1 3127 118 GINSENOSIDE RG1 REDUCED MICROGLIAL ACTIVATION AND MITOCHONDRIAL DYSFUNCTION TO ALLEVIATE DEPRESSION-LIKE BEHAVIOUR VIA THE GAS5/EZH2/SOCS3/NRF2 AXIS. GINSENOSIDE RG1 IS THE PRINCIPAL ACTIVE INGREDIENT IN GINSENG. THE ANTIDEPRESSANT EFFECTS OF RG1 HAVE BEEN VALIDATED; HOWEVER, THE SPECIFIC UNDERLYING MECHANISM OF THIS EFFECT NEEDS FURTHER RESEARCH. RATS WERE SUBJECTED TO THE CHRONIC RESTRAINT STRESS (CRS) DEPRESSION MODEL. RG1, OR A POSITIVE CONTROL DRUG, WAS ADMINISTERED TO THE RATS. DEPRESSION-LIKE BEHAVIOURS WERE EVALUATED THROUGH BEHAVIOURAL EXPERIMENTS. CYTOKINE, MRNA, PROTEIN, ATP, AND MITOCHONDRIA DNA LEVELS WERE DETECTED USING THE INDICATED METHODS. LENTIVIRUS-PACKAGED PLASMIDS WERE INJECTED INTO THE RAT BRAIN FOR GAS5 OVEREXPRESSION OR KNOCKDOWN. IN VITRO MITOCHONDRIAL DYSFUNCTION WAS EVALUATED BY DETECTING MITOCHONDRIAL REACTIVE OXYGEN SPECIES AND MITOCHONDRIAL MEMBRANE POTENTIAL. DIRECT INTERACTION BETWEEN GAS5 AND EZH2 WAS VALIDATED BY RNA IMMUNOPRECIPITATION AND RNA PULL-DOWN ASSAY. THE ENRICHMENT OF EZH2 AND H3K27ME3 WAS EVALUATED THROUGH CHROMATIN IMMUNOPRECIPITATION QUANTITATIVE REAL-TIME PCR. RG1 TREATMENT ALLEVIATED DEPRESSION-LIKE BEHAVIOURS, MICROGLIAL ACTIVATION, AND MITOCHONDRIAL DYSFUNCTION IN CRS RATS. SIMILARLY, GAS5 KNOCKDOWN REVEALED A SIMILAR PROTECTIVE EFFECT OF RG1 TREATMENT. GAS5 OVEREXPRESSION IN THE RAT BRAIN COMPROMISED THE PROTECTIVE EFFECT OF RG1 TREATMENT. MOREOVER, RG1 TREATMENT OR GAS5 KNOCKDOWN ATTENUATED MICROGLIAL ACTIVATION AND MITOCHONDRIAL DYSFUNCTION IN VITRO. MECHANICALLY, GAS5 WAS SUPPRESSED SOCS3 AND NRF2 EXPRESSION BY FACILITATING EZH2-MEDIATED TRANSCRIPTIONAL REPRESSION. RG1 ATTENUATED MICROGLIAL ACTIVATION AND IMPROVED MITOCHONDRIAL DYSFUNCTION IN DEPRESSION BY DOWNREGULATING GAS5 EXPRESSION. MECHANICALLY, GAS5 MIGHT REGULATE MICROGLIAL ACTIVATION AND MITOCHONDRIAL DYSFUNCTION VIA THE EPIGENETIC SUPPRESSION OF NRF2 AND SOCS3.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
2  433  32 ANTIDEPRESSANT TREATMENT IS ASSOCIATED WITH EPIGENETIC ALTERATIONS OF HOMER1 PROMOTER IN A MOUSE MODEL OF CHRONIC DEPRESSION. BACKGROUND: UNDERSTANDING THE NEUROBIOLOGY OF DEPRESSION AND THE MECHANISM OF ACTION OF THERAPEUTIC MEASURES IS CURRENTLY A RESEARCH PRIORITY. WE HAVE SHOWN THAT THE EXPRESSION OF THE SYNAPTIC PROTEIN HOMER1A CORRELATES WITH DEPRESSION-LIKE BEHAVIOR AND ITS INDUCTION IS A COMMON MECHANISM OF ACTION OF DIFFERENT ANTIDEPRESSANT TREATMENTS. HOWEVER, THE MECHANISM OF HOMER1A REGULATION IS STILL UNKNOWN. METHODS: WE COMBINED THE CHRONIC DESPAIR MOUSE MODEL (CDM) OF CHRONIC DEPRESSION WITH DIFFERENT ANTIDEPRESSANT TREATMENTS. DEPRESSION-LIKE BEHAVIOR WAS CHARACTERIZED BY FORCED SWIM AND TAIL SUSPENSION TESTS, AND VIA AUTOMATIC MEASUREMENT OF SUCROSE PREFERENCE IN INTELLICAGE. THE HOMER1 MRNA EXPRESSION AND PROMOTER DNA METHYLATION WERE ANALYZED IN CORTEX AND PERIPHERAL BLOOD BY QRT-PCR AND PYROSEQUENCING. RESULTS: CDM MICE SHOW DECREASED HOMER1A AND HOMER1B/C MRNA EXPRESSION IN CORTEX AND BLOOD SAMPLES, WHILE CHRONIC TREATMENT WITH IMIPRAMINE AND FLUOXETINE OR ACUTE KETAMINE APPLICATION INCREASES THEIR LEVEL ONLY IN THE CORTEX. THE QUANTITATIVE ANALYSES OF THE METHYLATION OF 7 CPG SITES, LOCATED ON THE HOMER1 PROMOTER REGION CONTAINING SEVERAL CRE BINDING SITES, SHOW