1 2732 157 EXPLORING THE EPIGENETIC REGULATED MODULATION OF FIBROBLAST GROWTH FACTOR 21 INVOLVEMENT IN HIGH-FAT DIET ASSOCIATED PARKINSON'S DISEASE IN RATS. IMBALANCE IN BRAIN GLUCOSE METABOLISM AND EPIGENETIC MODULATION DURING THE DISEASE COURSE OF INSULIN RESISTANCE (IR) ASSOCIATED WITH PARKINSON'S DISEASE (PD) RISK REMAINS A PRIME CONCERN. FIBROBLAST GROWTH FACTOR 21 (FGF21), THE METABOLIC HORMONE, IMPROVES INSULIN SENSITIVITY AND ELICITS ANTI-DIABETIC PROPERTIES. CHRONIC STRESS DURING BRAIN IR MAY MODULATE THE FGF21 EXPRESSION AND ITS DYNAMIC RELEASE VIA EPIGENETIC MODIFICATIONS. METFORMIN REGULATES AND INCREASES THE EXPRESSION OF FGF21 WHICH CAN BE MODULATING IN OBESITY, DIABETES, AND IR. HENCE, THIS STUDY WAS DESIGNED TO INVESTIGATE THE FGF21 EXPRESSION MODULATION VIA AN EPIGENETIC MECHANISM IN PD AND WHETHER METFORMIN (MF), AN AUTOPHAGY ACTIVATOR, AND SODIUM BUTYRATE (NAB), A PAN HISTONE DEACETYLASE INHIBITOR, ALONE AND IN COMBINATION, EXERT ANY THERAPEUTIC BENEFIT IN PD PATHOLOGY EXACERBATED BY HIGH-FAT DIET (HFD). OUR RESULTS PORTRAY THAT THE COMBINATION TREATMENT WITH MF AND NAB POTENTIALLY ATTENUATED THE ABNORMAL LIPID PROFILE AND INCREASED MOTOR PERFORMANCE FOR THE RATS FED WITH HFD FOR 8 WEEKS FOLLOWED BY INTRASTRIATAL 6-HYDROXY DOPAMINE ADMINISTRATION. THE ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA) ESTIMATIONS OF C-REACTIVE PROTEIN, TUMOR NECROSIS FACTOR-ALPHA, INTERLEUKIN-1 BETA AND 6, AND FGF21 EXHIBITED EXTENSIVE DOWNREGULATION AFTER TREATMENT WITH THE COMBINATION. LASTLY, MRNA, WESTERN BLOT, HISTOLOGICAL, AND CRESYL VIOLET STAINING DEPICTED THAT THE COMBINATION TREATMENT CAN RESTORE DEGENERATED NEURONAL DENSITY AND INCREASE THE PROTEIN LEVEL COMPARED TO THE DISEASE GROUP. THE FINDINGS FROM THE STUDY EFFECTIVELY CONCLUDE THAT THE EPIGENETIC MECHANISM INVOLVED IN FGF21 MEDIATED FUNCTIONAL ABNORMALITIES IN IR-LINKED PD PATHOLOGY. HENCE, COMBINED TREATMENT WITH MF AND NAB MAY PROVE TO BE A NOVEL COMBINATION IN AMELIORATING IR-ASSOCIATED PD IN RATS, PROBABLY VIA THE UPREGULATION OF FGF21 EXPRESSION. 2023 2 2437 36 EPIGENETIC SILENCING OF SONIC HEDGEHOG ELICITS ANTITUMOR IMMUNE RESPONSE AND SUPPRESSES TUMOR GROWTH BY INHIBITING THE HEDGEHOG SIGNALING PATHWAY IN METASTATIC SPINE TUMORS IN SPRAGUE-DAWLEY RATS. BACKGROUND: PATIENTS WITH METASTATIC SPINE TUMORS MAY SUFFER FROM PAIN OR NEUROLOGIC DEFICIT, AND THE DISEASE MAY BE DETECTED IN PATIENTS WITH A KNOWN MALIGNANCY. SONIC HEDGEHOG (SHH) HAS RECEIVED SPECIAL ATTENTION DUE TO ITS ROLE IN CANCERS. THEREFORE, THIS STUDY INVESTIGATED THE EFFECTS OF EPIGENETIC SILENCING OF SHH ON ANTITUMOR IMMUNE RESPONSE AND TUMOR GROWTH BY REGULATING THE HEDGEHOG (HH) SIGNALING PATHWAY IN METASTATIC SPINE TUMORS. METHODS: RAT MODELS OF METASTATIC SPINE TUMORS WERE SUCCESSFULLY ESTABLISHED. WE FIRST CALCULATED THE TUMOR VOLUME AND THE INHIBITION RATE OF TUMOR GROWTH TO INVESTIGATE THE EFFECT OF SHH ON TUMOR GROWTH. AFTERWARDS, IMMUNOHISTOCHEMISTRY WAS USED TO DETERMINE WHETHER PROLIFERATION WAS DELAYED BY SHH DEPLETION, AND THE 3-(4,5-DIMETHYLTHIAZOL-2-YL)-2,5-DIPHENYLTETRAZOLIUM BROMIDE ASSAY WAS CONDUCTED TO TEST THE CHANGES IN THE LYMPHOCYTE TRANSFORMATION RATE IN THE SPLEEN TRIGGERED BY SHH SILENCING. THEN, THE INFLUENCE OF SHH DEPLETION ON IMMUNE FUNCTION WAS INVESTIGATED. LATER, QUANTITATIVE REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION AND WESTERN BLOT ASSAY WERE PERFORMED TO EXPLORE THE HH SIGNALING PATHWAY-RELATED FACTORS. FINALLY, WE ADDED THE HH SIGNALING PATHWAY INHIBITOR, GDC-0449, TO CONFIRM THE ROLE OF THE PATHWAY IN TUMOR PROGRESSION. RESULTS: INITIALLY, WE OBSERVED THAT SHH DEPLETION WAS A NEGATIVE FACTOR FOR TUMOR GROWTH. AFTERWARDS, IT WAS REVEALED THAT EPIGENETIC SILENCING OF SHH SERVED AS AN INHIBITOR FACTOR FOR THE FUNCTION OF SPLEEN LYMPHOCYTE TRANSFORMATION AND INFLAMMATION WHILE PROMOTING ANTITUMOR IMMUNE FUNCTION. CONCLUSION: OUR PRELIMINARY RESULTS INDICATE THAT EPIGENETIC SILENCING OF SHH ELICITS AN ANTITUMOR IMMUNE RESPONSE AND SUPPRESSES TUMOR GROWTH BY INHIBITING THE HH SIGNALING PATHWAY IN METASTATIC SPINE TUMORS. 