1 4297 125 MICRORNA-1224 SPLICING CIRCULARRNA-FILIP1L IN AN AGO2-DEPENDENT MANNER REGULATES CHRONIC INFLAMMATORY PAIN VIA TARGETING UBR5. DYSFUNCTIONS OF GENE TRANSCRIPTION AND TRANSLATION IN THE NOCICEPTIVE PATHWAYS PLAY THE CRITICAL ROLE IN DEVELOPMENT AND MAINTENANCE OF CHRONIC PAIN. CIRCULAR RNAS (CIRCRNAS) ARE EMERGING AS NEW PLAYERS IN REGULATION OF GENE EXPRESSION, BUT WHETHER AND HOW CIRCRNAS ARE INVOLVED IN CHRONIC PAIN REMAIN ELUSIVE. WE SHOWED HERE THAT COMPLETE FREUND'S ADJUVANT-INDUCED CHRONIC INFLAMMATION PAIN SIGNIFICANTLY INCREASED CIRCRNA-FILIP1L (FILAMIN A INTERACTING PROTEIN 1-LIKE) EXPRESSION IN SPINAL NEURONS OF MICE. BLOCKAGE OF THIS INCREASE ATTENUATED COMPLETE FREUND'S ADJUVANT-INDUCED NOCICEPTIVE BEHAVIORS, AND OVEREXPRESSION OF SPINAL CIRCRNA-FILIP1L IN NAIVE MICE MIMICKED THE NOCICEPTIVE BEHAVIORS AS EVIDENCED BY DECREASED THERMAL AND MECHANICAL NOCICEPTIVE THRESHOLD. FURTHERMORE, WE FOUND THAT MATURE CIRCRNA-FILIP1L EXPRESSION WAS NEGATIVELY REGULATED BY MIRNA-1224 VIA BINDING AND SPLICING OF PRECURSOR OF CIRCRNA-FILIP1L (PRE-CIRCRNA-FILIP1L) IN THE ARGONAUTE-2 (AGO2)-DEPENDENT MANNER. INCREASE OF SPINAL CIRCRNA-FILIP1L EXPRESSION RESULTED FROM THE DECREASE OF MIRNA-1224 EXPRESSION UNDER CHRONIC INFLAMMATION PAIN STATE. MIRNA-1224 KNOCKDOWN OR AGO2 OVEREXPRESSION INDUCED NOCICEPTIVE BEHAVIORS IN NAIVE MICE, WHICH WAS PREVENTED BY THE KNOCKDOWN OF SPINAL CIRCRNA-FILIP1L. FINALLY, WE DEMONSTRATED THAT A UBIQUITIN PROTEIN LIGASE E3 COMPONENT N-RECOGNIN 5 (UBR5), VALIDATED AS A TARGET OF CIRCRNA-FILIP1L, PLAYS A PIVOTAL ROLE IN REGULATION OF NOCICEPTION BY SPINAL CIRCRNA-FILIP1L. THESE DATA SUGGEST THAT MIRNA-1224-MEDIATED AND AGO2-DEPENDENT MODULATION OF SPINAL CIRCRNA-FILIP1L EXPRESSION REGULATES NOCICEPTION VIA TARGETING UBR5, REVEALING A NOVEL EPIGENETIC MECHANISM OF INTERACTION BETWEEN MIRNA AND CIRCRNA IN CHRONIC INFLAMMATION PAIN.SIGNIFICANCE STATEMENT CIRCRNAS ARE EMERGING AS NEW PLAYERS IN REGULATION OF GENE EXPRESSION. HERE, WE FOUND THAT THE INCREASE OF CIRCRNA-FILIP1L MEDIATED BY MIRNA-1224 IN AN AGO2-DEPENDENT WAY IN THE SPINAL CORD IS INVOLVED IN REGULATION OF NOCICEPTION VIA TARGETING UBR5 OUR STUDY REVEALS A NOVEL EPIGENETIC MECHANISM OF INTERACTION BETWEEN MIRNA AND CIRCRNA IN CHRONIC INFLAMMATION PAIN.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
2 4861  33 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 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
4  984  40 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
5  885  34 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