A SIGNIFICANT INCREASE IN DNA METHYLATION IN THE CORTEX OF CDM MICE. IN CONTRAST, ANTIDEPRESSANT TREATMENTS REDUCE THE METHYLATION LEVEL. LIMITATIONS: HOMER1 EXPRESSION AND PROMOTOR METHYLATION WERE NOT ANALYZED IN DIFFERENT BLOOD CELL TYPES. OTHER CPG SITES OF HOMER1 PROMOTER SHOULD BE INVESTIGATED IN FUTURE STUDIES. OUR EXPERIMENTAL APPROACH DOES NOT DISTINGUISH BETWEEN METHYLATION AND HYDROXYMETHYLATION. CONCLUSIONS: WE DEMONSTRATE THAT STRESS-INDUCED DEPRESSION-LIKE BEHAVIOR AND ANTIDEPRESSANT TREATMENTS ARE ASSOCIATED WITH EPIGENETIC ALTERATIONS OF HOMER1 PROMOTER, PROVIDING NEW INSIGHTS INTO THE MECHANISM OF ANTIDEPRESSANT TREATMENT.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
3 1328  37 DEPRESSION AND STRESS LEVELS INCREASE RISK OF LIVER CANCER THROUGH EPIGENETIC DOWNREGULATION OF HYPOCRETIN. RECENT STUDIES SUGGEST THAT HYPOCRETIN (HCRT, OREXIN) ARE INVOLVED IN STRESS REGULATION OF DEPRESSION THROUGH THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS. HOWEVER, THE MOLECULAR MECHANISM BY WHICH HYPOCRETIN REGULATE NEUROBIOLOGICAL RESPONSES IS UNKNOWN. HEREIN, THE EFFECTS OF CHRONIC STRESS ON THE EPIGENETIC MODIFICATION OF HCRT AND ITS ASSOCIATION WITH DEPRESSION WERE EXPLORED WITH REGARD TO A POTENTIAL ROLE IN CANCER PROGRESSION. IN THE STUDY, SPRAGUE DAWLEY (SD) RATS WERE USED TO ESTABLISH AN ANIMAL MODEL OF CANCER WITH DEPRESSION BY ADMINISTRATING N-NITROSODIETHYLAMINE (DEN) AND CHRONIC UNPREDICTABLE MILD STRESS (CUMS). RNA-SEQUENCING WAS USED TO DETECT DIFFERENTIALLY EXPRESSED GENES IN THE HIPPOCAMPUS OF RATS AND QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION (QRT-PCR) WAS USED TO VALIDATE THE RESULTS OF RNA-SEQUENCING. THE STATUS OF HCRT PROMOTER METHYLATION WAS ASSESSED BY METHYLATION SPECIFIC POLYMERASE CHAIN REACTION. BEHAVIORAL TESTS SHOWED THAT RATS EXPOSED TO CUMS HAD SIGNIFICANT DEPRESSIVE-LIKE BEHAVIORS. THE NUMBER OF LIVER TUMORS AND TUMOR LOAD IN DEPRESSED RATS EXPOSED TO CUMS WAS HIGHER THAN IN SD RATS WITHOUT CUMS. RNA-SEQUENCING REVEALED THAT HCRT WAS ONE OF THE MOST SIGINIFICANTLY DOWNREGULATED GENE IN THE HIPPOCAMPUS OF SD RATS WITH CUMS COMPARED TO NON-STRESSED GROUP, WHICH WAS VALIDATED BY QRT-PCR. HCRT MRNA EXPRESSION WAS DOWNREGULATED AND THE PROMOTER FOR HCRT WAS HYPER-METHYLATED IN THOSE WITH DEPRESSION. THESE RESULTS IDENTIFIED A CRITICAL ROLE FOR CHRONIC PSYCHOLOGICAL STRESSORS IN TUMORIGENESIS AND CANCER PROGRESSION, VIA EPIGENETIC HCRT DOWNREGULATION. SUCH EPIGENETIC DOWNREGULATION MAY BE THE MOLECULAR BASIS FOR THE ASSOCIATION OF CANCER WITH DEPRESSION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
4 4580  32 N(6)-METHYLADENOSINE MODIFICATION OF FATTY ACID AMIDE HYDROLASE MESSENGER RNA IN CIRCULAR RNA STAG1-REGULATED ASTROCYTE DYSFUNCTION AND DEPRESSIVE-LIKE BEHAVIORS. BACKGROUND: N(6)-METHYLADENOSINE (M(6)A) IS THE MOST ABUNDANT EPIGENETIC MODIFICATION IN EUKARYOTIC MESSENGER RNAS AND IS ESSENTIAL FOR MULTIPLE RNA PROCESSING EVENTS IN PHYSIOLOGICAL AND PATHOLOGICAL PROCESSES. HOWEVER, PRECISELY HOW M(6)A METHYLATION IS INVOLVED IN MAJOR DEPRESSIVE DISORDER (MDD) IS NOT FULLY UNDERSTOOD. METHODS: CIRCULAR RNA STAG1 (CIRCSTAG1) WAS SCREENED FROM THE HIPPOCAMPUS OF CHRONIC UNPREDICTABLE STRESS-TREATED MICE USING HIGH-THROUGHPUT RNA SEQUENCING. MICROINJECTION