2018 3 374 24 AN ENDOSIRNA-BASED REPRESSION MECHANISM COUNTERACTS TRANSPOSON ACTIVATION DURING GLOBAL DNA DEMETHYLATION IN EMBRYONIC STEM CELLS. ERASURE OF DNA METHYLATION AND REPRESSIVE CHROMATIN MARKS IN THE MAMMALIAN GERMLINE LEADS TO RISK OF TRANSCRIPTIONAL ACTIVATION OF TRANSPOSABLE ELEMENTS (TES). HERE, WE USED MOUSE EMBRYONIC STEM CELLS (ESCS) TO IDENTIFY AN ENDOSIRNA-BASED MECHANISM INVOLVED IN SUPPRESSION OF TE TRANSCRIPTION. IN ESCS WITH DNA DEMETHYLATION INDUCED BY ACUTE DELETION OF DNMT1, WE SAW AN INCREASE IN SENSE TRANSCRIPTION AT TES, RESULTING IN AN ABUNDANCE OF SENSE/ANTISENSE TRANSCRIPTS LEADING TO HIGH LEVELS OF ARGONAUTE2 (AGO2)-BOUND SMALL RNAS. INHIBITION OF DICER OR AGO2 EXPRESSION REVEALED THAT SMALL RNAS ARE INVOLVED IN AN IMMEDIATE RESPONSE TO DEMETHYLATION-INDUCED TRANSPOSON ACTIVATION, WHILE THE DEPOSITION OF REPRESSIVE HISTONE MARKS FOLLOWS AS A CHRONIC RESPONSE. IN VIVO, WE ALSO FOUND TE-SPECIFIC ENDOSIRNAS PRESENT DURING PRIMORDIAL GERM CELL DEVELOPMENT. OUR RESULTS SUGGEST THAT ANTISENSE TE TRANSCRIPTION IS A "TRAP" THAT ELICITS AN ENDOSIRNA RESPONSE TO RESTRAIN ACUTE TRANSPOSON ACTIVITY DURING EPIGENETIC REPROGRAMMING IN THE MAMMALIAN GERMLINE. 2017 4 4935 23 PATERNAL COCAINE TAKING ELICITS EPIGENETIC REMODELING AND MEMORY DEFICITS IN MALE PROGENY. PATERNAL ENVIRONMENTAL PERTURBATIONS INCLUDING EXPOSURE TO DRUGS OF ABUSE CAN PRODUCE PROFOUND EFFECTS ON THE PHYSIOLOGY AND BEHAVIOR OF OFFSPRING VIA EPIGENETIC MODIFICATIONS. HERE WE SHOW THAT ADULT DRUG-NAIVE MALE OFFSPRING OF COCAINE-EXPOSED SIRES HAVE MEMORY FORMATION DEFICITS AND ASSOCIATED REDUCTIONS IN NMDA RECEPTOR-MEDIATED HIPPOCAMPAL SYNAPTIC PLASTICITY. REDUCED LEVELS OF THE ENDOGENOUS NMDA RECEPTOR CO-AGONIST D-SERINE WERE ACCOMPANIED BY INCREASED EXPRESSION OF THE D-SERINE DEGRADING ENZYME D-AMINO ACID OXIDASE (DAO1) IN THE HIPPOCAMPUS OF COCAINE-SIRED MALE PROGENY. INCREASED DAO1 TRANSCRIPTION WAS ASSOCIATED WITH ENRICHMENT OF PERMISSIVE EPIGENETIC MARKS ON HISTONE PROTEINS IN THE HIPPOCAMPUS OF MALE COCAINE-SIRED PROGENY, SOME OF WHICH WERE ENHANCED NEAR THE DAO1 LOCUS. FINALLY, HIPPOCAMPAL ADMINISTRATION OF D-SERINE REVERSED BOTH THE MEMORY FORMATION AND SYNAPTIC PLASTICITY DEFICITS. COLLECTIVELY, THESE RESULTS DEMONSTRATE THAT PATERNAL COCAINE EXPOSURE PRODUCES EPIGENETIC REMODELING IN THE HIPPOCAMPUS LEADING TO NMDA RECEPTOR-DEPENDENT MEMORY FORMATION AND SYNAPTIC PLASTICITY IMPAIRMENTS ONLY IN MALE PROGENY, WHICH HAS SIGNIFICANT IMPLICATIONS FOR THE MALE DESCENDANTS OF CHRONIC COCAINE USERS. 2017 5 2785 32 EZH2 REGULATES SPINAL NEUROINFLAMMATION IN RATS WITH NEUROPATHIC PAIN. ALTERATION IN GENE EXPRESSION ALONG THE PAIN SIGNALING PATHWAY IS A KEY MECHANISM CONTRIBUTING TO THE GENESIS OF NEUROPATHIC PAIN. ACCUMULATING STUDIES HAVE SHOWN THAT EPIGENETIC REGULATION PLAYS A CRUCIAL ROLE IN NOCICEPTIVE PROCESS IN THE SPINAL DORSAL HORN. IN THIS PRESENT STUDY, WE INVESTIGATED THE ROLE OF ENHANCER OF ZESTE HOMOLOG-2 (EZH2), A SUBUNIT OF THE POLYCOMB REPRESSIVE COMPLEX 2, IN THE SPINAL DORSAL HORN IN THE GENESIS OF NEUROPATHIC PAIN IN RATS INDUCED BY PARTIAL SCIATIC NERVE LIGATION. EZH2 IS A HISTONE METHYLTRANSFERASE, WHICH CATALYZES THE METHYLATION OF HISTONE H3 ON K27 (H3K27), RESULTING IN GENE SILENCING. WE FOUND THAT LEVELS OF EZH2 AND TRI-METHYLATED H3K27 (H3K27TM) IN THE SPINAL DORSAL HORN WERE INCREASED IN RATS WITH NEUROPATHIC PAIN ON DAY 3 AND DAY 10 POST NERVE INJURIES. EZH2 WAS PREDOMINANTLY EXPRESSED IN NEURONS IN THE SPINAL DORSAL HORN UNDER NORMAL CONDITIONS. THE NUMBER OF NEURONS WITH EZH2 EXPRESSION WAS INCREASED AFTER NERVE INJURY. MORE STRIKINGLY, NERVE INJURY DRASTICALLY INCREASED THE NUMBER OF MICROGLIA WITH EZH2 EXPRESSION BY MORE THAN SEVENFOLD. INTRATHECAL INJECTION OF THE EZH2 INHIBITOR ATTENUATED THE DEVELOPMENT AND MAINTENANCE OF MECHANICAL AND THERMAL HYPERALGESIA IN RATS WITH NERVE INJURY. SUCH ANALGESIC EFFECTS WERE CONCURRENTLY ASSOCIATED WITH THE REDUCED LEVELS OF EZH2, H3K27TM, IBA1, GFAP, TNF-ALPHA, IL-1BETA, AND MCP-1 IN THE SPINAL DORSAL HORN IN RATS WITH NERVE INJURY. OUR RESULTS HIGHLY SUGGEST THAT TARGETING THE EZH2 SIGNALING PATHWAY COULD BE AN EFFECTIVE APPROACH FOR THE MANAGEMENT OF NEUROPATHIC PAIN. 2017 6 2783 27 EZH2 METHYLTRANSFERASE REGULATES NEUROINFLAMMATION AND NEUROPATHIC PAIN. RECENT STUDIES BY US AND OTHERS HAVE SHOWN THAT ENHANCER OF ZESTE HOMOLOG-2 (EZH2), A HISTONE METHYLTRANSFERASE, IN GLIAL CELLS REGULATES THE GENESIS OF NEUROPATHIC PAIN BY MODULATING THE PRODUCTION OF PROINFLAMMATORY CYTOKINES AND CHEMOKINES. IN THIS REVIEW, WE SUMMARIZE RECENT ADVANCES IN THIS RESEARCH AREA. EZH2 IS A SUBUNIT OF POLYCOMB REPRESSIVE COMPLEX 2 (PRC2), WHICH PRIMARILY SERVES AS A HISTONE METHYLTRANSFERASE TO CATALYZE METHYLATION OF HISTONE 3 ON LYSINE 27 (H3K27), ULTIMATELY RESULTING IN TRANSCRIPTIONAL REPRESSION. ANIMALS WITH NEUROPATHIC PAIN EXHIBIT INCREASED EZH2 ACTIVITY AND NEUROINFLAMMATION OF THE INJURED NERVE, SPINAL CORD, AND ANTERIOR CINGULATE CORTEX. INHIBITION OF EZH2 WITH DZNEP OR GSK-126 AMELIORATES NEUROINFLAMMATION AND NEUROPATHIC PAIN. EZH2 PROTEIN EXPRESSION