6 4499  29 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
7 2203  46 EPIGENETIC MODIFICATION OF SPINAL MIR-219 EXPRESSION REGULATES CHRONIC INFLAMMATION PAIN BY TARGETING CAMKIIGAMMA. EMERGING EVIDENCE HAS SHOWN THAT MIRNA-MEDIATED GENE EXPRESSION MODULATION CONTRIBUTES TO CHRONIC PAIN, BUT ITS FUNCTIONAL REGULATORY MECHANISM REMAINS UNKNOWN. HERE, WE FOUND THAT COMPLETE FREUND'S ADJUVANT (CFA)-INDUCED CHRONIC INFLAMMATION PAIN SIGNIFICANTLY REDUCED MIRNA-219 (MIR-219) EXPRESSION IN MICE SPINAL NEURONS. FURTHERMORE, THE EXPRESSION OF SPINAL CAMKIIGAMMA, AN EXPERIMENTALLY VALIDATED TARGET OF MIR-219, WAS INCREASED IN CFA MICE. OVEREXPRESSION OF SPINAL MIR-219 PREVENTED AND REVERSED THERMAL HYPERALGESIA AND MECHANICAL ALLODYNIA AND SPINAL NEURONAL SENSITIZATION INDUCED BY CFA. CONCURRENTLY, INCREASED EXPRESSION OF SPINAL CAMKIIGAMMA WAS REVERSED BY MIR-219 OVEREXPRESSION. DOWNREGULATION OF SPINAL MIR-219 IN NAIVE MICE INDUCED PAIN-RESPONSIVE BEHAVIORS AND INCREASED P-NMDAR1 EXPRESSION, WHICH COULD BE INHIBITED BY KNOCKDOWN OF CAMKIIGAMMA. BISULFITE SEQUENCING SHOWED THAT CFA INDUCED THE HYPERMETHYLATION OF CPG ISLANDS IN THE MIR-219 PROMOTER. TREATMENT WITH DEMETHYLATION AGENT 5'-AZA-2'-DEOXYCYTIDINE MARKEDLY ATTENUATED PAIN BEHAVIOR AND SPINAL NEURONAL SENSITIZATION, WHICH WAS ACCOMPANIED WITH THE INCREASE OF SPINAL MIR-219 AND DECREASE OF CAMKIIGAMMA EXPRESSION. TOGETHER, WE CONCLUDE THAT METHYLATION-MEDIATED EPIGENETIC MODIFICATION OF SPINAL MIR-219 EXPRESSION REGULATES CHRONIC INFLAMMATORY PAIN BY TARGETING CAMKIIGAMMA.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
8 6059  35 THE DEVELOPMENT OF A SENSITIVE FLUORESCENT PROTEIN-BASED TRANSCRIPT REPORTER FOR HIGH THROUGHPUT SCREENING OF NEGATIVE MODULATORS OF LNCRNAS. WHILE THE HUMAN GENOME IS PERVASIVELY TRANSCRIBED, <2% OF THE HUMAN GENOME IS TRANSCRIBED INTO PROTEIN-CODING MRNAS, LEAVING MOST OF THE TRANSCRIPTS AS NONCODING RNAS, SUCH AS MICRORNAS AND LONG-NONCODING RNAS (LNCRNAS), WHICH ARE CRITICAL COMPONENTS OF EPIGENETIC REGULATION. LNCRNAS ARE EMERGING AS CRITICAL REGULATORS OF GENE EXPRESSION AND GENOMIC STABILITY. HOWEVER, IT REMAINS LARGELY UNKNOWN ABOUT HOW LNCRNAS ARE REGULATED. HERE, WE DEVELOP A HIGHLY SENSITIVE AND DYNAMIC REPORTER THAT ALLOWS US TO IDENTIFY AND/OR MONITOR NEGATIVE MODULATORS OF LNCRNA TRANSCRIPT LEVELS IN A HIGH THROUGHPUT FASHION. SPECIFICALLY, WE ENGINEER A FLUORESCENT FUSION PROTEIN BY FUSING THREE COPIES OF THE PEST DESTRUCTION DOMAIN OF MOUSE ORNITHINE DECARBOXYLASE (MODC) TO THE C-TERMINAL END OF THE CODON-OPTIMIZED BILIRUBIN-INDUCIBLE FLUORESCENT PROTEIN, DESIGNATED AS DBIFP, AND