1 5426 152 REGULATION OF SIRTUIN EXPRESSION IN AUTOIMMUNE NEUROINFLAMMATION: INDUCTION OF SIRT1 IN OLIGODENDROCYTE PROGENITOR CELLS. IN MULTIPLE SCLEROSIS (MS) REGENERATION OF OLIGODENDROCYTES FOLLOWING INFLAMMATORY DEMYELINATION IS LIMITED BY THE COMPROMISED ABILITY OF PROGENITORS TO REPOPULATE LESIONED AREAS AND TRANSITION TO FUNCTIONALLY COMPETENT OLIGODENDROCYTES. REGARDING UNDERLYING MECHANISMS, THE INVOLVEMENT OF EPIGENETIC PROCESSES HAS BEEN SUGGESTED, E.G. THE CONTRIBUTION OF HISTONE DEACETYLASES (HDAC) KNOWN TO REGULATE OLIGODENDROCYTE PROGENITOR CELL (OPC) DIFFERENTIATION. HOWEVER, THEIR PRECISE EXPRESSION PATTERNS, PARTICULAR OF REDOX-SENSITIVE NAD(+) HDACS, REMAINS LARGELY UNKNOWN. IN THIS STUDY, WE DETERMINED THE EXPRESSION AND ACTIVITY OF SIRTUINS, MEMBERS OF THE HDAC CLASS III FAMILY WITH A SPECIFIC FOCUS ON SIRT1, PREVIOUSLY ASSOCIATED WITH NEURODEGENERATIVE, INFLAMMATORY AND DEMYELINATING DISORDERS OF THE CENTRAL NERVOUS SYSTEM (CNS). BY INVESTIGATING MOUSE EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS (EAE), A MODEL FOR MS, WE FOUND THAT TRANSCRIPTION OF SIRT1, SIRT2 AND SIRT6 WAS SIGNIFICANTLY INCREASED IN THE CNS DURING CHRONIC DISEASE STAGES. WE CONFIRMED THIS FINDING FOR SIRT1 PROTEIN EXPRESSION AND WERE ABLE TO LOCALIZE UPREGULATED SIRT1 IN NUCLEI OF NG2(+) OR PDGFRALPHA(+) OPCS IN DEMYELINATED BRAIN LESIONS. IN CULTURED MOUSE A2B5(+) OPCS BLOCKADE OF SIRT1 ACTIVITY BY THE SMALL MOLECULE COMPOUND EX527 ENHANCED MITOTIC ACTIVITY BUT DID NOT AFFECT THE CAPACITY TO DIFFERENTIATE. A SIMILAR PATTERN WAS DETECTABLE IN OPCS DERIVED FROM SIRT1-DEFICIENT ANIMALS. TAKEN TOGETHER, OUR DATA SUGGEST THAT SIRT1 INHIBITION MAY HELP TO EXPAND THE ENDOGENOUS POOL OF OPCS WITHOUT AFFECTING THEIR DIFFERENTIATION. 2019 2 808 37 CHANGED HISTONE ACETYLATION PATTERNS IN NORMAL-APPEARING WHITE MATTER AND EARLY MULTIPLE SCLEROSIS LESIONS. THE EPIGENETIC IDENTITY OF OLIGODENDROCYTES IS MODULATED BY POSTTRANSLATIONAL MODIFICATIONS OF HISTONES. ACETYLATION OF HISTONE H3 RESULTS FROM THE BALANCE BETWEEN THE ACTIVITY OF HISTONE ACETYLTRANSFERASES (HATS) AND HISTONE DEACETYLASES AND MODULATES TRANSCRIPTIONAL ACTIVATION. WE HAVE PREVIOUSLY SHOWN THAT, IN RODENTS, HISTONE DEACETYLATION FAVORS OLIGODENDROCYTE DIFFERENTIATION, WHEREAS ACETYLATION IS ASSOCIATED WITH INCREASED LEVELS OF TRANSCRIPTIONAL INHIBITORS OF OLIGODENDROCYTE DIFFERENTIATION. HERE, WE REPORT, IN HUMANS BRAINS, A SHIFT TOWARD HISTONE ACETYLATION IN THE WHITE MATTER OF THE FRONTAL LOBES OF AGED SUBJECTS AND IN PATIENTS WITH CHRONIC MULTIPLE SCLEROSIS (MS). INCREASED IMMUNOREACTIVITY FOR ACETYLATED HISTONE H3 WAS OBSERVED IN THE NUCLEI OF NOGOA+ OLIGODENDROCYTES IN A SUBSET OF MS SAMPLES. THESE CHANGES WERE ASSOCIATED WITH HIGH LEVELS OF TRANSCRIPTIONAL INHIBITORS OF OLIGODENDROCYTE DIFFERENTIATION (I.E., TCF7L2, ID2, AND SOX2) AND HIGHER HAT TRANSCRIPT LEVELS (I.E., CBP, P300) IN FEMALE MS PATIENTS COMPARED WITH NON-NEUROLOGICAL CONTROLS AND CORRELATED WITH DISEASE DURATION. CHROMATIN IMMUNOPRECIPITATION FROM SAMPLES OF MS PATIENTS REVEALED ENRICHMENT OF ACETYL-HISTONE H3 AT THE PROMOTER OF THE INCREASED TARGET GENES (I.E., TCF7L2). THE DATA IN CHRONIC LESIONS CONTRASTED WITH FINDINGS IN EARLY MS LESIONS, WHERE A MARKED OLIGODENDROGLIAL HISTONE DEACETYLATION WAS OBSERVED. TOGETHER, THESE DATA SUGGEST THAT HISTONE DEACETYLATION IS A PROCESS THAT OCCURS AT THE EARLY STAGES OF THE DISEASE AND WHOSE EFFICIENCY DECREASES WITH DISEASE DURATION. 