INCREASES UPON ACTIVATION OF TOLL-LIKE RECEPTOR 4 AND CALCITONIN GENE-RELATED PEPTIDE RECEPTORS, DOWNREGULATION OF MIR-124-3P AND MIR-378 MICRORNAS, OR UPREGULATION OF LNCENC1 AND MALAT1 LONG NONCODING RNAS. GENES SUPPRESSED BY EZH2 INCLUDE SUPPRESSOR OF CYTOKINE SIGNALING 3 (SOCS3), NUCLEAR FACTOR (ERYTHROID-DERIVED 2)-LIKE-2 FACTOR (NRF2), MIR-29B-3P, MIR-146A-5P, AND BRAIN-SPECIFIC ANGIOGENESIS INHIBITOR 1 (BAI1). PRO-INFLAMMATORY MEDIATORS FACILITATE NEURONAL ACTIVATION ALONG PAIN-SIGNALING PATHWAYS BY SENSITIZING NOCICEPTORS IN THE PERIPHERY, AS WELL AS ENHANCING EXCITATORY SYNAPTIC ACTIVITIES AND SUPPRESSING INHIBITORY SYNAPTIC ACTIVITIES IN THE CNS. THESE STUDIES COLLECTIVELY REVEAL THAT EZH2 IS IMPLICATED IN SIGNALING PATHWAYS KNOWN TO BE KEY PLAYERS IN THE PROCESS OF NEUROINFLAMMATION AND GENESIS OF NEUROPATHIC PAIN. THEREFORE, TARGETING THE EZH2 SIGNALING PATHWAY MAY OPEN A NEW AVENUE TO MITIGATE NEUROINFLAMMATION AND NEUROPATHIC PAIN. 2023 7 2479 28 EPIGENETIC UPREGULATION OF CXCL12 EXPRESSION MEDIATES ANTITUBULIN CHEMOTHERAPEUTICS-INDUCED NEUROPATHIC PAIN. CLINICALLY, MICROTUBULE-TARGETED AGENTS-INDUCED NEUROPATHIC PAIN HAMPERS CHEMOTHERAPEUTICS FOR PATIENTS WITH CANCER. HERE, WE FOUND THAT APPLICATION OF PACLITAXEL OR VINCRISTINE INCREASED THE PROTEIN AND MRNA EXPRESSION OF CXCL12 AND FREQUENCY AND AMPLITUDE OF MINIATURE EXCITATORY POST SYNAPTIC CURRENTS (MEPSCS) IN SPINAL DORSAL HORN NEURONS. SPINAL LOCAL APPLICATION OF CXCL12 INDUCED THE LONG-TERM POTENTIATION OF NOCICEPTIVE SYNAPTIC TRANSMISSION AND INCREASED THE AMPLITUDE OF MEPSCS. INHIBITION OF CXCL12 USING THE TRANSGENIC MICE (CXCL12) OR NEUTRALIZING ANTIBODY OR SIRNA AMELIORATED THE MEPSC'S ENHANCEMENT AND MECHANICAL ALLODYNIA. IN ADDITION, PACLITAXEL AND VINCRISTINE BOTH COULD INCREASE THE PHOSPHORYLATION OF SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 (STAT3) AND THE ACETYLATION OF HISTONE H4 IN THE CXCL12-EXPRESSING NEURONS. IMMUNOPRECIPITATION AND CHROMATIN IMMUNOPRECIPITATION ASSAYS DEMONSTRATED THAT ANTITUBULIN CHEMOTHERAPEUTICS INCREASED THE BINDING OF STAT3 TO THE CXCL12 GENE PROMOTER AND THE INTERACTION BETWEEN STAT3 AND P300, AND CONTRIBUTED TO THE ENHANCED TRANSCRIPTION OF CXCL12 BY INCREASING THE ACETYLATION OF HISTONE H4 IN CXCL12 GENE PROMOTER. INHIBITION OF STAT3 BY INTRATHECAL INJECTION OF ADENO-ASSOCIATED VIRUS ENCODING CRE AND GREEN FLUORESCENT PROTEIN INTO STAT3 MICE OR INHIBITOR S3I-201 INTO RATS SUPPRESSED THE CXCL12 UPSURGE BY DECREASING THE ACETYLATION OF HISTONE H4. FINALLY, BLOCKADE OF CXCR4 BUT NOT CXCR7 AMELIORATED THE PACLITAXEL- OR VINCRISTINE-INDUCED MECHANICAL ALLODYNIA. TOGETHER, THESE RESULTS SUGGESTED THAT ENHANCED INTERACTION BETWEEN STAT3 AND P300 MEDIATED THE EPIGENETIC UPREGULATION OF CXCL12 IN DORSAL HORN NEURONS, WHICH CONTRIBUTED TO THE ANTITUBULIN CHEMOTHERAPEUTICS-INDUCED PERSISTENT PAIN. 2017 8 4906 34 P300 EXERTS AN EPIGENETIC ROLE IN CHRONIC NEUROPATHIC PAIN THROUGH ITS ACETYLTRANSFERASE ACTIVITY IN RATS FOLLOWING CHRONIC CONSTRICTION INJURY (CCI). BACKGROUND: NEUROPATHIC PAIN IS DETRIMENTAL TO HUMAN HEALTH; HOWEVER, ITS PATHOGENESIS STILL REMAINS LARGELY UNKNOWN. OVEREXPRESSION OF PAIN-ASSOCIATED GENES AND INCREASED NOCICEPTIVE SOMATO-SENSITIVITY ARE WELL OBSERVED IN NEUROPATHIC PAIN. THE IMPORTANCE OF EPIGENETIC MECHANISMS IN REGULATING THE EXPRESSION OF PRO- OR ANTI-NOCICEPTIVE GENES HAS BEEN REVEALED BY STUDIES RECENTLY, AND WE HYPOTHESIZE THAT THE TRANSCRIPTIONAL COACTIVATOR AND THE HISTONE ACETYLTRANSFERASE E1A BINDING PROTEIN P300 (P300), AS A PART OF THE EPIGENETIC MECHANISMS OF GENE REGULATION, MAY BE INVOLVED IN THE PATHOGENESIS OF NEUROPATHIC PAIN INDUCED BY CHRONIC CONSTRICTION INJURY (CCI). TO TEST THIS HYPOTHESIS, TWO DIFFERENT APPROACHES WERE USED IN THIS STUDY: (I) DOWN-REGULATING P300 WITH SPECIFIC SMALL HAIRPIN RNA (SHRNA) AND (II) CHEMICAL INHIBITION OF P300 ACETYLTRANSFERASE ACTIVITY BY A SMALL MOLECULE INHIBITOR, C646. RESULTS: USING THE CCI RAT MODEL, WE FOUND THAT THE P300 EXPRESSION WAS INCREASED IN THE LUMBAR SPINAL CORD ON DAY 14 AFTER CCI. THE TREATMENT WITH INTRATHECAL P300 SHRNA REVERSED CCI-INDUCED MECHANICAL ALLODYNIA AND THERMAL HYPERALGESIA, AND SUPPRESSED THE EXPRESSION OF CYCLOOXYGENASE-2 (COX-2), A NEUROPATHIC PAIN-ASSOCIATED FACTOR. FURTHERMORE, C646, AN INHIBITOR OF P300 ACETYLTRANSFERASE, ALSO ATTENUATED MECHANICAL ALLODYNIA AND THERMAL HYPERALGESIA, ACCOMPANIED BY A SUPPRESSED COX-2 EXPRESSION, IN THE SPINAL CORD. CONCLUSIONS: THE RESULTS SUGGEST THAT, THROUGH ITS ACETYLTRANSFERASE ACTIVITY IN THE SPINAL CORD AFTER CCI, P300 EPIGENETICALLY PLAYS AN IMPORTANT ROLE IN NEUROPATHIC PAIN. INHIBITING P300, USING INTERFERING RNA OR C646, MAY BE A PROMISING APPROACH TO THE DEVELOPMENT OF NEW NEUROPATHIC PAIN THERAPIES. 