SHOW THAT THE DBIFP PROTEIN IS HIGHLY DESTABILIZED, COMPARED WITH THE COMMONLY-USED EGFP PROTEIN. WE FURTHER DEMONSTRATE THAT THE DBIFP SIGNAL IS EFFECTIVELY DOWN-REGULATED WHEN THE DBIFP AND MOUSE LNCRNA H19 CHIMERIC TRANSCRIPT IS SILENCED BY MOUSE H19-SPECIFIC SIRNAS. THEREFORE, OUR RESULTS STRONGLY SUGGEST THAT THE DBIFP FUSION PROTEIN MAY SERVE AS A SENSITIVE AND DYNAMIC TRANSCRIPT REPORTER TO MONITOR THE INHIBITION OF LNCRNAS BY MICRORNAS, SYNTHETIC REGULATORY RNA MOLECULES, RNA BINDING PROTEINS, AND/OR SMALL MOLECULE INHIBITORS SO THAT NOVEL AND EFFICACIOUS INHIBITORS TARGETING THE EPIGENETIC CIRCUIT CAN BE DISCOVERED TO TREAT HUMAN DISEASES SUCH AS CANCER AND OTHER CHRONIC DISORDERS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
9 5474  30 RESTORATION OF HISTONE ACETYLATION AMELIORATES DISEASE AND METABOLIC ABNORMALITIES IN A FUS MOUSE MODEL. DYSREGULATION OF EPIGENETIC MECHANISMS IS EMERGING AS A CENTRAL EVENT IN NEURODEGENERATIVE DISORDERS, INCLUDING AMYOTROPHIC LATERAL SCLEROSIS (ALS). IN MANY MODELS OF NEURODEGENERATION, GLOBAL HISTONE ACETYLATION IS DECREASED IN THE AFFECTED NEURONAL TISSUES. HISTONE ACETYLATION IS CONTROLLED BY THE ANTAGONISTIC ACTIONS OF TWO PROTEIN FAMILIES -THE HISTONE ACETYLTRANSFERASES (HATS) AND THE HISTONE DEACETYLASES (HDACS). DRUGS INHIBITING HDAC ACTIVITY ARE ALREADY USED IN THE CLINIC AS ANTI-CANCER AGENTS. THE AIM OF THIS STUDY WAS TO EXPLORE THE THERAPEUTIC POTENTIAL OF HDAC INHIBITION IN THE CONTEXT OF ALS. WE DISCOVERED THAT TRANSGENIC MICE OVEREXPRESSING WILD-TYPE FUS ("TG FUS+/+"), WHICH RECAPITULATE MANY ASPECTS OF HUMAN ALS, SHOWED REDUCED GLOBAL HISTONE ACETYLATION AND ALTERATIONS IN METABOLIC GENE EXPRESSION, RESULTING IN A DYSREGULATED METABOLIC HOMEOSTASIS. CHRONIC TREATMENT OF TG FUS+/+ MICE WITH ACY-738, A POTENT HDAC INHIBITOR THAT CAN CROSS THE BLOOD-BRAIN BARRIER, AMELIORATED THE MOTOR PHENOTYPE AND SUBSTANTIALLY EXTENDED THE LIFE SPAN OF THE TG FUS+/+ MICE. AT THE MOLECULAR LEVEL, ACY-738 RESTORED GLOBAL HISTONE ACETYLATION AND METABOLIC GENE EXPRESSION, THEREBY RE-ESTABLISHING METABOLITE LEVELS IN THE SPINAL CORD. TAKEN TOGETHER, OUR FINDINGS LINK EPIGENETIC ALTERATIONS TO METABOLIC DYSREGULATION IN ALS PATHOLOGY, AND HIGHLIGHT ACY-738 AS A POTENTIAL THERAPEUTIC STRATEGY TO TREAT THIS DEVASTATING DISEASE.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
10 3141  35 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