2011 3 6531 36 TRANSCRIPTIONAL REGULATION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) BY METHYL CPG BINDING PROTEIN 2 (MECP2): A NOVEL MECHANISM FOR RE-MYELINATION AND/OR MYELIN REPAIR INVOLVED IN THE TREATMENT OF MULTIPLE SCLEROSIS (MS). MULTIPLE SCLEROSIS (MS) IS A CHRONIC PROGRESSIVE, NEUROLOGICAL DISEASE CHARACTERIZED BY THE TARGETED IMMUNE SYSTEM-MEDIATED DESTRUCTION OF CENTRAL NERVOUS SYSTEM (CNS) MYELIN. AUTOREACTIVE CD4+ T HELPER CELLS HAVE A KEY ROLE IN ORCHESTRATING MS-INDUCED MYELIN DAMAGE. ONCE ACTIVATED, CIRCULATING TH1-CELLS SECRETE A VARIETY OF INFLAMMATORY CYTOKINES THAT FOSTER THE BREAKDOWN OF BLOOD-BRAIN BARRIER (BBB) EVENTUALLY INFILTRATING INTO THE CNS. INSIDE THE CNS, THEY BECOME REACTIVATED UPON EXPOSURE TO THE MYELIN STRUCTURAL PROTEINS AND CONTINUE TO PRODUCE INFLAMMATORY CYTOKINES SUCH AS TUMOR NECROSIS FACTOR ALPHA (TNFALPHA) THAT LEADS TO DIRECT ACTIVATION OF ANTIBODIES AND MACROPHAGES THAT ARE INVOLVED IN THE PHAGOCYTOSIS OF MYELIN. PROLIFERATING OLIGODENDROCYTE PRECURSORS (OPS) MIGRATING TO THE LESION SITES ARE CAPABLE OF ACUTE REMYELINATION BUT UNABLE TO COMPLETELY REPAIR OR RESTORE THE IMMUNE SYSTEM-MEDIATED MYELIN DAMAGE. THIS RESULTS IN VARIOUS PERMANENT CLINICAL NEUROLOGICAL DISABILITIES SUCH AS COGNITIVE DYSFUNCTION, FATIGUE, BOWEL/BLADDER ABNORMALITIES, AND NEUROPATHIC PAIN. AT PRESENT, THERE IS NO CURE FOR MS. RECENT REMYELINATION AND/OR MYELIN REPAIR STRATEGIES HAVE FOCUSED ON THE ROLE OF THE NEUROTROPHIN BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) AND ITS UPSTREAM TRANSCRIPTIONAL REPRESSOR METHYL CPG BINDING PROTEIN (MECP2). RESEARCH IN THE FIELD OF EPIGENETIC THERAPEUTICS INVOLVING HISTONE DEACETYLASE (HDAC) INHIBITORS AND LYSINE ACETYL TRANSFERASE (KAT) INHIBITORS IS BEING EXPLORED TO REPRESS THE DETRIMENTAL EFFECTS OF MECP2. THIS REVIEW WILL ADDRESS THE ROLE OF MECP2 AND BDNF IN REMYELINATION AND/OR MYELIN REPAIR AND THE POTENTIAL OF HDAC AND KAT INHIBITORS AS NOVEL THERAPEUTIC INTERVENTIONS FOR MS. 2016 4 6117 44 THE EPIGENETIC DRUG TRICHOSTATIN A AMELIORATES EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS VIA T CELL TOLERANCE INDUCTION AND IMPAIRED INFLUX OF T CELLS INTO THE SPINAL CORD. MULTIPLE SCLEROSIS IS A T CELL MEDIATED CHRONIC DEMYELINATING DISEASE OF THE CENTRAL NERVOUS SYSTEM. ALTHOUGH CURRENTLY AVAILABLE THERAPIES REDUCE RELAPSES, THEY DO NOT FACILITATE TOLERIZATION OF MYELIN ANTIGEN-SPECIFIC T LYMPHOCYTES TO ENSURE PROLONGED PROTECTION AGAINST MULTIPLE SCLEROSIS. HERE, WE SHOW THAT TREATMENT OF NOD MICE WITH THE HISTONE DEACETYLASE INHIBITOR, TRICHOSTATIN A AFFORDS ROBUST PROTECTION AGAINST MYELIN PEPTIDE INDUCED EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS, A MOUSE MODEL OF MULTIPLE SCLEROSIS. PROTECTION WAS ACCOMPANIED BY HISTONE HYPERACETYLATION, AND REDUCED INFLAMMATION AND AXONAL DAMAGE IN THE SPINAL CORD. DRUG TREATMENT DIMINISHED THE GENERATION OF CD4(+) MEMORY T CELLS AND INDUCED TOLERANCE IN CD4(+) T CELLS RECOGNIZING THE IMMUNIZING MYELIN PEPTIDE. DURING THE EARLY IMMUNIZATION PERIOD, CD4(+) T CELLS PRODUCING GM-CSF+IFN-GAMMA, GM-CSF+IL-17A, AS WELL AS THOSE EXPRESSING BOTH IL-17A+IFN-GAMMA (DOUBLE-PRODUCERS) WERE DETECTED IN THE SECONDARY LYMPHOID ORGANS FOLLOWED BY THE APPEARANCE OF CELLS PRODUCING IFN-GAMMA AND GM-CSF. ON THE OTHER HAND, IFN-GAMMA PRODUCING TH1 CELLS APPEAR FIRST IN THE SPINAL CORD FOLLOWED BY CELLS PRODUCING IL-17A AND GM-CSF. TREATMENT WITH TRICHOSTATIN A SUBSTANTIALLY REDUCED THE FREQUENCIES OF ALL T CELLS SECRETING VARIOUS LYMPHOKINES BOTH IN THE PERIPHERY AND IN THE SPINAL CORD. THESE DATA INDICATE THAT EPIGENETIC MODIFICATIONS INDUCED BY HISTONE HYPERACETYLATION FACILITATES T CELL TOLERANCE INDUCTION IN THE PERIPHERY LEADING TO REDUCED MIGRATION OF T CELLS TO THE SPINAL CORD AND MITIGATION OF NEURONAL DAMAGE AND IMPROVED CLINICAL OUTCOME. THESE RESULTS SUGGEST THAT EPIGENETIC MODULATION OF THE GENOME MAY SIMILARLY OFFER BENEFITS TO MULTIPLE SCLEROSIS PATIENTS VIA ABROGATING THE FUNCTION OF ENCEPHALITOGENIC T LYMPHOCYTES WITHOUT EXERTING SEVERE SIDE EFFECTS ASSOCIATED WITH CURRENTLY USED DISEASE-MODIFYING THERAPIES. 