2012 9 4506 26 MRTF-A MEDIATES LPS-INDUCED PRO-INFLAMMATORY TRANSCRIPTION BY INTERACTING WITH THE COMPASS COMPLEX. CHRONIC INFLAMMATION UNDERSCORES THE PATHOGENESIS OF A RANGE OF HUMAN DISEASES. LIPOPOLYSACCHARIDE (LPS) ELICITS STRONG PRO-INFLAMMATORY RESPONSES IN MACROPHAGES THROUGH THE TRANSCRIPTION FACTOR NF-KAPPAB. THE EPIGENETIC MECHANISM UNDERLYING LPS-INDUCED PRO-INFLAMMATORY TRANSCRIPTION IS NOT FULLY UNDERSTOOD. HEREIN, WE DESCRIBE A ROLE FOR MYOCARDIN-RELATED TRANSCRIPTION FACTOR A (MRTF-A, ALSO KNOWN AS MKL1) IN THIS PROCESS. MRTF-A OVEREXPRESSION ENHANCED NF-KAPPAB-DEPENDENT PRO-INFLAMMATORY TRANSCRIPTION, WHEREAS MRTF-A SILENCING INHIBITED THIS PROCESS. MRTF-A DEFICIENCY ALSO REDUCED THE SYNTHESIS OF PRO-INFLAMMATORY MEDIATORS IN A MOUSE MODEL OF COLITIS. LPS PROMOTED THE RECRUITMENT OF MRTF-A TO THE PROMOTERS OF PRO-INFLAMMATORY GENES IN AN NF-KAPPAB-DEPENDENT MANNER. RECIPROCALLY, MRTF-A INFLUENCED THE NUCLEAR ENRICHMENT AND TARGET BINDING OF NF-KAPPAB. MECHANISTICALLY, MRTF-A WAS NECESSARY FOR THE ACCUMULATION OF ACTIVE HISTONE MODIFICATIONS ON NF-KAPPAB TARGET PROMOTERS BY COMMUNICATING WITH THE HISTONE H3K4 METHYLTRANSFERASE COMPLEX (COMPASS). SILENCING OF INDIVIDUAL MEMBERS OF COMPASS, INCLUDING ASH2, WDR5 AND SET1 (ALSO KNOWN AS SETD1A), DOWNREGULATED THE PRODUCTION OF PRO-INFLAMMATORY MEDIATORS AND IMPAIRED THE NF-KAPPAB KINETICS. IN SUMMARY, OUR WORK HAS UNCOVERED A PREVIOUSLY UNKNOWN FUNCTION FOR MRTF-A AND PROVIDED INSIGHTS INTO THE RATIONALIZED DEVELOPMENT OF ANTI-INFLAMMATORY THERAPEUTIC STRATEGIES. 2014 10 3175 35 H2AX PHOSPHORYLATION REGULATED BY P38 IS INVOLVED IN BIM EXPRESSION AND APOPTOSIS IN CHRONIC MYELOGENOUS LEUKEMIA CELLS INDUCED BY IMATINIB. INCREASING EVIDENCE SUGGESTS THAT HISTONE H2AX PLAYS A CRITICAL ROLE IN REGULATION OF TUMOR CELL APOPTOSIS AND ACTS AS A NOVEL HUMAN TUMOR SUPPRESSOR PROTEIN. HOWEVER, THE ACTION OF H2AX IN CHRONIC MYELOGENOUS LEUKEMIA (CML) CELLS IS UNKNOWN. THE DETAILED MECHANISM AND EPIGENETIC REGULATION BY H2AX REMAIN ELUSIVE IN CANCER CELLS. HERE, WE REPORT THAT H2AX WAS INVOLVED IN APOPTOSIS OF CML CELLS. OVEREXPRESSION OF H2AX INCREASED APOPTOTIC SENSITIVITY OF CML CELLS (K562) INDUCED BY IMATINIB. HOWEVER, OVEREXPRESSION OF SER139-MUTATED H2AX (BLOCKING PHOSPHORYLATION) DECREASED SENSITIVITY OF K562 CELLS TO APOPTOSIS. SIMILARLY, KNOCKDOWN OF H2AX MADE K562 CELLS RESISTANT TO APOPTOTIC INDUCTION. THESE RESULTS REVEALED THAT THE FUNCTION OF H2AX INVOLVED IN APOPTOSIS IS STRICTLY RELATED TO ITS PHOSPHORYLATION (SER139). OUR DATA FURTHER INDICATED THAT IMATINIB MAY STIMULATE MITOGEN-ACTIVATED PROTEIN KINASE (MAPK) FAMILY MEMBER P38, AND H2AX PHOSPHORYLATION FOLLOWED A SIMILAR TIME COURSE, SUGGESTING A PARALLEL RESPONSE. H2AX PHOSPHORYLATION CAN BE BLOCKED BY P38 SIRNA OR ITS INHIBITOR. THESE DATA DEMONSTRATED THAT H2AX PHOSPHORYLATION WAS REGULATED BY P38 MAPK PATHWAY IN K562 CELLS. HOWEVER, THE P38 MAPK DOWNSTREAM, MITOGEN- AND STRESS-ACTIVATED PROTEIN KINASE-1 AND -2, WHICH PHOSPHORYLATED HISTONE H3, WERE NOT REQUIRED FOR H2AX PHOSPHORYLATION DURING APOPTOSIS. FINALLY, WE PROVIDED EPIGENETIC EVIDENCE THAT H2AX PHOSPHORYLATION REGULATED APOPTOSIS-RELATED GENE BIM EXPRESSION. BLOCKING OF H2AX PHOSPHORYLATION INHIBITED BIM GENE EXPRESSION. TAKEN TOGETHER, THESE DATA DEMONSTRATED THAT H2AX PHOSPHORYLATION REGULATED BY P38 IS INVOLVED IN BIM EXPRESSION AND APOPTOSIS IN CML CELLS INDUCED BY IMATINIB. 2014 11 4908 36 P53 ACTIVATION BY NI(II) IS A HIF-1ALPHA INDEPENDENT RESPONSE CAUSING CASPASES 9/3-MEDIATED APOPTOSIS IN HUMAN LUNG CELLS. HYPOXIA MIMIC NICKEL(II) IS A HUMAN RESPIRATORY CARCINOGEN WITH A SUSPECTED EPIGENETIC MODE OF ACTION. WE EXAMINED WHETHER NI(II) ELICITS A TOXICOLOGICALLY SIGNIFICANT ACTIVATION OF THE TUMOR SUPPRESSOR P53, WHICH IS TYPICALLY ASSOCIATED WITH GENOTOXIC RESPONSES. WE FOUND THAT TREATMENTS OF H460 HUMAN LUNG EPITHELIAL CELLS WITH NICL2 CAUSED ACTIVATING PHOSPHORYLATION AT P53-SER15, ACCUMULATION OF P53 PROTEIN AND DEPLETION OF ITS INHIBITOR MDM4 (HDMX). CONFIRMING THE ACTIVATION OF P53, ITS KNOCKDOWN SUPPRESSED THE ABILITY OF NI(II) TO UPREGULATE MDM2 AND P21 (CDKN1A). UNLIKE DNA DAMAGE, INDUCTION OF GADD45A BY NI(II) WAS P53-INDEPENDENT. NI(II) ALSO INCREASED P53-SER15 PHOSPHORYLATION AND P21 EXPRESSION IN NORMAL HUMAN LUNG FIBROBLASTS. ALTHOUGH NI(II)-INDUCED STABILIZATION OF HIF-1ALPHA OCCURRED EARLIER, IT HAD NO EFFECT ON P53 ACCUMULATION