OF CIRCSTAG1 LENTIVIRUS INTO THE MOUSE HIPPOCAMPUS WAS USED TO OBSERVE THE ROLE OF CIRCSTAG1 IN DEPRESSION. SUCROSE PREFERENCE, FORCED SWIM, AND TAIL SUSPENSION TESTS WERE PERFORMED TO EVALUATE THE DEPRESSIVE-LIKE BEHAVIORS OF MICE. ASTROCYTE DYSFUNCTION WAS EXAMINED BY GFAP IMMUNOSTAINING AND 3D RECONSTRUCTION. METHYLATED RNA IMMUNOPRECIPITATION SEQUENCE ANALYSIS WAS USED TO IDENTIFY DOWNSTREAM TARGETS OF CIRCSTAG1/ALKBH5 (ALKB HOMOLOG 5) AXIS. CELL COUNTING KIT-8 ASSAY WAS PERFORMED TO EVALUATE ASTROCYTE VIABILITY IN VITRO. RESULTS: CIRCSTAG1 WAS SIGNIFICANTLY DECREASED IN THE CHRONIC UNPREDICTABLE STRESS-TREATED MOUSE HIPPOCAMPUS AND IN PERIPHERAL BLOOD OF PATIENTS WITH MDD. OVEREXPRESSION OF CIRCSTAG1 NOTABLY ATTENUATED ASTROCYTE DYSFUNCTION AND DEPRESSIVE-LIKE BEHAVIORS INDUCED BY CHRONIC UNPREDICTABLE STRESS. FURTHER EXAMINATION INDICATED THAT OVEREXPRESSED CIRCSTAG1 CAPTURED ALKBH5 AND DECREASED THE TRANSLOCATION OF ALKBH5 INTO THE NUCLEUS, LEADING TO INCREASED M(6)A METHYLATION OF FATTY ACID AMIDE HYDROLASE (FAAH) MESSENGER RNA AND DEGRADATION OF FAAH IN ASTROCYTES WITH SUBSEQUENT ATTENUATION OF DEPRESSIVE-LIKE BEHAVIORS AND ASTROCYTE LOSS INDUCED BY CORTICOSTERONE IN VITRO. CONCLUSIONS: OUR FINDINGS DISSECT THE FUNCTIONAL LINK BETWEEN CIRCSTAG1 AND M(6)A METHYLATION IN THE CONTEXT OF MDD, PROVIDING EVIDENCE THAT CIRCSTAG1 MAY BE A NOVEL THERAPEUTIC TARGET FOR MDD.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
5 4742  26 NOVEL HISTONE MODIFICATIONS IN MICROGLIA DERIVED FROM A MOUSE MODEL OF CHRONIC PAIN. AS THE RESIDENT IMMUNE CELLS IN THE CENTRAL NERVOUS SYSTEM, MICROGLIA PLAY AN IMPORTANT ROLE IN THE MAINTENANCE OF ITS HOMEOSTASIS. DYSREGULATION OF MICROGLIA HAS BEEN ASSOCIATED WITH THE DEVELOPMENT AND MAINTENANCE OF CHRONIC PAIN. HOWEVER, THE RELEVANT MOLECULAR PATHWAYS REMAIN POORLY DEFINED. IN THIS STUDY, WE USED A MASS SPECTROMETRY-BASED PROTEOMIC APPROACH TO SCREEN POTENTIAL CHANGES OF HISTONE PROTEIN MODIFICATIONS IN MICROGLIA ISOLATED FROM THE BRAIN OF CONTROL AND CISPLATIN-INDUCED NEUROPATHIC PAIN ADULT C57BL/6J MALE MICE. WE IDENTIFIED SEVERAL NOVEL MICROGLIAL HISTONE MODIFICATIONS ASSOCIATED WITH PAIN, INCLUDING STATISTICALLY SIGNIFICANTLY DECREASED HISTONE H3.1 LYSINE 27 MONO-METHYLATION (H3.1K27ME1, 54.8% OF CONTROL) AND H3 LYSINE 56 TRI-METHYLATION (7.5% OF CONTROL), AS WELL AS A TREND SUGGESTING INCREASED H3 TYROSINE 41 NITRATION. WE FURTHER INVESTIGATED THE FUNCTIONAL ROLE OF H3.1K27ME1 AND FOUND THAT TREATMENT OF CULTURED MICROGLIAL CELLS FOR 4 CONSECUTIVE DAYS WITH 1-10 MUM OF NCDM-64, A POTENT AND SELECTIVE INHIBITOR OF LYSINE DEMETHYLASE 7A, AN ENZYME RESPONSIBLE FOR THE DEMETHYLATION OF H3K27ME1, DOSE-DEPENDENTLY ELEVATED ITS LEVELS WITH A GREATER THAN A TWO-FOLD INCREASE OBSERVED AT 10 MUM COMPARED TO VEHICLE-TREATED CONTROL CELLS. MOREOVER, PRETREATMENT OF MICE WITH NCDM-64 (10 OR 25 MG/KG/DAY, I.P.) PRIOR TO CISPLATIN TREATMENT PREVENTED THE DEVELOPMENT OF NEUROPATHIC PAIN IN MICE. THE IDENTIFICATION OF SPECIFIC CHROMATIN MARKS IN MICROGLIA ASSOCIATED WITH CHRONIC PAIN MAY YIELD CRITICAL INSIGHT INTO THE CONTRIBUTION OF MICROGLIA TO THE DEVELOPMENT AND MAINTENANCE OF PAIN, AND OPENS NEW AVENUES FOR THE DEVELOPMENT OF NOVEL NONOPIOID THERAPEUTICS FOR THE EFFECTIVE MANAGEMENT OF CHRONIC PAIN.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