11 6664  48 UPREGULATION OF LNCRNA71132 IN THE SPINAL CORD REGULATES HYPERSENSITIVITY IN A RAT MODEL OF BONE CANCER PAIN. BONE CANCER PAIN (BCP) IS A PERVASIVE CLINICAL SYMPTOM WHICH IMPAIRS THE QUALITY LIFE. LONG NONCODING RNAS (LNCRNAS) ARE ENRICHED IN THE CENTRAL NERVOUS SYSTEM AND PLAY INDISPENSABLE ROLES IN NUMEROUS BIOLOGICAL PROCESSES, WHILE ITS REGULATORY FUNCTION IN NOCICEPTIVE INFORMATION PROCESSING REMAINS ELUSIVE. HERE, WE REPORTED THAT FUNCTIONAL MODULATORY ROLE OF ENSRNOT00000071132 (LNCRNA71132) IN THE BCP PROCESS AND SPONGING WITH MIR-143 AND ITS DOWNSTREAM GPR85-DEPENDENT SIGNALING CASCADE. SPINAL LNCRNA71132 WAS REMARKABLY INCREASED IN THE RAT MODEL OF BONE CANCER PAIN. THE KNOCKDOWN OF SPINAL LNCRNA71132 REVERTED BCP BEHAVIORS AND SPINAL C-FOS NEURONAL SENSITIZATION. OVEREXPRESSION OF SPINAL LNCRNA71132 IN NAIVE RAT GENERATED PAIN BEHAVIORS, WHICH WERE ACCOMPANIED BY INCREASED SPINAL C-FOS NEURONAL SENSITIZATION. FURTHERMORE, IT WAS FOUND THAT LNCRNA71132 PARTICIPATES IN THE MODULATION OF BCP BY INVERSELY REGULATING THE PROCESSING OF MIR-143-5P. IN ADDITION, AN INCREASE IN EXPRESSION OF SPINAL LNCRNA71132 RESULTED IN THE DECREASE IN EXPRESSION OF MIR-143 UNDER THE BCP STATE. FINALLY, IT WAS FOUND THAT MIR-143-5P REGULATES PAIN BEHAVIORS BY TARGETING GPR85. OVEREXPRESSION OF MIR-143-5P IN THE SPINAL CORD REVERTED THE NOCICEPTIVE BEHAVIORS TRIGGERED BY BCP, ACCOMPANIED BY A DECREASE IN EXPRESSION OF SPINAL GPR85 PROTEIN, BUT NO INFLUENCE ON EXPRESSION OF GPR85 MRNA. THE FINDINGS OF THIS STUDY INDICATE THAT LNCRNA71132 WORKS AS A MIRNA SPONGE IN MIR-143-5P-MEDIATED POSTTRANSCRIPTIONAL MODULATION OF GPR85 EXPRESSION IN BCP. THEREFORE, EPIGENETIC INTERVENTIONS AGAINST LNCRNA71132 MAY POTENTIALLY WORK AS NOVEL TREATMENT AVENUES IN TREATING NOCICEPTIVE HYPERSENSITIVITY TRIGGERED BY BONE CANCER.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
12 2470  42 EPIGENETIC TRANSCRIPTIONAL ACTIVATION OF MONOCYTE CHEMOTACTIC PROTEIN 3 CONTRIBUTES TO LONG-LASTING NEUROPATHIC PAIN. A MULTIPLEX ANALYSIS FOR PROFILING THE EXPRESSION OF CANDIDATE GENES ALONG WITH EPIGENETIC MODIFICATION MAY LEAD TO A BETTER UNDERSTANDING OF THE COMPLEX MACHINERY OF NEUROPATHIC PAIN. IN THE PRESENT STUDY, WE FOUND THAT PARTIAL SCIATIC NERVE LIGATION MOST REMARKABLY INCREASED THE EXPRESSION OF MONOCYTE CHEMOTACTIC PROTEIN 3 (MCP-3, KNOWN AS CCL7) A TOTAL OF 33 541 GENES IN THE SPINAL CORD, WHICH LASTED FOR 4 WEEKS. THIS INCREASE IN MCP-3 GENE TRANSCRIPTION WAS ACCOMPANIED BY THE DECREASED TRIMETHYLATION OF HISTONE H3 AT LYS27 AT THE MCP-3 PROMOTER. THE INCREASED MCP-3 EXPRESSION ASSOCIATED WITH ITS EPIGENETIC MODIFICATION OBSERVED IN THE SPINAL CORD WAS ALMOST ABOLISHED IN INTERLEUKIN 6 KNOCKOUT MICE WITH PARTIAL SCIATIC NERVE LIGATION. CONSISTENT WITH