AND SER15 PHOSPHORYLATION. NI(II)-TREATED H460 CELLS SHOWED NO EVIDENCE OF NECROSIS AND THEIR APOPTOSIS AND CLONOGENIC DEATH WERE SUPPRESSED BY P53 KNOCKDOWN. THE APOPTOTIC ROLE OF P53 INVOLVED A TRANSCRIPTION-DEPENDENT PROGRAM TRIGGERING THE INITIATOR CASPASE 9 AND ITS DOWNSTREAM EXECUTIONER CASPASE 3. TWO MOST PROMINENTLY UPREGULATED PROAPOPTOTIC GENES BY NI(II) WERE PUMA AND NOXA BUT ONLY PUMA INDUCTION REQUIRED P53. KNOCKDOWN OF P53 ALSO LED TO DEREPRESSION OF ANTIAPOPTOTIC MCL1 IN NI(II)-TREATED CELLS. OVERALL, OUR RESULTS INDICATE THAT P53 PLAYS A MAJOR ROLE IN APOPTOTIC DEATH OF HUMAN LUNG CELLS BY NI(II). CHRONIC EXPOSURE TO NI(II) MAY PROMOTE SELECTION OF RESISTANT CELLS WITH INACTIVATED P53, PROVIDING AN EXPLANATION FOR THE ORIGIN OF P53 MUTATIONS BY THIS EPIGENETIC CARCINOGEN. 2013 12 6519 28 TRANSCRIPTIONAL AND EPIGENETIC REGULATION OF INTERLEUKIN-2 GENE IN ACTIVATED T CELLS BY MORPHINE. CHRONIC MORPHINE INHIBITS INTERLEUKIN-2 (IL-2) AT BOTH THE TRANSCRIPTIONAL AND PROTEIN SYNTHESIS LEVELS. THE MOLECULAR MECHANISMS BY WHICH MORPHINE DECREASES IL-2 ARE NOT FULLY UNDERSTOOD. THE PRODUCTION OF IL-2 IS TIGHTLY REGULATED BY SEVERAL TRANSCRIPTION FACTORS THAT BIND TO THE IL-2 PROMOTER. HEREIN, WE SHOW THAT CHRONIC MORPHINE TREATMENT RESULTS IN AN INCREASE IN CAMP LEVELS WITH A CONCURRENT UP-REGULATION OF THE CAMP INDUCIBLE REPRESSOR INDUCIBLE CAMP EARLY REPRESSOR (ICER)/CAMP RESPONSE ELEMENT MODULATOR (CREM) AND DOWN-REGULATION OF P-CAMP-RESPONSE ELEMENT-BINDING PROTEIN (CREB) IN ACTIVATED T CELLS. FURTHERMORE, ICER COMPETES FOR P-CREB BINDING TO THE CAMP-RESPONSIVE ELEMENTS (CRES) SITE. THIS LEADS TO THE UNCOUPLING OF CBP/P300 THEREBY ABROGATING IL-2 TRANSCRIPTION. OVEREXPRESSION OF EITHER ANTISENSE CREM OR CREB PLASMID RESCUED MORPHINE-INDUCED INHIBITION OF IL-2 PROMOTER ACTIVITY AND PROTEIN PRODUCTION. IN ADDITION, WE ALSO FOUND THAT CHRONIC MORPHINE TREATMENT INHIBITED THE ACETYLATION AND TRIMETHYLATION OF HISTONES AND DECREASED BOTH DNA DEMETHYLATION AND ACCESSIBILITY OF THE IL-2 PROMOTER. THESE FINDINGS SUGGEST THAT CHRONIC MORPHINE TREATMENT MAY FUNCTION THROUGH BOTH TRANSCRIPTIONAL AND EPIGENETIC MECHANISMS TO INHIBIT IL-2 PRODUCTION. 2007 13 2365 29 EPIGENETIC REGULATION OF SPINAL CXCR2 SIGNALING IN INCISIONAL HYPERSENSITIVITY IN MICE. BACKGROUND: THE REGULATION OF GENE EXPRESSION IN NOCICEPTIVE PATHWAYS CONTRIBUTES TO THE INDUCTION AND MAINTENANCE OF PAIN SENSITIZATION. HISTONE ACETYLATION IS A KEY EPIGENETIC MECHANISM CONTROLLING CHROMATIN STRUCTURE AND GENE EXPRESSION. CHEMOKINE CC MOTIF RECEPTOR 2 (CXCR2) IS A PROINFLAMMATORY RECEPTOR IMPLICATED IN NEUROPATHIC AND INFLAMMATORY PAIN AND IS KNOWN TO BE REGULATED BY HISTONE ACETYLATION IN SOME SETTINGS. THE AUTHORS SOUGHT TO INVESTIGATE THE ROLE OF HISTONE ACETYLATION ON SPINAL CXCR2 SIGNALING AFTER INCISION. METHODS: GROUPS OF 5-8 MICE UNDERWENT HIND PAW INCISION. SUBEROYLANILIDE HYDROXAMIC ACID AND ANACARDIC ACID WERE USED TO INHIBIT HISTONE DEACETYLASE AND HISTONE ACETYLTRANSFERASE, RESPECTIVELY. BEHAVIORAL MEASURES OF THERMAL AND MECHANICAL SENSITIZATION AS WELL AS HYPERALGESIC PRIMING WERE USED. BOTH MESSAGE RNA QUANTIFICATION AND CHROMATIN IMMUNOPRECIPITATION ANALYSIS WERE USED TO STUDY THE REGULATION OF CXCR2 AND LIGAND EXPRESSION. FINALLY, THE SELECTIVE CXCR2 ANTAGONIST SB225002 WAS ADMINISTERED INTRATHECALLY TO REVEAL THE FUNCTION OF SPINAL CXCR2 RECEPTORS AFTER HIND PAW INCISION. RESULTS: SUBEROYLANILIDE HYDROXAMIC ACID SIGNIFICANTLY EXACERBATED MECHANICAL SENSITIZATION AFTER INCISION. CONVERSELY, ANACARDIC ACID REDUCED INCISIONAL SENSITIZATION AND ALSO ATTENUATED INCISION-INDUCED HYPERALGESIC PRIMING. OVERALL, ACETYLATED HISTONE H3 AT LYSINE 9 WAS INCREASED IN SPINAL CORD TISSUES AFTER INCISION, AND ENHANCED ASSOCIATION OF ACETYLATED HISTONE H3 AT LYSINE 9 WITH THE PROMOTER REGIONS OF CXCR2 AND KERATINOCYTE-DERIVED CHEMOKINE (CXCL1) WAS OBSERVED AS WELL. BLOCKING CXCR2 REVERSED MECHANICAL HYPERSENSITIVITY AFTER HIND PAW INCISION. CONCLUSIONS: HISTONE MODIFICATION IS AN IMPORTANT EPIGENETIC MECHANISM REGULATING INCISION-INDUCED NOCICEPTIVE SENSITIZATION. THE SPINAL CXCR2 SIGNALING PATHWAY IS ONE EPIGENETICALLY REGULATED PATHWAY CONTROLLING EARLY AND LATENT SENSITIZATION AFTER INCISION. 