6 5205  32 PRENATAL STRESS CHANGES THE GLYCOPROTEIN GPM6A GENE EXPRESSION AND INDUCES EPIGENETIC CHANGES IN RAT OFFSPRING BRAIN. PRENATAL STRESS (PS) EXERTS STRONG IMPACT ON FETAL BRAIN DEVELOPMENT AND ON ADULT OFFSPRING BRAIN FUNCTIONS. PREVIOUS WORK DEMONSTRATED THAT CHRONIC STRESS ALTERS THE MRNA EXPRESSION OF GPM6A, A NEURONAL GLYCOPROTEIN INVOLVED IN FILOPODIUM EXTENSION. IN THIS WORK, WE ANALYZED THE EFFECT OF PS ON GPM6A EXPRESSION AND THE EPIGENETIC MECHANISMS INVOLVED. PREGNANT WISTAR RATS RECEIVED RESTRAINT STRESS DURING THE LAST WEEK OF GESTATION. MALE OFFSPRING WERE SACRIFICED ON POSTNATAL DAYS 28 AND 60. HIPPOCAMPUS AND PREFRONTAL CORTEX SAMPLES WERE ANALYZED FOR GENE EXPRESSION (QPCR FOR MRNAS AND MICRORNAS), METHYLATION STATUS (BISULFITE CONVERSION) AND PROTEIN LEVELS. HIPPOCAMPAL NEURONS IN CULTURE WERE USED TO ANALYZE MICRORNA OVEREXPRESSION EFFECTS. PRENATAL STRESS INDUCED CHANGES IN GPM6A LEVELS IN BOTH TISSUES AND AT BOTH AGES ANALYZED, INDICATING A PERSISTENT EFFECT. TWO CPG ISLANDS IN THE GPM6A GENE WERE IDENTIFIED. VARIATIONS IN THE METHYLATION PATTERN AT THREE SPECIFIC CPGS WERE FOUND IN HIPPOCAMPUS, BUT NOT IN PFC SAMPLES FROM PS OFFSPRING. MICRORNAS PREDICTED TO TARGET GPM6A WERE IDENTIFIED IN SILICO. QPCR MEASUREMENTS SHOWED THAT PS MODIFIED THE EXPRESSION OF SEVERAL MICRORNAS IN BOTH TISSUES, BEING MICRORNA-133B THE MOST SIGNIFICANTLY ALTERED. FURTHER STUDIES OVEREXPRESSING THIS MICRORNA IN NEURONAL CULTURES SHOWED A REDUCTION IN GMP6A MRNA AND PROTEIN LEVEL. MOREOVER FILOPODIUM DENSITY WAS ALSO REDUCED, SUGGESTING THAT GPM6A FUNCTION WAS AFFECTED. GESTATIONAL STRESS AFFECTED GPM6A GENE EXPRESSION IN OFFSPRING LIKELY THROUGH CHANGES IN METHYLATION STATUS AND IN POSTTRANSCRIPTIONAL REGULATION BY MICRORNAS. THUS, OUR FINDINGS PROPOSE GPM6A AS A NOVEL TARGET FOR EPIGENETIC REGULATION DURING PRENATAL STRESS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
7 4499  21 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
8 6429  33 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
9 6804  38 [EPIGENETIC REGULATION IN DEPRESSION]. RECENT RESEARCH HAS RAISED THE NOTION THAT EPIGENETIC MECHANISMS (E.G., DNA METHYLATION AND HISTONE MODIFICATIONS), WHICH EXERT LASTING CONTROL OVER GENE EXPRESSION WITHOUT ALTERING THE GENETIC CODE, COULD MEDIATE STABLE CHANGES IN BRAIN FUNCTION. HOWEVER, THE ROLE OF ENVIRONMENTAL FACTORS ALONG WITH GENETIC FACTORS IN THE EPIGENETIC REGULATION OF THE PATHOGENESIS OF DEPRESSION IS LARGELY UNKNOWN. TWO GENETICALLY DISTINCT MICE STRAINS, BALB/C (BALB) AND C57BL/6 (B6), EXHIBIT DIFFERENT BEHAVIORAL RESPONSES TO CHRONIC STRESS. WITH CHRONIC STRESS, BALB MICE SHOWED DEPRESSIVE-LIKE BEHAVIORS, BUT NOT B6 MICE, AND GLIAL CELL-DERIVED NEUROTROPHIC FACTOR (GDNF) EXPRESSION LEVEL WAS DECREASED IN THE VENTRAL STRIATUM OF BALB MICE BUT INCREASED IN B6 MICE. IN BALB MICE, DEPRESSIVE-LIKE BEHAVIORS AND DECREASED GDNF EXPRESSION WERE RECOVERED BY CHRONIC ANTIDEPRESSANT TREATMENT. THEREFORE, WE USED THESE TWO MICE STRAINS TO INVESTIGATE HOW THE EPIGENETIC STATUS OF THE GDNF GENE IN THE VENTRAL STRIATUM MODULATES STRESS VULNERABILITY. BOTH MICE STRAINS SHOWED INCREASED DNA METHYLATION LEVELS AND MECP2 RECRUITMENT IN THE GDNF PROMOTER