2017 5 5591 46 ROLE OF THE EPIGENETIC FACTOR SIRT7 IN NEUROINFLAMMATION AND NEUROGENESIS. EPIGENETIC REGULATORS ARE INCREASINGLY RECOGNIZED AS RELEVANT MODULATORS IN THE IMMUNE AND NERVOUS SYSTEM. THE CLASS OF SIRTUINS CONSISTS OF NAD(+)-DEPENDENT HISTONE DEACETYLASES THAT REGULATE TRANSCRIPTION. SIRTUIN FAMILY MEMBER SIRT1 HAS ALREADY BEEN SHOWN TO INFLUENCE THE DISEASE COURSE IN AN ANIMAL MODEL OF AUTOIMMUNE NEUROINFLAMMATION (EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS (EAE). A ROLE OF SIRT7, A RELATED EPIGENETIC REGULATOR, ON IMMUNE SYSTEM REGULATION HAS BEEN PROPOSED BEFORE, AS THESE MICE ARE MORE SUSCEPTIBLE TO DEVELOP INFLAMMATORY CARDIOMYOPATHY. SIRT7(-/-) ANIMALS SHOWED NO DIFFERENCES IN CLINICAL SCORE COMPARED TO WILD-TYPE LITTERMATES AFTER EAE INDUCTION WITH MYELIN OLIGODENDROCYTE GLYCOPROTEIN (MOG) PEPTIDE (35-55), ALTHOUGH WE FOUND SUBTLE IMMUNE ALTERATIONS AT DIFFERENT PHASES OF EAE AND DECREASED SURVIVAL OF NEWLY GENERATED NEURONS IN THE HIPPOCAMPUS. OUR DATA INDICATE THAT SIRT7 HAS A SLIGHT PROTECTIVE IMPACT ON BOTH THE ADAPTIVE IMMUNE SYSTEM AND NEUROGENESIS. HOWEVER, OVERALL THIS EPIGENETIC FACTOR IS NOT CAPABLE OF IMPACTING THE ACUTE OR CHRONIC PHASE OF NEUROINFLAMMATION. 2018 6 4969 39 PATHOLOGICAL NEUROINFLAMMATORY CONVERSION OF REACTIVE ASTROCYTES IS INDUCED BY MICROGLIA AND INVOLVES CHROMATIN REMODELING. FOLLOWING BRAIN INJURY OR IN NEURODEGENERATIVE DISEASES, ASTROCYTES BECOME REACTIVE AND MAY SUFFER PATHOLOGICAL REMODELING, FEATURES OF WHICH ARE THE LOSS OF THEIR HOMEOSTATIC FUNCTIONS AND A PRO-INFLAMMATORY GAIN OF FUNCTION THAT FACILITATES NEURODEGENERATION. PHARMACOLOGICAL INTERVENTION TO MODULATE THIS ASTROGLIAL RESPONSE AND NEUROINFLAMMATION IS AN INTERESTING NEW THERAPEUTIC RESEARCH STRATEGY, BUT IT STILL REQUIRES A DEEPER UNDERSTANDING OF THE UNDERLYING CELLULAR AND MOLECULAR MECHANISMS OF THE PHENOMENON. BASED ON THE KNOWN MICROGLIAL-ASTROGLIAL INTERACTION, THE PROMINENT ROLE OF THE NUCLEAR FACTOR KAPPA B (NF-KAPPAB) PATHWAY IN MEDIATING ASTROGLIAL PATHOLOGICAL PRO-INFLAMMATORY GAIN OF FUNCTION, AND ITS ABILITY TO RECRUIT CHROMATIN-REMODELING ENZYMES, WE FIRST EXPLORED THE MICROGLIAL ROLE IN THE INITIATION OF ASTROGLIAL PRO-INFLAMMATORY CONVERSION AND THEN MONITORED THE PROGRESSION OF EPIGENETIC CHANGES IN THE ASTROCYTIC CHROMATIN. DIFFERENT CONFIGURATIONS OF PRIMARY GLIAL CULTURE WERE USED TO MODULATE MICROGLIA-ASTROCYTE CROSSTALK WHILE INDUCING PRO-INFLAMMATORY GAIN OF FUNCTION BY LIPOPOLYSACCHARIDE (LPS) EXPOSURE. IN VIVO, BRAIN ISCHEMIA BY CORTICAL DEVASCULARIZATION (PIAL DISRUPTION) WAS PERFORMED TO VERIFY THE PRESENCE OF EPIGENETIC MARKS IN REACTIVE ASTROCYTES. OUR RESULTS SHOWED THAT 1) MICROGLIA IS REQUIRED TO INITIATE THE PATHOLOGICAL CONVERSION OF ASTROCYTES BY TRIGGERING THE NF-KAPPAB SIGNALING PATHWAY; 2) THIS INTERACTION IS MEDIATED BY SOLUBLE FACTORS AND INDUCES STABLE ASTROGLIAL PHENOTYPIC CHANGES; 3) THE PATHOLOGICAL CONVERSION PROMOTES CHROMATIN REMODELING WITH STABLE INCREASE IN H3K9K14AC, TEMPORARY INCREASE IN H3K27AC, AND TEMPORARY REDUCTION IN HETEROCHROMATIN MARK H3K9ME3; AND 4) IN VIVO REACTIVE ASTROCYTES SHOW INCREASED H3K27AC MARK IN THE NEUROINFLAMMATORY MILIEU FROM THE ISCHEMIC PENUMBRA. OUR FINDINGS INDICATE THAT ASTROGLIAL PATHOLOGICAL PRO-INFLAMMATORY GAIN OF FUNCTION IS ASSOCIATED WITH PROFOUND CHANGES IN THE CONFIGURATION OF ASTROCYTIC CHROMATIN, WHICH IN TURN ARE INITIATED BY MICROGLIA-DERIVED CUES. THESE RESULTS OPEN A NEW AVENUE IN THE STUDY OF POTENTIAL PHARMACOLOGICAL INTERVENTIONS THAT MODIFY THE INITIATION AND STABILIZATION OF ASTROGLIAL PATHOLOGICAL REMODELING, WHICH WOULD BE USEFUL IN ACUTE AND CHRONIC CNS INJURY. EPIGENETIC CHANGES REPRESENT A PLAUSIBLE PHARMACOLOGICAL TARGET TO INTERFERE WITH THE STABILIZATION OF THE PATHOLOGICAL ASTROGLIAL PHENOTYPE. 