2013 14 3370 37 HISTONE MODIFICATION OF NEDD4 UBIQUITIN LIGASE CONTROLS THE LOSS OF AMPA RECEPTORS AND COGNITIVE IMPAIRMENT INDUCED BY REPEATED STRESS. STRESS AND THE MAJOR STRESS HORMONE CORTICOSTERONE INDUCE PROFOUND INFLUENCES IN THE BRAIN. ALTERED HISTONE MODIFICATION AND TRANSCRIPTIONAL DYSFUNCTION HAVE BEEN IMPLICATED IN STRESS-RELATED MENTAL DISORDERS. WE PREVIOUSLY FOUND THAT REPEATED STRESS CAUSED AN IMPAIRMENT OF PREFRONTAL CORTEX (PFC)-MEDIATED COGNITIVE FUNCTIONS BY INCREASING THE UBIQUITINATION AND DEGRADATION OF AMPA-TYPE GLUTAMATE RECEPTORS VIA A MECHANISM DEPENDING ON THE E3 UBIQUITIN LIGASE NEDD4. HERE, WE DEMONSTRATED THAT IN PFC OF REPEATEDLY STRESSED RATS, ACTIVE GLUCOCORTICOID RECEPTOR HAD THE INCREASED BINDING TO THE GLUCOCORTICOID RESPONSE ELEMENT OF HISTONE DEACETYLASE 2 (HDAC2) PROMOTER, RESULTING IN THE UPREGULATION OF HDAC2. INHIBITION OR KNOCK-DOWN OF HDAC2 BLOCKED THE STRESS-INDUCED IMPAIRMENT OF SYNAPTIC TRANSMISSION, AMPAR EXPRESSION, AND RECOGNITION MEMORY. FURTHERMORE, WE FOUND THAT, IN STRESSED ANIMALS, THE HDAC2-DEPENDENT DOWNREGULATION OF HISTONE METHYLTRANSFERASE EHMT2 (G9A) LED TO THE LOSS OF REPRESSIVE HISTONE METHYLATION AT THE NEDD4-1 PROMOTER AND THE TRANSCRIPTIONAL ACTIVATION OF NEDD4. THESE RESULTS HAVE PROVIDED AN EPIGENETIC MECHANISM AND A POTENTIAL TREATMENT STRATEGY FOR THE DETRIMENTAL EFFECTS OF CHRONIC STRESS. SIGNIFICANCE STATEMENT: PROLONGED STRESS EXPOSURE CAN INDUCE ALTERED HISTONE MODIFICATION AND TRANSCRIPTIONAL DYSFUNCTION, WHICH MAY UNDERLIE THE PROFOUND INFLUENCE OF STRESS IN REGULATING BRAIN FUNCTIONS. WE REPORT AN IMPORTANT FINDING ABOUT THE EPIGENETIC MECHANISM CONTROLLING THE DETRIMENTAL EFFECTS OF REPEATED STRESS ON SYNAPTIC TRANSMISSION AND COGNITIVE FUNCTION. FIRST, IT HAS REVEALED THE STRESS-INDUCED ALTERATION OF KEY EPIGENETIC REGULATORS HDAC2 AND EHMT2, WHICH DETERMINES THE SYNAPTIC AND BEHAVIORAL EFFECTS OF REPEATED STRESS. SECOND, IT HAS UNCOVERED THE STRESS-INDUCED HISTONE MODIFICATION OF THE TARGET GENE NEDD4, AN E3 LIGASE THAT IS CRITICALLY INVOLVED IN THE UBIQUITINATION AND DEGRADATION OF AMPA RECEPTORS AND COGNITION. THIRD, IT HAS PROVIDED THE EPIGENETIC APPROACH, HDAC2 INHIBITION OR KNOCK-DOWN, TO RESCUE SYNAPTIC AND COGNITIVE FUNCTIONS IN STRESSED ANIMALS. 2016 15 5050 30 PHARMACOLOGICAL MIMICKING OF CALORIC RESTRICTION ELICITS EPIGENETIC REPROGRAMMING OF DIFFERENTIATED CELLS TO STEM-LIKE SELF-RENEWAL STATES. NETWORKS OF ONCOGENES AND TUMOR SUPPRESSOR GENES THAT CONTROL CANCER CELL PROLIFERATION ALSO REGULATE STEM CELL RENEWAL AND POSSIBLY STEM CELL AGING. BECAUSE (DE)DIFFERENTIATION PROCESSES MIGHT DICTATE TUMOR CELLS TO RETROGRESS TO A MORE STEM-LIKE STATE IN RESPONSE TO AGING-RELEVANT EPIGENETIC AND/OR ENVIRONMENTAL PLAYERS, WE RECENTLY ENVISIONED THAT CULTURED HUMAN CANCER CELLS MIGHT BE USED AS RELIABLE MODELS TO TEST THE ABILITY OF ANTIAGING INTERVENTIONS FOR PROMOTING THE INITIATION AND MAINTENANCE OF SELF-RENEWING DIVISIONS. CANCER CELL LINES NATURALLY BEARING UNDETECTABLE AMOUNTS OF STEM/PROGENITOR-LIKE CELL POPULATIONS WERE CONTINUOUSLY CULTURED IN THE PRESENCE OF THE CALORIC RESTRICTION MIMETIC METFORMIN FOR SEVERAL MONTHS. MICROARRAY TECHNOLOGY WAS EMPLOYED TO PROFILE EXPRESSION OF GENES RELATED TO THE IDENTIFICATION, GROWTH, AND DIFFERENTIATION OF STEM CELLS. DETECTION OF FUNCTIONALLY RELATED GENE GROUPS USING A PATHWAY ANALYSIS PACKAGE PROVIDED ANNOTATED GENETIC SIGNATURES OVER- AND UNDEREXPRESSED IN RESPONSE TO PHARMACOLOGICAL MIMICKING OF CALORIC RESTRICTION. BY FOLLOWING THIS METHODOLOGICAL APPROACH, WE RECENTLY OBTAINED DATA FITTING A MODEL IN WHICH, IN RESPONSE TO CHRONIC IMPAIRMENT OF CELLULAR BIOENERGETICS IMPOSED BY METFORMIN-INDUCED MITOCHONDRIAL UNCOUPLING AS ASSESSED BY THE PHOSPHORYLATION STATE OF CAMP-RESPONSE ELEMENT BINDING PROTEIN (CREB), TUMOR CELLS CAN RETROGRESS FROM A DIFFERENTIATED STATE TO A MORE CD44(+) STEM-LIKE PRIMITIVE STATE EPIGENETICALLY GOVERNED BY THE POLYCOMB-GROUP SUPPRESSOR BMI1-A CRUCIAL "STEMNESS" GENE INVOLVED IN THE EPIGENETIC MAINTENANCE OF ADULT STEM CELLS. THESE FINDINGS MIGHT PROVIDE A NOVEL MOLECULAR AVENUE TO INVESTIGATE IF ANTIAGING BENEFITS FROM CALORIC RESTRICTION MIMETICS MIGHT RELATE TO THEIR ABILITY TO EPIGENETICALLY REPROGRAM STEMNESS WHILE PROLONGING THE CAPACITY OF STEM-LIKE CELL STATES TO PROLIFERATE, DIFFERENTIATE, AND REPLACE MATURE CELLS IN ADULT AGING TISSUES. 