THESE FINDINGS, A SINGLE INTRATHECAL INJECTION OF RECOMBINANT PROTEINS OF INTERLEUKIN 6 SIGNIFICANTLY INCREASED MCP-3 MESSENGER RNA WITH A DECREASE IN THE LEVEL OF LYS27 TRIMETHYLATION OF HISTONE H3 AT THE MCP-3 PROMOTER IN THE SPINAL CORD OF MICE. FURTHERMORE, DELETION OF THE C-C CHEMOKINE RECEPTOR TYPE 2 (CCR2) GENE, WHICH ENCODES A RECEPTOR FOR MCP-3, FAILED TO AFFECT THE ACCELERATION OF MCP-3 EXPRESSION IN THE SPINAL CORD AFTER PARTIAL SCIATIC NERVE LIGATION. A ROBUST INCREASE IN MCP-3 PROTEIN, WHICH LASTED FOR UP TO 2 WEEKS AFTER SURGERY, IN THE DORSAL HORN OF THE SPINAL CORD OF MICE WITH PARTIAL SCIATIC NERVE LIGATION WAS SEEN MOSTLY IN ASTROCYTES, BUT NOT MICROGLIA OR NEURONS. ON THE OTHER HAND, THE INCREASES IN BOTH MICROGLIA AND ASTROCYTES IN THE SPINAL CORD BY PARTIAL SCIATIC NERVE LIGATION WERE MOSTLY ABOLISHED IN INTERLEUKIN 6 KNOCKOUT MICE. MOREOVER, THIS INCREASE IN MICROGLIA WAS ALMOST ABOLISHED BY CCR2 GENE DELETION, WHEREAS THE INCREASE IN ASTROCYTES WAS NOT AFFECTED IN NERVE-LIGATED MICE THAT LACKED THE CCR2 GENE. WE ALSO FOUND THAT EITHER IN VIVO OR IN VITRO TREATMENT WITH MCP-3 CAUSED ROBUST MICROGLIA ACTIVATION. UNDER THESE CONDITIONS, INTRATHECAL ADMINISTRATION OF MCP-3 ANTIBODY SUPPRESSED THE INCREASE IN MICROGLIA WITHIN THE MOUSE SPINAL CORD AND NEUROPATHIC PAIN-LIKE BEHAVIOURS AFTER NERVE INJURY. WITH THE USE OF A FUNCTIONAL MAGNETIC RESONANCE IMAGING ANALYSIS, WE DEMONSTRATED THAT A SINGLE INTRATHECAL INJECTION OF MCP-3 INDUCED DRAMATIC INCREASES IN SIGNAL INTENSITY IN PAIN-RELATED BRAIN REGIONS. THESE FINDINGS SUGGEST THAT INCREASED MCP-3 EXPRESSION ASSOCIATED WITH INTERLEUKIN 6 DEPENDENT EPIGENETIC MODIFICATION AT THE MCP-3 PROMOTER AFTER NERVE INJURY, MOSTLY IN SPINAL ASTROCYTES, MAY SERVE TO FACILITATE ASTROCYTE-MICROGLIA INTERACTION IN THE SPINAL CORD AND COULD PLAY A CRITICAL ROLE IN THE NEUROPATHIC PAIN-LIKE STATE.	2013	

13 1695  31 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14 6429  34 THE UPREGULATION OF NLRP3 INFLAMMASOME IN DORSAL ROOT GANGLION BY TEN-ELEVEN TRANSLOCATION METHYLCYTOSINE DIOXYGENASE 2 (TET2) CONTRIBUTED TO DIABETIC NEUROPATHIC PAIN IN MICE. BACKGROUND: THE NUCLEOTIDE OLIGOMERIZATION DOMAIN (NOD)-LIKE RECEPTOR FAMILY PYRIN DOMAIN CONTAINING 3 (NLRP3) IN DORSAL ROOT GANGLION (DRG) CONTRIBUTES TO PAIN HYPERSENSITIVITY IN MULTIPLE NEUROPATHIC PAIN MODELS, BUT THE FUNCTION OF THE NLRP3 IN DIABETIC NEUROPATHIC PAIN (DNP) AND THE REGULATION MECHANISM ARE STILL LARGELY UNKNOWN. EPIGENETIC REGULATION PLAYS A VITAL ROLE IN THE CONTROLLING OF GENE EXPRESSION. TEN-ELEVEN TRANSLOCATION METHYLCYTOSINE DIOXYGENASE 