2021 7 2856 47 FROM METHYLATION TO MYELINATION: EPIGENOMIC AND TRANSCRIPTOMIC PROFILING OF CHRONIC INACTIVE DEMYELINATED MULTIPLE SCLEROSIS LESIONS. IN THE PROGRESSIVE PHASE OF MULTIPLE SCLEROSIS (MS), THE HAMPERED DIFFERENTIATION CAPACITY OF OLIGODENDROCYTE PRECURSOR CELLS (OPCS) EVENTUALLY RESULTS IN REMYELINATION FAILURE. WE HAVE PREVIOUSLY SHOWN THAT DNA METHYLATION OF ID2/ID4 IS HIGHLY INVOLVED IN OPC DIFFERENTIATION AND REMYELINATION. IN THIS STUDY, WE TOOK AN UNBIASED APPROACH BY DETERMINING GENOME-WIDE DNA METHYLATION PATTERNS WITHIN CHRONICALLY DEMYELINATED MS LESIONS AND INVESTIGATED HOW CERTAIN EPIGENETIC SIGNATURES RELATE TO OPC DIFFERENTIATION CAPACITY. WE COMPARED GENOME-WIDE DNA METHYLATION AND TRANSCRIPTIONAL PROFILES BETWEEN CHRONICALLY DEMYELINATED MS LESIONS AND MATCHED NORMAL-APPEARING WHITE MATTER (NAWM), MAKING USE OF POST-MORTEM BRAIN TISSUE (N = 9/GROUP). DNA METHYLATION DIFFERENCES THAT INVERSELY CORRELATED WITH MRNA EXPRESSION OF THEIR CORRESPONDING GENES WERE VALIDATED FOR THEIR CELL-TYPE SPECIFICITY IN LASER-CAPTURED OPCS USING PYROSEQUENCING. THE CRISPR-DCAS9-DNMT3A/TET1 SYSTEM WAS USED TO EPIGENETICALLY EDIT HUMAN-IPSC-DERIVED OLIGODENDROCYTES TO ASSESS THE EFFECT ON CELLULAR DIFFERENTIATION. OUR DATA SHOW HYPERMETHYLATION OF CPGS WITHIN GENES THAT CLUSTER IN GENE ONTOLOGIES RELATED TO MYELINATION AND AXON ENSHEATHMENT. CELL TYPE-SPECIFIC VALIDATION INDICATES A REGION-DEPENDENT HYPERMETHYLATION OF MBP, ENCODING FOR MYELIN BASIC PROTEIN, IN OPCS OBTAINED FROM WHITE MATTER LESIONS COMPARED TO NAWM-DERIVED OPCS. BY ALTERING THE DNA METHYLATION STATE OF SPECIFIC CPGS WITHIN THE PROMOTOR REGION OF MBP, USING EPIGENETIC EDITING, WE SHOW THAT CELLULAR DIFFERENTIATION AND MYELINATION CAN BE BIDIRECTIONALLY MANIPULATED USING THE CRISPR-DCAS9-DNMT3A/TET1 SYSTEM IN VITRO. OUR DATA INDICATE THAT OPCS WITHIN CHRONICALLY DEMYELINATED MS LESIONS ACQUIRE AN INHIBITORY PHENOTYPE, WHICH TRANSLATES INTO HYPERMETHYLATION OF CRUCIAL MYELINATION-RELATED GENES. ALTERING THE EPIGENETIC STATUS OF MBP CAN RESTORE THE DIFFERENTIATION CAPACITY OF OPCS AND POSSIBLY BOOST (RE)MYELINATION. 2023 8 5710 34 SIRT1 DEFICIENCY IN MICROGLIA CONTRIBUTES TO COGNITIVE DECLINE IN AGING AND NEURODEGENERATION VIA EPIGENETIC REGULATION OF IL-1BETA. AGING IS THE PREDOMINANT RISK FACTOR FOR NEURODEGENERATIVE DISEASES. ONE KEY PHENOTYPE AS THE BRAIN AGES IS AN ABERRANT INNATE IMMUNE RESPONSE CHARACTERIZED BY PROINFLAMMATION. HOWEVER, THE MOLECULAR MECHANISMS UNDERLYING AGING-ASSOCIATED PROINFLAMMATION ARE POORLY DEFINED. WHETHER CHRONIC INFLAMMATION PLAYS A CAUSAL ROLE IN COGNITIVE DECLINE IN AGING AND NEURODEGENERATION HAS NOT BEEN ESTABLISHED. HERE WE REPORT A MECHANISTIC LINK BETWEEN CHRONIC INFLAMMATION AND AGING MICROGLIA AND A CAUSAL ROLE OF AGING MICROGLIA IN NEURODEGENERATIVE COGNITIVE DEFICITS. WE SHOWED THAT SIRT1 IS REDUCED WITH THE AGING OF MICROGLIA AND THAT MICROGLIAL SIRT1 DEFICIENCY HAS A CAUSATIVE ROLE IN AGING- OR TAU-MEDIATED MEMORY DEFICITS VIA IL-1BETA UPREGULATION IN MICE. INTERESTINGLY, THE SELECTIVE ACTIVATION OF IL-1BETA TRANSCRIPTION BY SIRT1 DEFICIENCY IS LIKELY MEDIATED THROUGH HYPOMETHYLATING THE SPECIFIC CPG SITES ON IL-1BETA PROXIMAL PROMOTER. IN HUMANS, HYPOMETHYLATION OF IL-1BETA IS STRONGLY ASSOCIATED WITH CHRONOLOGICAL AGE AND WITH ELEVATED IL-1BETA TRANSCRIPTION. OUR FINDINGS REVEAL A NOVEL EPIGENETIC MECHANISM IN AGING MICROGLIA THAT CONTRIBUTES TO COGNITIVE DEFICITS IN AGING AND NEURODEGENERATIVE DISEASES. 