2010 16 2772 29 EXTRACELLULAR ATP AND NEURODEGENERATION. ATP IS A POTENT SIGNALING MOLECULE ABUNDANTLY PRESENT IN THE CNS. IT ELICITS A WIDE ARRAY OF PHYSIOLOGICAL EFFECTS AND IS REGARDED AS THE PHYLOGENETICALLY MOST ANCIENT EPIGENETIC FACTOR PLAYING CRUCIAL BIOLOGICAL ROLES IN SEVERAL DIFFERENT TISSUES. THESE CAN RANGE FROM NEUROTRANSMISSION, SMOOTH MUSCLE CONTRACTION, CHEMOSENSORY SIGNALING, SECRETION AND VASODILATATION, TO MORE COMPLEX PHENOMENA SUCH AS IMMUNE RESPONSES, PAIN, MALE REPRODUCTION, FERTILIZATION AND EMBRYONIC DEVELOPMENT. ATP IS RELEASED INTO THE EXTRACELLULAR SPACE EITHER EXOCYTOTICALLY OR FROM DAMAGED AND DYING CELLS. IT IS OFTEN CO-RELEASED WITH OTHER NEUROTRANSMITTERS AND IT CAN INTERACT WITH GROWTH FACTORS AT BOTH RECEPTOR- AND/OR SIGNAL TRANSDUCTION-LEVEL. ONCE IN THE EXTRACELLULAR ENVIRONMENT, ATP BINDS TO SPECIFIC RECEPTORS TERMED P2. BASED ON PHARMACOLOGICAL PROFILES, ON SELECTIVITY OF COUPLING TO SECOND-MESSENGER PATHWAYS AND ON MOLECULAR CLONING, TWO MAIN SUBCLASSES WITH MULTIPLE SUBTYPES HAVE BEEN DISTINGUISHED. THEY ARE P2X, I.E. FAST CATION-SELECTIVE RECEPTOR CHANNELS (NA+, K+, CA2+), POSSESSING LOW AFFINITY FOR ATP AND RESPONSIBLE FOR FAST EXCITATORY NEUROTRANSMISSION, AND P2Y, I.E. SLOW G PROTEIN-COUPLED METABOTROPIC RECEPTORS, POSSESSING HIGHER AFFINITY FOR THE LIGAND. IN THE NERVOUS SYSTEM, THEY ARE BROADLY EXPRESSED IN BOTH NEURONS AND GLIAL CELLS AND CAN MEDIATE DUAL EFFECTS: SHORT-TERM SUCH AS NEUROTRANSMISSION, AND LONG-TERM SUCH AS TROPHIC ACTIONS. SINCE MASSIVE EXTRACELLULAR RELEASE OF ATP OFTEN OCCURS AFTER METABOLIC STRESS, BRAIN ISCHEMIA AND TRAUMA, PURINERGIC MECHANISMS ARE ALSO CORRELATED TO AND INVOLVED IN THE ETIOPATHOLOGY OF MANY NEURODEGENERATIVE CONDITIONS. FURTHERMORE, EXTRACELLULAR ATP PER SE IS TOXIC FOR PRIMARY NEURONAL DISSOCIATED AND ORGANOTYPIC CNS CULTURES FROM CORTEX, STRIATUM AND CEREBELLUM AND P2 RECEPTORS CAN MEDIATE AND AGGRAVATE HYPOXIC SIGNALING IN MANY CNS NEURONS. CONVERSELY, SEVERAL P2 RECEPTOR ANTAGONISTS ABOLISH THE CELL DEATH FATE OF PRIMARY NEURONAL CULTURES EXPOSED TO EXCESSIVE GLUTAMATE, SERUM/POTASSIUM DEPRIVATION, HYPOGLYCEMIA AND CHEMICAL HYPOXIA. IN PARALLEL WITH THESE DETRIMENTAL EFFECTS, ALSO TROPHIC FUNCTIONS HAVE BEEN EXTENSIVELY DESCRIBED FOR EXTRACELLULAR PURINES (BOTH FOR NEURONAL AND NON-NEURONAL CELLS), BUT THESE MIGHT EITHER AGGRAVATE OR AMELIORATE THE NORMAL CELLULAR CONDITIONS. IN SUMMARY, EXTRACELLULAR ATP PLAYS A VERY COMPLEX ROLE NOT ONLY IN THE REPAIR, REMODELING AND SURVIVAL OCCURRING IN THE NERVOUS SYSTEM, BUT EVEN IN CELL DEATH AND THIS CAN OCCUR EITHER AFTER NORMAL DEVELOPMENTAL CONDITIONS, AFTER INJURY, OR ACUTE AND CHRONIC DISEASES. 2003 17 1652 33 DOPAMINE SIGNALING LEADS TO LOSS OF POLYCOMB REPRESSION AND ABERRANT GENE ACTIVATION IN EXPERIMENTAL PARKINSONISM. POLYCOMB GROUP (PCG) PROTEINS BIND TO AND REPRESS GENES IN EMBRYONIC STEM CELLS THROUGH LINEAGE COMMITMENT TO THE TERMINAL DIFFERENTIATED STATE. PCG REPRESSED GENES ARE COMMONLY CHARACTERIZED BY THE PRESENCE OF THE EPIGENETIC HISTONE MARK H3K27ME3, CATALYZED BY THE POLYCOMB REPRESSIVE COMPLEX 2. HERE, WE PRESENT IN VIVO EVIDENCE FOR A PREVIOUSLY UNRECOGNIZED PLASTICITY OF PCG-REPRESSED GENES IN TERMINALLY DIFFERENTIATED BRAIN NEURONS OF PARKISONIAN MICE. WE SHOW THAT ACUTE ADMINISTRATION OF THE DOPAMINE PRECURSOR, L-DOPA, INDUCES A REMARKABLE INCREASE IN H3K27ME3S28 PHOSPHORYLATION. THE INDUCTION OF THE H3K27ME3S28P HISTONE MARK SPECIFICALLY OCCURS IN MEDIUM SPINY NEURONS EXPRESSING DOPAMINE D1 RECEPTORS AND IS DEPENDENT ON MSK1 KINASE ACTIVITY AND DARPP-32-MEDIATED INHIBITION OF PROTEIN PHOSPHATASE-1. CHROMATIN IMMUNOPRECIPITATION (CHIP) EXPERIMENTS SHOWED THAT INCREASED H3K27ME3S28P WAS ACCOMPANIED BY REDUCED PCG BINDING TO REGULATORY REGIONS OF GENES. AN ANALYSIS OF THE GENOME WIDE DISTRIBUTION OF L-DOPA-INDUCED H3K27ME3S28 PHOSPHORYLATION BY CHIP SEQUENCING (CHIP-SEQ) IN COMBINATION WITH EXPRESSION ANALYSIS BY RNA-SEQUENCING (RNA-SEQ) SHOWED THAT THE INDUCTION OF H3K27ME3S28P CORRELATED WITH INCREASED EXPRESSION OF A SUBSET OF PCG REPRESSED GENES. WE FOUND THAT INDUCTION OF H3K27ME3S28P PERSISTED DURING CHRONIC L-DOPA ADMINISTRATION TO PARKISONIAN MICE AND CORRELATED WITH ABERRANT GENE EXPRESSION. WE PROPOSE THAT DOPAMINERGIC TRANSMISSION CAN ACTIVATE PCG REPRESSED GENES IN THE ADULT BRAIN AND THEREBY CONTRIBUTE TO LONG-TERM MALADAPTIVE RESPONSES INCLUDING THE MOTOR COMPLICATIONS, OR DYSKINESIA, CAUSED BY PROLONGED ADMINISTRATION OF L-DOPA IN PARKINSON'S DISEASE. 