2 (TET2) IS A DNA DEMETHYLASE THAT CONTRIBUTES TO TRANSCRIPTIONAL ACTIVATION. TET2 IS ALSO INVOLVED IN HIGH GLUCOSE (HG)-INDUCED PATHOLOGY. METHODS: DNP WAS INDUCED IN MICE VIA THE INTRAPERITONEAL INJECTION OF STREPTOZOTOCIN (STZ) FOR FIVE CONSECUTIVE DAYS AND THE MECHANICAL THRESHOLD WAS EVALUATED IN STZ-DIABETIC MICE BY USING VON FREY HAIRS. THE EXPRESSION LEVEL OF THE NLRP3 PATHWAY AND TET2 IN DRG WERE DETERMINED THROUGH MOLECULAR BIOLOGY EXPERIMENTS. THE REGULATION OF THE NLRP3 PATHWAY BY TET2 WAS EXAMINED IN IN VITRO AND IN VIVO CONDITIONS. RESULTS: IN THE PRESENT RESEARCH, WE FIRST ESTABLISHED THE DNP MODEL AND FOUND THAT NLRP3 PATHWAY WAS ACTIVATED IN DRG. THE TREATMENT OF NLRP3 INHIBITOR MCC950 ALLEVIATED THE MECHANICAL ALLODYNIA OF DNP MICE. THEN WE REVEALED THAT IN STZ-DIABETIC MICE DRG, THE GENOMIC DNA WAS DEMETHYLATED, AND THE EXPRESSION OF DNA DEMETHYLASE TET2 WAS INCREASED EVIDENTLY. USING RNA-SEQUENCING ANALYSIS, WE FOUND THAT THE EXPRESSION OF TXNIP, A GENE THAT ENCODES A THIOREDOXIN-INTERACTING PROTEIN (TXNIP) WHICH MEDIATES NLRP3 ACTIVATION, WAS ELEVATED IN THE DRG AFTER STZ TREATMENT. IN ADDITION, KNOCKING DOWN OF TET2 EXPRESSION IN DRG USING TET2-SIRNA SUPPRESSED THE MRNA EXPRESSION OF TXNIP AND SUBSEQUENTLY INHIBITED THE EXPRESSION/ACTIVATION OF NLRP3 INFLAMMASOME IN VITRO AND IN VIVO AS WELL AS RELIEVED THE PAIN SENSITIVITY OF DNP ANIMALS. CONCLUSION: THE RESULTS SUGGESTED THAT THE UPREGULATION OF THE TXNIP/NLRP3 PATHWAY BY TET2 IN DRG WAS INVOLVED IN THE PAIN HYPERSENSITIVITY OF THE DNP MODEL.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
15 4742  32 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
16 2246  26 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
17 1689  34 DUAL HDAC/BRD4 INHIBITORS RELIEVES NEUROPATHIC PAIN BY ATTENUATING INFLAMMATORY RESPONSE IN MICROGLIA AFTER SPARED NERVE INJURY. DESPITE THE EFFORT ON DEVELOPING NEW TREATMENTS, THERAPY FOR NEUROPATHIC PAIN IS STILL A CLINICAL CHALLENGE AND COMBINATION THERAPY REGIMES OF TWO OR MORE DRUGS ARE OFTEN NEEDED TO IMPROVE EFFICACY. ACCUMULATING EVIDENCE SHOWS AN ALTERED EXPRESSION AND ACTIVITY OF HISTONE ACETYLATION ENZYMES IN CHRONIC PAIN CONDITIONS AND RESTORATION OF THESE ABERRANT EPIGENETIC MODIFICATIONS PROMOTES PAIN-RELIEVING ACTIVITY. RECENT STUDIES SHOWED A SYNERGISTIC ACTIVITY IN NEUROPATHIC PAIN MODELS BY COMBINATION OF HISTONE DEACETYLASES (HDACS) AND BROMODOMAIN AND EXTRA-TERMINAL DOMAIN (BET) INHIBITORS. ON THESE PREMISES, THE PRESENT STUDY INVESTIGATED THE PHARMACOLOGICAL PROFILE OF NEW DUAL HDAC/BRD4 INHIBITORS, NAMED SUM52 AND SUM35, IN THE