORTANT ROLE IN THE DEVELOPMENT OR MAINTENANCE OF PERSISTENT PAIN AND POSSIBLY THE TRANSITION OF ACUTE PAIN TO CHRONIC PAIN, THUS SHEDDING LIGHT IN A DIRECTION FOR DEVELOPMENT OF NEW THERAPEUTICS FOR PERSISTENT PAIN. 2015