2014 18 2590 34 EPIGENETICS OF PROTEASOME INHIBITION IN THE LIVER OF RATS FED ETHANOL CHRONICALLY. AIM: TO EXAMINE THE EFFECTS OF ETHANOL-INDUCED PROTEASOME INHIBITION, AND THE EFFECTS OF PROTEASOME INHIBITION IN THE REGULATION OF EPIGENETIC MECHANISMS. METHODS: RATS WERE FED ETHANOL FOR 1 MO USING THE TSUKAMOTO-FRENCH MODEL AND WERE COMPARED TO RATS GIVEN THE PROTEASOME INHIBITOR PS-341 (BORTEZOMIB, VELCADE(TM)) BY INTRAPERITONEAL INJECTION. MICROARRAY ANALYSIS AND REAL TIME PCR WERE PERFORMED AND PROTEASOME ACTIVITY ASSAYS AND WESTERN BLOT ANALYSIS WERE PERFORMED USING ISOLATED NUCLEI. RESULTS: CHRONIC ETHANOL FEEDING CAUSED A SIGNIFICANT INHIBITION OF THE UBIQUITIN PROTEASOME PATHWAY IN THE NUCLEUS, WHICH LED TO CHANGES IN THE TURNOVER OF TRANSCRIPTIONAL FACTORS, HISTONE-MODIFYING ENZYMES, AND, THEREFORE, AFFECTED EPIGENETIC MECHANISMS. CHRONIC ETHANOL FEEDING WAS RELATED TO AN INCREASE IN HISTONE ACETYLATION, AND IT IS HYPOTHESIZED THAT THE PROTEASOME PROTEOLYTIC ACTIVITY REGULATED HISTONE MODIFICATIONS BY CONTROLLING THE STABILITY OF HISTONE MODIFYING ENZYMES, AND, THEREFORE, REGULATED THE CHROMATIN STRUCTURE, ALLOWING EASY ACCESS TO CHROMATIN BY RNA POLYMERASE, AND, THUS, PROPER GENE EXPRESSION. PROTEASOME INHIBITION BY PS-341 INCREASED HISTONE ACETYLATION SIMILAR TO CHRONIC ETHANOL FEEDING. IN ADDITION, PROTEASOME INHIBITION CAUSED DRAMATIC CHANGES IN HEPATIC REMETHYLATION REACTIONS AS THERE WAS A SIGNIFICANT DECREASE IN THE ENZYMES RESPONSIBLE FOR THE REGENERATION OF S-ADENOSYLMETHIONINE, AND, IN PARTICULAR, A SIGNIFICANT DECREASE IN THE BETAINE-HOMOCYSTEINE METHYLTRANSFERASE ENZYME. THIS SUGGESTED THAT HYPOMETHYLATION WAS ASSOCIATED WITH PROTEASOME INHIBITION, AS INDICATED BY THE DECREASE IN HISTONE METHYLATION. CONCLUSION: THE ROLE OF PROTEASOME INHIBITION IN REGULATING EPIGENETIC MECHANISMS, AND ITS LINK TO LIVER INJURY IN ALCOHOLIC LIVER DISEASE, IS THUS A PROMISING APPROACH TO STUDY LIVER INJURY DUE TO CHRONIC ETHANOL CONSUMPTION. 2009 19 2476 28 EPIGENETIC UPREGULATION OF CCL2 AND CCL3 VIA HISTONE MODIFICATIONS IN INFILTRATING MACROPHAGES AFTER PERIPHERAL NERVE INJURY. TO GAIN INSIGHT INTO THE EPIGENETIC REGULATION OF CC-CHEMOKINE LIGAND (CCL) 2 AND CCL3, KEY PLAYERS IN THE PERIPHERAL SENSITIZATION LEADING TO NEUROPATHIC PAIN, WE EXAMINED THE RELATIONSHIP BETWEEN HISTONE H3 MODIFICATION AND THE UPREGULATION OF THESE MOLECULES USING A MOUSE MODEL OF NEUROPATHIC PAIN AFTER PARTIAL SCIATIC NERVE LIGATION (PSL). WE FOUND THAT CIRCUITING BONE MARROW (BM)-DERIVED MACROPHAGES INFILTRATED INTO THE INJURED SCIATIC NERVE (SCN) USING ENHANCED GREEN FLUORESCENT PROTEIN CHIMERIC MICE. THE MRNA LEVELS OF CCL2, CCL3 AND THEIR RECEPTORS (CCR2 AND CCR1/CCR5, RESPECTIVELY) WERE INCREASED IN THE INJURED SCN. CHROMATIN IMMUNOPRECIPITATION ASSAY REVEALED THAT LEVELS OF LYSINE 9-ACETYLATED HISTONE H3 (H3K9AC) AND LYSINE 4-TRIMETHYLATED H3 (H3K4ME(3)) IN THE PROMOTER REGIONS OF THE CCL2 AND CCL3 GENES WERE INCREASED IN THE INJURED SCN AFTER PSL, INDICATING THE ENHANCEMENT OF GENE EXPRESSION. IMMUNOREACTIVITY FOR H3K9AC AND H3K4ME(3) WAS LOCALIZED IN THE NUCLEI OF INFILTRATING BM-DERIVED CELLS AND CCL-EXPRESSING CELLS IN THE INJURED SCN. WE OBSERVED H3K9AC AND H3K4ME(3) MAINLY IN THE NUCLEI OF RECRUITED MACROPHAGES ON DAY 7 AFTER PSL. FURTHERMORE, UPREGULATION OF CCLS AND CCRS WERE SUPPRESSED BY HISTONE ACETYLTRANSFERASE INHIBITOR, ANACARDIC ACID. TAKEN TOGETHER, OUR FINDINGS DEMONSTRATE THAT CCL2 AND CCL3 ARE UPREGULATED IN THE INJURED PERIPHERAL NERVE THROUGH EPIGENETIC HISTONE MODIFICATION IN INFILTRATING IMMUNE CELLS SUCH AS MACROPHAGES. THESE CHEMOKINE CASCADES MAY SUBSEQUENTLY ELICIT CHRONIC NEUROINFLAMMATION FOLLOWING NERVE INJURY. 2013 20 3319 25 HISTONE ACETYLATION AND HISTONE DEACETYLATION IN NEUROPATHIC PAIN: AN UNRESOLVED PUZZLE? CHRONIC PAIN IS BROADLY CLASSIFIED INTO SOMATIC, VISCERAL OR NEUROPATHIC PAIN DEPENDING UPON THE LOCATION AND EXTENT OF PAIN PERCEPTION. EVIDENCES FROM DIFFERENT ANIMAL STUDIES SUGGEST THAT INFLAMMATORY OR NEUROPATHIC PAIN IS ASSOCIATED WITH ALTERED ACETYLATION AND DEACETYLATION OF HISTONE PROTEINS, WHICH RESULT IN ABNORMAL TRANSCRIPTION OF NOCICEPTIVE PROCESSING GENES. THERE HAVE BEEN A NUMBER OF STUDIES INDICATING THAT NERVE INJURY UP-REGULATES HISTONE DEACETYLASE ENZYMES, WHICH LEADS TO INCREASED HISTONE DEACETYLATION AND INDUCE CHRONIC PAIN. TREATMENT WITH HISTONE DEACETYLASE INHIBITORS RELIEVES PAIN BY NORMALIZING NERVE INJURY-INDUCED DOWN REGULATION OF METABOTROPIC GLUTAMATE RECEPTORS, GLUTAMATE TRANSPORTERS, GLUTAMIC ACID DECARBOXYLASE 65, NEURON RESTRICTIVE SILENCER FACTOR AND SERUM AND GLUCOCORTICOID INDUCIBLE KINASE 1. ON THE OTHER HAND, A FEW STUDIES REFER TO INCREASED EXPRESSION OF HISTONE ACETYLASE ENZYMES IN RESPONSE TO NERVE INJURY THAT PROMOTES HISTONE ACETYLATION LEADING TO PAIN INDUCTION. TREATMENT WITH HISTONE ACETYL TRANSFERASE INHIBITORS HAVE BEEN REPORTED TO RELIEVE CHRONIC PAIN BY BLOCKING THE UP-REGULATION OF CHEMOKINES AND CYCLOOXYGENASE-2, THE CRITICAL FACTORS ASSOCIATED WITH HISTONE ACETYLATION-INDUCED PAIN. THE PRESENT REVIEW DESCRIBES THE DUAL ROLE OF HISTONE ACETYLATION/DEACETYLATION IN DEVELOPMENT OR ATTENUATION OF NEUROPATHIC PAIN ALONG WITH THE UNDERLYING MECHANISMS. 2017