2015 9 5711 38 SIRT1 IS A HIGHLY NETWORKED PROTEIN THAT MEDIATES THE ADAPTATION TO CHRONIC PHYSIOLOGICAL STRESS. SIRT1 IS A NAD(+)-DEPENDENT PROTEIN DEACETYLASE THAT HAS A VERY LARGE NUMBER OF ESTABLISHED PROTEIN SUBSTRATES AND AN EQUALLY IMPRESSIVE LIST OF BIOLOGICAL FUNCTIONS THOUGHT TO BE REGULATED BY ITS ACTIVITY. PERHAPS AS NOTABLE IS THE REMARKABLE NUMBER OF POINTS OF CONFLICT CONCERNING THE ROLE OF SIRT1 IN BIOLOGICAL PROCESSES. FOR EXAMPLE, EVIDENCE EXISTS SUGGESTING THAT SIRT1 IS A TUMOR SUPPRESSOR, IS AN ONCOGENE, OR HAS NO EFFECT ON ONCOGENESIS. SIMILARLY, SIRT1 IS VARIABLY REPORTED TO INDUCE, INHIBIT, OR HAVE NO EFFECT ON AUTOPHAGY. WE BELIEVE THAT THE RESOLUTION OF MANY CONFLICTING RESULTS IS POSSIBLE BY CONSIDERING RECENT REPORTS INDICATING THAT SIRT1 IS AN IMPORTANT HUB INTERACTING WITH A COMPLEX NETWORK OF PROTEINS THAT COLLECTIVELY REGULATE A WIDE VARIETY OF BIOLOGICAL PROCESSES INCLUDING CANCER AND AUTOPHAGY. A NUMBER OF THE INTERACTING PROTEINS ARE THEMSELVES HUBS THAT, LIKE SIRT1, UTILIZE INTRINSICALLY DISORDERED REGIONS FOR THEIR PROMISCUOUS INTERACTIONS. MANY STUDIES INVESTIGATING SIRT1 FUNCTION HAVE BEEN CARRIED OUT ON CELL LINES CARRYING UNDETERMINED NUMBERS OF ALTERATIONS TO THE PROTEINS COMPRISING THE SIRT1 NETWORK OR ON INBRED MOUSE STRAINS CARRYING FIXED MUTATIONS AFFECTING SOME OF THESE PROTEINS. THUS, THE EFFECTS OF MODULATING SIRT1 AMOUNT AND/OR ACTIVITY ARE IMPORTANTLY DETERMINED BY THE GENETIC BACKGROUND OF THE CELL (OR THE INBRED STRAIN OF MICE), AND THE EFFECTS ATTRIBUTED TO SIRT1 ARE SYNTHETIC WITH THE BACKGROUND OF MUTATIONS AND EPIGENETIC DIFFERENCES BETWEEN CELLS AND ORGANISMS. WORK ON MICE CARRYING ALTERATIONS TO THE SIRT1 GENE SUGGESTS THAT THE NETWORK IN WHICH SIRT1 FUNCTIONS PLAYS AN IMPORTANT ROLE IN MEDIATING PHYSIOLOGICAL ADAPTATION TO VARIOUS SOURCES OF CHRONIC STRESS SUCH AS CALORIE RESTRICTION AND CALORIE OVERLOAD. WHETHER THE CATALYTIC ACTIVITY OF SIRT1 AND THE NUCLEAR CONCENTRATION OF THE CO-FACTOR, NAD(+), ARE RESPONSIBLE FOR MODULATING THIS ACTIVITY REMAINS TO BE DETERMINED. HOWEVER, THE EFFECT OF MODULATING SIRT1 ACTIVITY MUST BE INTERPRETED IN THE CONTEXT OF THE CELL OR TISSUE UNDER INVESTIGATION. INDEED, FOR SIRT1, WE ARGUE THAT CONTEXT IS EVERYTHING. 2013 10 4772 34 NUCLEAR SIRTUINS AND INFLAMMATORY SIGNALING PATHWAYS. THE REGULATION OF CHRONIC INFLAMMATION HAS RECEIVED CONSIDERABLE RESEARCH ATTENTION IN RECENT YEARS BECAUSE OF ITS CONTRIBUTION TO THE PATHOGENESIS OF CHRONIC DISEASES SUCH AS ARTHRITIS, DIABETES, METABOLIC SYNDROME AND OBESITY. THUS, STRATEGIES THAT INHIBIT THE INFLAMMATORY STATE MAY BE BENEFICIAL IN IMPROVING THE PATHOPHYSIOLOGY OF SEVERAL INFLAMMATION-RELATED DISORDERS. SIRTUINS ARE A FAMILY OF HISTONE DEACETYLASES THAT CONTAIN SEVEN ENZYMATIC ACTIVITIES IN MAMMALS (SIRT1-SIRT7) AND FUNCTION TO SUPPRESS GENE TRANSCRIPTION BY EPIGENETIC MECHANISMS. NUCLEAR SIRTUINS (SIRT 1, 2, 6 AND 7) IN PARTICULAR MAY PLAY AN IMPORTANT ROLE IN THE REGULATION OF INFLAMMATORY RESPONSES. IN THE PRESENT REVIEW, WE ASSESSED THE ROLES OF NUCLEAR SIRTUINS IN INFLAMMATORY REACTIONS: SIRT1 HAS BEEN SHOWN TO SUPPRESS NF-KAPPAB ACTIVITY, THE MASTER REGULATOR OF CELLULAR INFLAMMATORY RESPONSE, DECREASE COX-2 AND INOS PRODUCTION, AND INCREASE ANTIOXIDANT GENE EXPRESSION THAT SUPPRESSED INFLAMMATION. SIRT2 ACTIVITY INCLUDED THE DEACETYLATION OF P65 SUBUNIT OF NF-KAPPABETA AND RIP-1, WHILE SIRT6 HAS BEEN SHOWN TO INTERACT WITH P65/RELA BOUND TO THE NF-KAPPABETA PROMOTER REGION AND REPRESS TRANSCRIPTIONAL ACTIVITY. FURTHERMORE, RECENT STUDIES HAVE SHOWN THAT THE ABSENCE OF SIRT7 PRODUCED AN INCREASE IN INFLAMMATION, ILLUSTRATING THAT SIRT7 ALSO FUNCTIONED TO DECREASE INFLAMMATION. GIVEN THEIR SIGNIFICANT ROLES IN THE REGULATION OF CHRONIC INFLAMMATION, NUCLEAR SIRTUINS REPRESENT POTENTIAL THERAPEUTIC TARGETS IN THE CONTROL OF CHRONIC INFLAMMATORY DISEASES. 