SPARED NERVE INJURY (SNI) MODEL IN MICE AS INNOVATIVE STRATEGY TO SIMULTANEOUSLY INHIBIT HDACS AND BETS. INTRANASAL ADMINISTRATION OF SUM52 AND SUM35 ATTENUATED THERMAL AND MECHANICAL HYPERSENSITIVITY IN THE ABSENCE OF LOCOMOTOR SIDE EFFECTS. BOTH DUAL INHIBITORS SHOWED A PREFERENTIAL INTERACTION WITH BRD4-BD2 DOMAIN, AND SUM52 RESULTED THE MOST ACTIVE COMPOUND. SUM52 REDUCED MICROGLIA-MEDIATED SPINAL NEUROINFLAMMATION IN SPINAL CORD SECTIONS OF SNI MICE AS SHOWED BY REDUCTION OF IBA1 IMMUNOSTAINING, INDUCIBLE NITRIC OXIDE SYNTHASE (INOS) EXPRESSION, P65 NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) AND P38 MAPK OVER-PHOSPHORYLATION. A ROBUST DECREASE OF THE SPINAL PROINFLAMMATORY CYTOKINES CONTENT (IL-6, IL-1SS) WAS ALSO OBSERVED AFTER SUM52 TREATMENT. PRESENT RESULTS, SHOWING THE PAIN-RELIEVING ACTIVITY OF HDAC/BRD4 DUAL INHIBITORS, INDICATE THAT THE SIMULTANEOUS MODULATION OF BET AND HDAC ACTIVITY BY A SINGLE MOLECULE ACTING AS MULTI-TARGET AGENT MIGHT REPRESENT A PROMISE FOR NEUROPATHIC PAIN RELIEF.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
18 3002  25 GENETIC, EPIGENETIC AND POSTTRANSCRIPTIONAL MECHANISMS FOR TREATMENT OF MAJOR DEPRESSION: THE 5-HT1A RECEPTOR GENE AS A PARADIGM. MAJOR DEPRESSION AND ANXIETY ARE HIGHLY PREVALENT AND INVOLVE CHRONIC DYSREGULATION OF SEROTONIN, BUT THEY REMAIN POORLY UNDERSTOOD. HERE, WE REVIEW NOVEL TRANSCRIPTIONAL (GENETIC, EPIGENETIC) AND POSTTRANSCRIPTIONAL (MICRORNA, ALTERNATIVE SPLICING) MECHANISMS IMPLICATED IN MENTAL ILLNESS, FOCUSING ON A KEY SEROTONIN-RELATED REGULATOR, THE SEROTONIN 1A (5-HT1A) RECEPTOR. FUNCTIONAL SINGLE-NUCLEOTIDE POLYMORPHISMS AND STRESS-INDUCED DNA METHYLATION OF THE 5-HT1A PROMOTER CONVERGE TO DIFFERENTIALLY ALTER PRE- AND POSTSYNAPTIC 5-HT1A RECEPTOR EXPRESSION ASSOCIATED WITH MAJOR DEPRESSION AND REDUCED THERAPEUTIC RESPONSE TO SEROTONERGIC ANTIDEPRESSANTS. MAJOR DEPRESSION IS ALSO ASSOCIATED WITH ALTERED LEVELS OF SPLICE FACTORS AND MICRORNA, POSTTRANSCRIPTIONAL MECHANISMS THAT REGULATE RNA STABILITY. THE HUMAN 5-HT1A 3'-UNTRANSLATED REGION IS ALTERNATIVELY SPLICED, REMOVING MICRORNA SITES AND INCREASING 5-HT1A EXPRESSION, WHICH IS REDUCED IN MAJOR DEPRESSION AND MAY BE GENOTYPE-DEPENDENT. THUS, THE 5-HT1A RECEPTOR GENE ILLUSTRATES THE CONVERGENCE OF GENETIC, EPIGENETIC AND POSTTRANSCRIPTIONAL MECHANISMS IN GENE EXPRESSION, NEURODEVELOPMENT AND NEUROPLASTICITY, AND MAJOR DEPRESSION. UNDERSTANDING GENE REGULATORY MECHANISMS COULD ENHANCE THE DETECTION, CATEGORIZATION AND PERSONALIZED TREATMENT OF MAJOR DEPRESSION.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