REGION. HOWEVER, HISTONE H3 ACETYLATION LEVEL WAS DECREASED IN BALB MICE, BUT INCREASED IN B6 MICE. FURTHERMORE, BALB MICE SHOWED INCREASED HISTONE DEACETYLASE2 (HDAC2) EXPRESSION LEVEL AND RE-CHIP ASSAY REVEALED HDAC2-MECP2 COMPLEX IN BALB MICE. OUR RESULTS INDICATE THE CRUCIAL ROLE OF HISTONE MODIFICATION BY HDAC2 AND MECP2 COMPLEX FOR THE CONTROL OF GDNF EXPRESSION AND SUBSEQUENT BEHAVIORAL RESPONSES TO CHRONIC STRESS, IN OTHER WORDS, THE SUSCEPTIBILITY TO STRESS. IN ADDITION, WE INVESTIGATED THE EFFECT OF ANTIDEPRESSANTS ON THE EPIGENETIC REGULATION OF GDNF EXPRESSION. WE FOUND A REDUCED LEVEL OF HDAC4 RECRUITMENT AT THE GDNF PROMOTER REGION WITH ANTIDEPRESSANTS. THUS, OUR DATA SUGGEST THAT ANTIDEPRESSANTS INCREASE TRANSCRIPTIONAL ACTIVITY OF THE GDNF GENE THROUGH THE MODULATION OF HISTONE ACETYLATION BY HDAC4. FINALLY, WE EXAMINED THE EXPRESSIONS OF GDNF AND EPIGENETIC-RELATED MOLECULES MRNAS WITH MAJOR DEPRESSIVE AND BIPOLAR DISORDER PATIENTS BY USING QUANTITATIVE REAL-TIME PCR. WE FOUND THE ABERRANT EXPRESSION OF GDNF AND EPIGENETIC-RELATED GENES INCLUDING HDAC2 AND HDAC4 IN MOOD DISORDER PATIENTS. THUS, OUR DATA PROVIDE NOVEL INSIGHTS SUGGESTING THAT EPIGENETIC MECHANISMS OF GDNF EXPRESSION ARE INVOLVED IN THE PATHOGENESIS OR PATHOPHYSIOLOGY OF DEPRESSION.	2012	
                                                                                                                                                                                                                                                                                                                
10  984  31 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
11 5832  24 STRESS-INDUCED EPIGENETIC CHANGES IN HIPPOCAMPAL MKP-1 PROMOTE PERSISTENT DEPRESSIVE BEHAVIORS. CHRONIC STRESS INDUCES PERSISTENT DEPRESSIVE BEHAVIORS. STRESS-INDUCED TRANSCRIPTIONAL ALTERATION OVER THE HOMEOSTATIC RANGE IN STRESS HORMONE-SENSITIVE BRAIN REGIONS IS BELIEVED TO UNDERLIE LONG-LASTING DEPRESSIVE BEHAVIORS. HOWEVER, THE DETAILED MECHANISMS BY WHICH CHRONIC STRESS CAUSES THOSE ADAPTIVE CHANGES ARE NOT CLEARLY UNDERSTOOD. IN THE PRESENT STUDY, WE INVESTIGATED WHETHER EPIGENETIC CHANGES REGULATE STRESS-INDUCED DEPRESSIVE BEHAVIORS. WE FOUND THAT CHRONIC STRESS IN MICE DOWNREGULATES THE EPIGENETIC FACTORS HDAC2 AND SUV39H1 IN THE HIPPOCAMPUS. A SERIES OF FOLLOW-UP ANALYSES INCLUDING CHIP ASSAY AND SIRNA-MEDIATED FUNCTIONAL ANALYSES REVEAL THAT GLUCOCORTICOIDS RELEASED BY STRESS CUMULATIVELY INCREASE MKP-1 EXPRESSION IN THE HIPPOCAMPUS, AND INCREASED MKP-1 THEN DEBILITATES P-CREB AND PPARGAMMA, WHICH IN TURN SUPPRESS THE EPIGENETIC FACTORS HDAC2 AND SUV39H1. FURTHERMORE, HDAC2 AND SUV39H1 NORMALLY SUPPRESS THE TRANSCRIPTION OF THE MKP-1, AND THEREFORE THE REDUCED EXPRESSION OF HDAC2 AND SUV39H1 INCREASES MKP-1 EXPRESSION. ACCORDINGLY, REPEATED STRESS PROGRESSIVELY STRENGTHENS A VICIOUS CYCLE OF THE MKP-1 SIGNALING CASCADE THAT FACILITATES DEPRESSIVE BEHAVIORS. THESE RESULTS SUGGEST THAT THE HIPPOCAMPAL STRESS ADAPTATION SYSTEM COMPRISING HDAC2/SUV39H1-REGULATED MKP-1 SIGNALING NETWORK DETERMINES THE VULNERABILITY TO CHRONIC STRESS AND THE MAINTENANCE OF DEPRESSIVE BEHAVIORS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