2017 11 6527 37 TRANSCRIPTIONAL CONTROL OF MALADAPTIVE AND PROTECTIVE RESPONSES IN ALCOHOLICS: A ROLE OF THE NF-KAPPAB SYSTEM. ALCOHOL DEPENDENCE AND ASSOCIATED COGNITIVE IMPAIRMENT APPEAR TO RESULT FROM MALADAPTIVE NEUROPLASTICITY IN RESPONSE TO CHRONIC ALCOHOL CONSUMPTION, NEUROINFLAMMATION AND NEURODEGENERATION. THE INHERENT STABILITY OF BEHAVIORAL ALTERATIONS ASSOCIATED WITH THE ADDICTED STATE SUGGESTS THAT TRANSCRIPTIONAL AND EPIGENETIC MECHANISMS ARE OPERATIVE. NF-KAPPAB TRANSCRIPTION FACTORS ARE REGULATORS OF SYNAPTIC PLASTICITY AND INFLAMMATION, AND RESPONSIVE TO A VARIETY OF STIMULI INCLUDING ALCOHOL. THESE FACTORS ARE ABUNDANT IN THE BRAIN WHERE THEY HAVE DIVERSE FUNCTIONS THAT DEPEND ON THE COMPOSITION OF THE NF-KAPPAB COMPLEX AND CELLULAR CONTEXT. IN NEURON CELL BODIES, NF-KAPPAB IS CONSTITUTIVELY ACTIVE, AND INVOLVED IN NEURONAL INJURY AND NEUROPROTECTION. HOWEVER, AT THE SYNAPSE, NF-KAPPAB IS PRESENT IN A LATENT FORM AND UPON ACTIVATION IS TRANSPORTED TO THE CELL NUCLEUS. IN GLIA, NF-KAPPAB IS INDUCIBLE AND REGULATES INFLAMMATORY PROCESSES THAT EXACERBATE ALCOHOL-INDUCED NEURODEGENERATION. ANIMAL STUDIES DEMONSTRATE THAT ACUTE ALCOHOL EXPOSURE TRANSIENTLY ACTIVATES NF-KAPPAB, WHICH INDUCES NEUROINFLAMMATORY RESPONSES AND NEURODEGENERATION. POSTMORTEM STUDIES OF BRAINS OF HUMAN ALCOHOLICS SUGGEST THAT REPEATED CYCLES OF ALCOHOL CONSUMPTION AND WITHDRAWAL CAUSE ADAPTIVE CHANGES IN THE NF-KAPPAB SYSTEM THAT MAY PERMIT THE SYSTEM TO BETTER TOLERATE EXCESSIVE STIMULATION. THIS TYPE OF TOLERANCE, ENSURING A LOW DEGREE OF RESPONSIVENESS TO APPLIED STIMULI, APPARENTLY DIFFERS FROM THAT IN THE IMMUNE SYSTEM, AND MAY REPRESENT A COMPENSATORY RESPONSE THAT PROTECTS BRAIN CELLS AGAINST ALCOHOL NEUROTOXICITY. THIS VIEW IS SUPPORTED BY FINDINGS SHOWING PREFERENTIAL DOWNREGULATION OF PRO-APOPTOTIC GENE EXPRESSION IN THE AFFECTED BRAIN AREAS IN HUMAN ALCOHOLICS. ALTHOUGH FURTHER VERIFICATION IS NEEDED, WE SPECULATE THAT NF-KAPPAB-DRIVEN NEUROINFLAMMATION AND DISRUPTION TO NEUROPLASTICITY PLAY A SIGNIFICANT ROLE IN REGULATING ALCOHOL DEPENDENCE AND COGNITIVE IMPAIRMENT. 2011 12 1035 48 CLASS I HISTONE DEACETYLASE INHIBITION IMPROVES PANCREATITIS OUTCOME BY LIMITING LEUKOCYTE RECRUITMENT AND ACINAR-TO-DUCTAL METAPLASIA. BACKGROUND AND PURPOSE: PANCREATITIS IS A COMMON INFLAMMATION OF THE PANCREAS WITH RISING INCIDENCE IN MANY COUNTRIES. DESPITE IMPROVEMENTS IN DIAGNOSTIC TECHNIQUES, THE DISEASE IS ASSOCIATED WITH HIGH RISK OF SEVERE MORBIDITY AND MORTALITY AND THERE IS AN URGENT NEED FOR NEW THERAPEUTIC INTERVENTIONS. IN THIS STUDY, WE EVALUATED WHETHER HISTONE DEACETYLASES (HDACS), KEY EPIGENETIC REGULATORS OF GENE TRANSCRIPTION, ARE INVOLVED IN THE DEVELOPMENT OF THE DISEASE. EXPERIMENTAL APPROACH: WE ANALYSED HDAC REGULATION DURING CERULEIN-INDUCED ACUTE, CHRONIC AND AUTOIMMUNE PANCREATITIS USING DIFFERENT TRANSGENIC MOUSE MODELS. THE FUNCTIONAL RELEVANCE OF CLASS I HDACS WAS TESTED WITH THE SELECTIVE INHIBITOR MS-275 IN VIVO UPON PANCREATITIS INDUCTION AND IN VITRO IN ACTIVATED MACROPHAGES AND PRIMARY ACINAR CELL EXPLANTS. KEY RESULTS: HDAC EXPRESSION AND ACTIVITY WERE UP-REGULATED IN A TIME-DEPENDENT MANNER FOLLOWING INDUCTION OF PANCREATITIS, WITH THE HIGHEST ABUNDANCE OBSERVED FOR CLASS I HDACS. CLASS I HDAC INHIBITION DID NOT PREVENT THE INITIAL ACINAR CELL DAMAGE. HOWEVER, IT