19 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
20 6148  39 THE EXPRESSION OF TRANSCRIPTION FACTORS MECP2 AND CREB IS MODULATED IN INFLAMMATORY PELVIC PAIN. EARLY ACTIVATION OF TRANSCRIPTION FACTORS IS ONE OF THE EPIGENETIC MECHANISMS CONTRIBUTING TO THE INDUCTION AND MAINTENANCE OF CHRONIC PAIN STATES. PREVIOUS STUDIES IDENTIFIED THE CHANGES IN A NUMBER OF NOCICEPTION-RELATED GENES, SUCH AS CALCITONIN GENE-RELATED PEPTIDE (CGRP), SUBSTANCE P (SP), AND BRAIN-DERIVED NEUROTROPIC FACTOR (BDNF) IN THE PELVIC ORGANS AFTER TRANSIENT COLONIC INFLAMMATION. THE GENE AND PROTEIN EXPRESSION OF THESE NEUROPEPTIDES COULD BE MODULATED BY TRANSCRIPTION FACTORS METHYL-CPG-BINDING PROTEIN 2 (MECP2) AND CAMP RESPONSE ELEMENT-BINDING PROTEIN (CREB). IN THIS STUDY, WE AIMED TO EVALUATE TIME-DEPENDENT CHANGES IN THE EXPRESSION LEVELS OF MECP2 AND CREB IN THE LUMBOSACRAL (LS) SPINAL CORD AND SENSORY GANGLIA AFTER INFLAMMATION-INDUCED PELVIC PAIN IN RAT. ADULT SPRAGUE-DAWLEY RATS WERE TREATED WITH 2,4,6-TRINITROBENZENESULFONIC ACID (TNBS) TO INDUCE TRANSIENT COLONIC INFLAMMATION. LS (L6-S2) SPINAL CORD SEGMENTS AND RESPECTIVE DORSAL ROOT GANGLIAS (DRGS) WERE ISOLATED FROM CONTROL AND EXPERIMENTAL ANIMALS AT 1, 2, 6, 24 H AND 3 DAYS POST-TNBS TREATMENT. IMMUNOHISTOCHEMICAL (IHC) LABELING AND WESTERN BLOTTING EXPERIMENTS WERE PERFORMED TO ASSESS THE EXPRESSION OF MECP2, CREB AND THEIR PHOSPHORYLATED FORMS. TOTAL MECP2 EXPRESSION, BUT NOT PHOSPHORYLATED P-MECP2 (PS421MECP2) EXPRESSION WAS DETECTED IN THE CELLS OF THE SPINAL DORSAL HORN UNDER CONTROL CONDITIONS. COLONIC INFLAMMATION TRIGGERED A SIGNIFICANT DECREASE IN THE NUMBER OF MECP2-EXPRESSING NEURONS IN PARALLEL WITH ELEVATED NUMBERS OF PS421MECP2-EXPRESSING CELLS AT 2 H AND 6 H POST-TNBS. THE MAJORITY OF MECP2-POSITIVE CELLS (80 +/- 6%) CO-EXPRESSED CREB. TNBS TREATMENT CAUSED A TRANSIENT UP-REGULATION OF CREB-EXPRESSING CELLS AT 1 H POST-TNBS ONLY. THE NUMBER OF CELLS EXPRESSING PHOSPHORYLATED CREB (PS133CREB) DID NOT CHANGE AT 1 H AND 2 H POST-TNBS, BUT WAS DOWN-REGULATED BY THREE FOLDS AT 6 H POST-TNBS. ANALYSIS OF DRG SECTIONS REVEALED THAT THE NUMBER OF MECP2-POSITIVE NEURONS WAS UP-REGULATED BY TNBS TREATMENT, REACHING THREE-FOLD INCREASE AT 2 H POST-TNBS, AND EIGHT-FOLD INCREASE AT 6 H POST-TNBS (P </= 0.05 TO CONTROL). THESE DATA SHOWED EARLY CHANGES IN MECP2 AND CREB EXPRESSION IN THE DORSAL HORN OF THE SPINAL CORD AND SENSORY GANGLIA AFTER COLONIC INFLAMMATION, SUGGESTING A POSSIBLE CONTRIBUTION MECP2 AND CREB SIGNALING IN THE DEVELOPMENT OF VISCERAL HYPERALGESIA AND PELVIC PAIN FOLLOWING PERIPHERAL INFLAMMATION.	2018