12 2470  28 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 6148  26 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	
                                                                                                                                                                                                                             
14 2246  21 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
15 5825  24 STRESS MODULATES AHI1-DEPENDENT NUCLEAR LOCALIZATION OF TEN-ELEVEN TRANSLOCATION PROTEIN 2. MAJOR DEPRESSION DISORDER IS ONE OF THE MOST COMMON PSYCHIATRIC DISEASES. RECENT EVIDENCE SUPPORTS THAT ENVIRONMENTAL STRESS AFFECTS GENE EXPRESSION AND PROMOTES THE PATHOLOGICAL PROCESS OF DEPRESSION THROUGH EPIGENETIC MECHANISMS. THREE TEN-ELEVEN TRANSLOCATION (TET) ENZYMES ARE EPIGENETIC REGULATORS OF GENE EXPRESSION THAT PROMOTE 5-HYDROXYMETHYLCYTOSINE (5HMC) MODIFICATION OF GENES. HERE, WE SHOW THAT THE LOSS OF TET2 CAN INDUCE DEPRESSION-LIKE PHENOTYPES IN MICE. PARADOXICALLY, USING THE PARADIGMS OF CHRONIC STRESS, SUCH AS CHRONIC MILD STRESS AND CHRONIC SOCIAL DEFEAT STRESS, WE FOUND THAT DEPRESSIVE BEHAVIORS WERE ASSOCIATED WITH INCREASED TET2 EXPRESSION BUT DECREASED GLOBAL 5HMC LEVEL IN HIPPOCAMPUS. WE EXAMINED THE GENOME-WIDE 5HMC PROFILE IN THE HIPPOCAMPUS OF TET2 KNOCKOUT MICE AND IDENTIFIED 651 DYNAMICALLY HYDROXYMETHYLATED REGIONS, SOME OF WHICH OVERLAPPED WITH KNOWN DEPRESSION-ASSOCIATED LOCI. WE FURTHER SHOWED THAT CHRONIC STRESS COULD INDUCE THE ABNORMAL NUCLEAR TRANSLOCATION OF TET2 PROTEIN FROM CYTOSOL. THROUGH TET2 IMMUNOPRECIPITATION AND MASS SPECTRUM ANALYSES, WE IDENTIFIED A CELLULAR TRAFFICKING PROTEIN, ABELSON HELPER INTEGRATION SITE-1 (AHI1), WHICH COULD INTERACT WITH TET2 PROTEIN. AHI1 KNOCKOUT OR KNOCKDOWN CAUSED THE ACCUMULATION OF TET2 IN CYTOSOL. THE REDUCTION OF AHI1 PROTEIN UNDER CHRONIC STRESS EXPLAINED THE ABNORMAL AHI1-DEPENDENT NUCLEAR TRANSLOCATION OF TET2. THESE FINDINGS TOGETHER PROVIDE THE EVIDENCE FOR A CRITICAL ROLE OF MODULATING TET2 NUCLEAR TRANSLOCATION IN REGULATING STRESS RESPONSE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
16 6411  36 THE SITE SPECIFIC DEMETHYLATION IN THE 5'-REGULATORY AREA OF NMDA RECEPTOR 2B SUBUNIT GENE ASSOCIATED WITH CIE-INDUCED UP-REGULATION OF TRANSCRIPTION. BACKGROUND: THE NMDA RECEPTOR REPRESENTS A PARTICULARLY IMPORTANT SITE OF ETHANOL ACTION IN THE CNS. WE RECENTLY REPORTED THAT NMDA RECEPTOR 2B (NR2B) GENE EXPRESSION WAS PERSISTENTLY UP-REGULATED FOLLOWING CHRONIC INTERMITTENT ETHANOL (CIE) TREATMENT. INCREASING EVIDENCE THAT EPIGENETIC MECHANISMS ARE INVOLVED IN DYNAMIC AND LONG-LASTING REGULATION OF GENE EXPRESSION IN MULTIPLE NEUROADAPTIVE PROCESSES PROMPTED US TO INVESTIGATE THE ROLE OF DNA METHYLATION IN MEDIATING CIE-INDUCED UP-REGULATION OF NR2B GENE TRANSCRIPTION. TO DISSECT THE CHANGES OF DNA METHYLATION IN THE NR2B GENE, WE HAVE SCREENED A LARGE NUMBER OF CPG SITES WITHIN ITS 5'-REGULATORY AREA FOLLOWING CIE TREATMENT. METHODS: PRIMARY CORTICAL CULTURED NEURONS WERE SUBJECTED TO ETHANOL TREATMENT IN A CIE PARADIGM. BISULFITE CONVERSION FOLLOWED BY PYROSEQUENCING WAS USED FOR QUANTITATIVE MEASUREMENT AND ANALYSIS OF CPG METHYLATION STATUS WITHIN THE 5'-REGULATORY AREA OF THE NR2B GENE; CHROMATIN IMMUNOPRECIPITATION (CHIP) ASSAY WAS USED TO EXAMINE DNA LEVELS ASSOCIATED