EFFECTIVELY REDUCED THE INFILTRATION OF INFLAMMATORY CELLS, INCLUDING MACROPHAGES AND T CELLS, IN BOTH ACUTE AND CHRONIC PHASES OF THE DISEASE, AND DIRECTLY DISRUPTED MACROPHAGE ACTIVATION. IN ADDITION, MS-275 TREATMENT REDUCED DNA DAMAGE IN ACINAR CELLS AND LIMITED ACINAR DE-DIFFERENTIATION INTO ACINAR-TO-DUCTAL METAPLASIA IN A CELL-AUTONOMOUS MANNER BY IMPEDING THE EGF RECEPTOR SIGNALLING AXIS. CONCLUSIONS AND IMPLICATIONS: THESE RESULTS DEMONSTRATE THAT CLASS I HDACS ARE CRITICALLY INVOLVED IN THE DEVELOPMENT OF ACUTE AND CHRONIC FORMS OF PANCREATITIS AND SUGGEST THAT BLOCKADE OF CLASS I HDAC ISOFORMS IS A PROMISING TARGET TO IMPROVE THE OUTCOME OF THE DISEASE. 2017 13 3341 33 HISTONE DEACETYLASE-2 IS INVOLVED IN STRESS-INDUCED COGNITIVE IMPAIRMENT VIA HISTONE DEACETYLATION AND PI3K/AKT SIGNALING PATHWAY MODIFICATION. EXPOSURE TO CHRONIC STRESS UPREGULATES BLOOD GLUCOCORTICOID LEVELS AND IMPAIRS COGNITION VIA DIVERSE EPIGENETIC MECHANISMS, SUCH AS HISTONE DEACETYLATION. HISTONE DEACETYLATION CAN LEAD TO TRANSCRIPTIONAL SILENCING OF MANY PROTEINS INVOLVED IN COGNITION AND MAY ALSO CAUSE LEARNING AND MEMORY DYSFUNCTION. HISTONE DEACETYLASE?2 (HDAC2) HAS BEEN DEMONSTRATED TO EPIGENETICALLY BLOCK COGNITION VIA A REDUCTION IN THE HISTONE ACETYLATION LEVEL; HOWEVER, IT IS UNKNOWN WHETHER HDAC2 IS INVOLVED IN THE COGNITIVE DECLINE INDUCED BY CHRONIC STRESS. TO THE BEST OF AUTHORS' KNOWLEDGE, THIS IS THE FIRST STUDY TO DEMONSTRATE THAT THE STRESS HORMONE CORTICOSTEROID UPREGULATE HDAC2 PROTEIN LEVELS IN NEURO?2A CELLS AND CAUSE CELL INJURIES. HDAC2 KNOCKDOWN RESULTED IN A SIGNIFICANT AMELIORATION OF THE PATHOLOGICAL CHANGES IN N2A CELLS VIA THE UPREGULATION OF HISTONE ACETYLATION AND MODIFICATIONS IN THE PHOSPHOINOSITIDE 3?KINASE/PROTEIN KINASE B SIGNALING PATHWAY. IN ADDITION, THE HDAC2 PROTEIN LEVELS WERE UPREGULATED IN 12?MONTH?OLD FEMALE C57BL/6J MICE UNDER CHRONIC STRESS IN VIVO. TAKEN TOGETHER, THESE FINDINGS SUGGESTED THAT HDAC2 MAY BE AN IMPORTANT NEGATIVE REGULATOR INVOLVED IN CHRONIC STRESS?INDUCED COGNITIVE IMPAIRMENT. 2017 14 2493 45 EPIGENETICS AND CHROMATIN REMODELING PLAY A ROLE IN LUNG DISEASE. EPIGENETICS IS DEFINED AS HERITABLE CHANGES THAT AFFECT GENE EXPRESSION WITHOUT ALTERING THE DNA SEQUENCE. EPIGENETIC REGULATION OF GENE EXPRESSION IS FACILITATED THROUGH DIFFERENT MECHANISMS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS AND RNA-ASSOCIATED SILENCING BY SMALL NON-CODING RNAS. ALL THESE MECHANISMS ARE CRUCIAL FOR NORMAL DEVELOPMENT, DIFFERENTIATION AND TISSUE-SPECIFIC GENE EXPRESSION. THESE THREE SYSTEMS INTERACT AND STABILIZE ONE ANOTHER AND CAN INITIATE AND SUSTAIN EPIGENETIC SILENCING, THUS DETERMINING HERITABLE CHANGES IN GENE EXPRESSION. HISTONE ACETYLATION REGULATES DIVERSE CELLULAR FUNCTIONS INCLUDING INFLAMMATORY GENE EXPRESSION, DNA REPAIR AND CELL PROLIFERATION. TRANSCRIPTIONAL COACTIVATORS POSSESS INTRINSIC HISTONE ACETYLTRANSFERASE ACTIVITY AND THIS ACTIVITY DRIVES INFLAMMATORY GENE EXPRESSION. ELEVEN CLASSICAL HISTONE DEACETYLASES (HDACS) ACT TO REGULATE THE EXPRESSION OF DISTINCT SUBSETS OF INFLAMMATORY/IMMUNE GENES. THUS, LOSS OF HDAC ACTIVITY OR THE PRESENCE OF HDAC INHIBITORS CAN FURTHER ENHANCE INFLAMMATORY GENE EXPRESSION BY PRODUCING A GENE-SPECIFIC CHANGE IN HAT ACTIVITY. FOR EXAMPLE, HDAC2 EXPRESSION AND ACTIVITY ARE REDUCED IN LUNG MACROPHAGES, BIOPSY SPECIMENS, AND BLOOD CELLS FROM PATIENTS WITH SEVERE ASTHMA AND SMOKING ASTHMATICS, AS WELL AS IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). THIS MAY ACCOUNT, AT LEAST IN PART, FOR THE ENHANCED INFLAMMATION AND REDUCED STEROID RESPONSIVENESS SEEN IN THESE PATIENTS. OTHER PROTEINS, PARTICULARLY TRANSCRIPTION FACTORS, ARE ALSO ACETYLATED AND ARE TARGETS FOR DEACETYLATION BY HDACS AND SIRTUINS, A RELATED FAMILY OF 7 PREDOMINANTLY PROTEIN DEACETYLASES. THUS THE ACETYLATION/DEACETYLATION STATUS OF NF-KAPPAB AND THE GLUCOCORTICOID RECEPTOR CAN ALSO AFFECT THE OVERALL EXPRESSION PATTERN OF INFLAMMATORY GENES AND REGULATE THE INFLAMMATORY RESPONSE. UNDERSTANDING AND TARGETING SPECIFIC ENZYMES INVOLVED IN THIS PROCESS MIGHT LEAD TO NEW THERAPEUTIC AGENTS, PARTICULARLY IN SITUATIONS IN WHICH CURRENT ANTI-INFLAMMATORY THERAPIES ARE SUBOPTIMAL. 