WITH METHYLATION AND TRANSCRIPTION FACTOR BINDING. ELECTROPHORETIC MOBILITY SHIFT ASSAY (EMSA) AND IN VITRO DNA METHYLATION ASSAYS WERE PERFORMED TO DETERMINE THE DIRECT IMPACT OF DNA METHYLATION ON THE INTERACTION BETWEEN DNA AND TRANSCRIPTION FACTOR AND PROMOTER ACTIVITY. RESULTS: ANALYSIS OF INDIVIDUAL CPG METHYLATION SITES WITHIN THE NR2B 5'REGULATORY AREA REVEALED THREE REGIONS WITH CLUSTERS OF SITE-SPECIFIC CPG DEMETHYLATION FOLLOWING CIE TREATMENT AND WITHDRAWAL. THIS WAS CONFIRMED BY CHIP SHOWING SIMILAR DECREASES OF METHYLATED DNA IN THE SAME REGIONS. THE CIE-INDUCED DEMETHYLATION IS CHARACTERIZED BY BEING LOCATED NEAR CERTAIN TRANSCRIPTION FACTOR BINDING SEQUENCES, AP-1 AND CRE, AND OCCURRED DURING TREATMENT AS WELL AS AFTER ETHANOL WITHDRAWAL. FURTHERMORE, THE INCREASE IN VITRO OF METHYLATED DNA DECREASED TRANSCRIPTION FACTOR BINDING ACTIVITY AND PROMOTER ACTIVITY. AN ADDITIONAL CHIP ASSAY INDICATED THAT THE CIE-INDUCED DNA DEMETHYLATION IS ACCOMPANIED BY INCREASED OCCUPATION BY TRANSCRIPTION FACTORS. CONCLUSIONS: THESE RESULTS SUGGEST AN IMPORTANT ROLE OF DNA DEMETHYLATION IN MEDIATING CIE-INDUCED NR2B GENE UP-REGULATION, THUS IMPLICATING A NOVEL MOLECULAR SITE OF ALCOHOL ACTION.	2010	
                                                                                                                                                                                                                                                                                                                                                                   
17 4861  19 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
18 5339  25 QUETIAPINE TREATMENT REVERSES DEPRESSIVE-LIKE BEHAVIOR AND REDUCES DNA METHYLTRANSFERASE ACTIVITY INDUCED BY MATERNAL DEPRIVATION. STRESS IN EARLY LIFE HAS BEEN APPOINTED AS AN IMPORTANT PHENOMENON IN THE ONSET OF DEPRESSION AND POOR RESPONSE TO TREATMENT WITH CLASSICAL ANTIDEPRESSANTS. FURTHERMORE, CHILDHOOD TRAUMA TRIGGERS EPIGENETIC CHANGES, WHICH ARE ASSOCIATED WITH THE PATHOPHYSIOLOGY OF MAJOR DEPRESSIVE DISORDER (MDD). TREATMENT WITH ATYPICAL ANTIPSYCHOTICS SUCH AS QUETIAPINE, EXERTS THERAPEUTIC EFFECT FOR MDD PATIENTS AND INDUCES EPIGENETIC CHANGES. THIS STUDY AIMED TO ANALYZE THE EFFECT OF CHRONIC TREATMENT WITH QUETIAPINE (20MG/KG) ON DEPRESSIVE-LIKE BEHAVIOR OF RATS SUBMITTED TO MATERNAL DEPRIVATION (MD), AS WELL AS THE ACTIVITY OF HISTONE ACETYLATION BY THE ENZYMES HISTONE ACETYL TRANSFERASES (HAT) AND DEACETYLASES (HDAC) AND DNA METHYLATION, THROUGH DNA METHYLTRANSFERASE ENZYME (DNMT) IN THE PREFRONTAL CORTEX (PFC), NUCLEUS ACCUMBENS (NAC) AND HIPPOCAMPUS. MATERNALLY DEPRIVED RATS HAD A DEPRESSIVE-LIKE BEHAVIOR IN THE FORCED SWIMMING TEST AND AN INCREASE IN THE HDAC AND DNMT ACTIVITIES IN THE HIPPOCAMPUS AND NAC. TREATMENT WITH QUETIAPINE REVERSED DEPRESSIVE-LIKE BEHAVIOR AND REDUCED THE DNMT ACTIVITY IN THE HIPPOCAMPUS. THIS IS THE FIRST STUDY TO SHOW THE ANTIDEPRESSANT-LIKE EFFECT OF QUETIAPINE IN ANIMALS SUBJECTED TO MD AND A PROTECTIVE EFFECT BY QUETIAPINE IN REDUCING EPIGENETIC CHANGES INDUCED BY STRESS IN EARLY LIFE. THESE RESULTS REINFORCE AN IMPORTANT ROLE OF QUETIAPINE AS THERAPY FOR MDD.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
19 5152  31 PPM1F IN DENTATE GYRUS MODULATES ANXIETY-RELATED BEHAVIORS BY REGULATING BDNF EXPRESSION VIA AKT/JNK/P-H3S10 PATHWAY. ANXIETY IS A SERIOUS PSYCHIATRIC DISORDER, WITH A HIGHER INCIDENCE RATE IN WOMEN THAN IN MEN. PROTEIN PHOSPHATASE MG(2+)/MN(2+)-DEPENDENT 1F (PPM1F), A SERINE/THREONINE PHOSPHATASE, HAS BEEN SHOWN TO HAVE MULTIPLE BIOLOGICAL AND CELLULAR FUNCTIONS. HOWEVER, THE EFFECTS OF PPM1F AND ITS NEURONAL SUBSTRATES ON ANXIETY REMAIN LARGELY UNCLEAR. IN THIS STUDY, WE SHOWED THAT CHRONIC RESTRAINT STRESS (CRS) INDUCED ANXIETY-RELATED BEHAVIORS ONLY IN FEMALE MICE, WHILE ACUTE RESTRAINT STRESS (ARS) PRODUCED ANXIETY-RELATED BEHAVIORS IN BOTH MALE AND FEMALE MICE IN LIGHT-DARK AND ELEVATED PLUS MAZE TESTS AND INDUCED UPREGULATION OF PPM1F AND DOWNREGULATION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION IN THE HIPPOCAMPUS. ADENO-ASSOCIATED VIRUS-MEDIATED OVEREXPRESSION OF PPM1F OR CONDITIONAL KNOCKOUT OF BDNF IN DENTATE GYRUS (DG) LED TO A MORE PRONOUNCED ANXIETY-RELATED BEHAVIOR IN FEMALE THAN IN MALE MICE AS INDICATED BY THE BEHAVIORAL EVALUATIONS. MEANWHILE, OVEREXPRESSION OF PPM1F IN THE DG DECREASED TOTAL BDNF EXON-SPECIFIC MESSENGER RNA EXPRESSION IN THE HIPPOCAMPUS WITH THE DECREASED BINDING ACTIVITY OF PHOSPHORYLATED H3S10 TO ITS INDIVIDUAL PROMOTERS IN FEMALE MICE. FURTHERMORE, WE IDENTIFIED THAT OVEREXPRESSION OF PPM1F DECREASED THE PHOSPHORYLATION LEVELS OF AKT AND JNK IN THE HIPPOCAMPUS OF FEMALE MICE. THESE RESULTS MAY SUGGEST THAT PPM1F REGULATES ANXIETY-RELATED BEHAVIORS BY MODULATING BDNF EXPRESSION AND H3S10 PHOSPHORYLATION-MEDIATED EPIGENETIC MODIFICATION, WHICH MAY BE SERVED AS POTENTIALLY PATHOLOGICAL GENES ASSOCIATED WITH ANXIETY OR OTHER MENTAL DISEASES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
20 2672  25 ETHANOL-INDUCED EPIGENETIC REGULATIONS AT THE BDNF GENE IN C57BL/6J MICE. HIGH ETHANOL INTAKE IS WELL KNOWN TO INDUCE BOTH ANXIOLYTIC AND ANXIOGENIC EFFECTS, IN CORRELATION WITH CHROMATIN REMODELING IN THE AMYGDALOID BRAIN REGION AND DEFICITS IN CELL PROLIFERATION AND SURVIVAL IN THE HIPPOCAMPUS OF RODENTS. WHETHER ONLY MODERATE BUT CHRONIC ETHANOL INTAKE IN C57BL/6J MICE COULD ALSO HAVE AN IMPACT ON CHROMATIN REMODELING AND NEUROPLASTICITY WAS ADDRESSED HERE. CHRONIC ETHANOL CONSUMPTION IN A FREE CHOICE PARADIGM WAS FOUND TO INDUCE MARKED CHANGES IN THE EXPRESSION OF GENES IMPLICATED IN NEURAL DEVELOPMENT AND HISTONE POST-TRANSLATIONAL MODIFICATIONS IN THE MOUSE HIPPOCAMPUS. TRANSCRIPTS ENCODING NEURAL BHLH ACTIVATORS AND THOSE FROM BDNF EXONS II, III AND VI WERE UPREGULATED, WHEREAS THOSE FROM BDNF EXON VIII AND HDACS WERE DOWNREGULATED BY ETHANOL COMPARED WITH WATER CONSUMPTION. THESE ETHANOL-INDUCED CHANGES WERE ASSOCIATED WITH ENRICHMENT IN BOTH ACETYLATED H3 AT BDNF PROMOTER PVI AND TRIMETHYLATED H3 AT PII AND PIII. CONVERSELY, ACETYLATED H3 AT PIII AND PVIII AND TRIMETHYLATED H3 AT PVIII WERE DECREASED IN ETHANOL-EXPOSED MICE. IN PARALLEL, HIPPOCAMPAL BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) LEVELS AND TRKB-MEDIATED NEUROGENESIS IN THE DENTATE GYRUS WERE SIGNIFICANTLY ENHANCED BY ETHANOL CONSUMPTION. THESE RESULTS SUGGEST THAT, IN C57BL/6J MICE, CHRONIC AND MODERATE ETHANOL INTAKE PRODUCES MARKED EPIGENETIC CHANGES UNDERLYING BDNF OVEREXPRESSION AND DOWNSTREAM HIPPOCAMPAL NEUROGENESIS.	2015