2011 15 2067 36 EPIGENETIC CONTROL OF MACROPHAGE SHAPE TRANSITION TOWARDS AN ATYPICAL ELONGATED PHENOTYPE BY HISTONE DEACETYLASE ACTIVITY. INFLAMMATORY CHRONIC PATHOLOGIES ARE COMPLEX PROCESSES CHARACTERIZED BY AN IMBALANCE BETWEEN THE RESOLUTION OF THE INFLAMMATORY PHASE AND THE ESTABLISHMENT OF TISSUE REPAIR. THE MAIN PLAYERS IN THESE INFLAMMATORY PATHOLOGIES ARE BONE MARROW DERIVED MONOCYTES (BMDMS). HOWEVER, HOW MONOCYTE DIFFERENTIATION IS MODULATED TO GIVE RISE TO SPECIFIC MACROPHAGE SUBPOPULATIONS (M1 OR M2) THAT MAY EITHER MAINTAIN THE CHRONIC INFLAMMATORY PROCESS OR LEAD TO WOUND HEALING IS STILL UNCLEAR. CONSIDERING THAT INHIBITORS OF HISTONE DEACETYLASE (HDAC) HAVE AN ANTI-INFLAMMATORY ACTIVITY, WE ASKED WHETHER THIS ENZYME WOULD PLAY A ROLE ON MONOCYTE DIFFERENTIATION INTO M1 OR M2 PHENOTYPE AND IN THE CELL SHAPE TRANSITION THAT FOLLOWS. WE THEN INDUCED MURINE BONE MARROW PROGENITORS INTO MONOCYTE/MACROPHAGE DIFFERENTIATION PATHWAY USING MEDIA CONTAINING GM-CSF AND THE HDAC BLOCKER, TRICHOSTATIN A (TSA). WE FOUND THAT THE PHARMACOLOGICAL INHIBITION OF HDAC ACTIVITY LED TO A SHAPE TRANSITION FROM THE TYPICAL MACROPHAGE PANCAKE-LIKE SHAPE INTO AN ELONGATED MORPHOLOGY, WHICH WAS CORRELATED TO A MIXED M1/M2 PROFILE OF CYTOKINE AND CHEMOKINE SECRETION. OUR RESULTS PRESENT, FOR THE FIRST TIME, THAT HDAC ACTIVITY ACTS AS A REGULATOR OF MACROPHAGE DIFFERENTIATION IN THE ABSENCE OF LYMPHOCYTE STIMULI. WE PROPOSE THAT HDAC ACTIVITY DOWN REGULATES MACROPHAGE PLASTICITY FAVORING THE PRO-INFLAMMATORY PHENOTYPE. 2015 16 5279 32 PROMOTER-SPECIFIC RELEVANCE OF HISTONE MODIFICATIONS INDUCED BY DEXAMETHASONE DURING THE REGULATION OF PRO-INFLAMMATORY MEDIATORS. GLUCOCORTICOSTEROIDS (GCS) ARE WIDELY USED TO TREAT DIFFERENT KINDS OF CHRONIC INFLAMMATORY AND IMMUNE DISEASES THROUGH TRANSCRIPTIONAL REGULATION OF INFLAMMATORY GENES. MODULATION OF GENE EXPRESSION BY GCS IS KNOWN TO OCCUR THROUGH DIVERSE MECHANISMS OF VARYING RELEVANCE TO SPECIFIC CLASSES OF GENES. EPIGENETIC MODIFICATIONS ARE INDEED A PIVOTAL REGULATORY FEATURE OF GLUCOCORTICOID RECEPTOR AND OTHER TRANSCRIPTION FACTORS. IN THIS STUDY, HISTONE POST-TRANSLATIONAL MODIFICATIONS WERE INVESTIGATED FOR THEIR INVOLVEMENT IN THE REGULATION OF SELECTED PRO-INFLAMMATORY GENES - EXPRESSED IN HUMAN MONOCYTE-DERIVED MACROPHAGES - IN RESPONSE TO TREATMENT WITH SYNTHETIC GC DEXAMETHASONE (DEX). WE SHOW THAT HISTONE TAIL ACETYLATION STATUS IS MODIFIED FOLLOWING DEX ADMINISTRATION, THROUGH DISTINCT AND ALTERNATIVE MECHANISMS AT THE PROMOTERS OF INTERLEUKIN-8 AND INTERLEUKIN-23. IN ADDITION TO HISTONE H3 ACETYLATION, OUR RESULTS DEMONSTRATE THAT H3 LYSINE 4 TRIMETHYLATION IS AFFECTED FOLLOWING DRUG TREATMENT. 2014 17 4604 39 NEGATIVE EVIDENCE FOR A FUNCTIONAL ROLE OF NEURONAL DNMT3A IN PERSISTENT PAIN. TRADITIONALLY, NEUROSCIENCE HAS HAD TO RELY ON MIXED TISSUE ANALYSIS TO EXAMINE TRANSCRIPTIONAL AND EPIGENETIC CHANGES IN THE CONTEXT OF NERVOUS SYSTEM FUNCTION OR PATHOLOGY. HOWEVER, PARTICULARLY WHEN STUDYING CHRONIC PAIN CONDITIONS, THIS APPROACH CAN BE FLAWED, SINCE IT NEGLECTS TO TAKE INTO ACCOUNT THE SHIFTING CONTRIBUTION OF DIFFERENT CELL TYPES ACROSS EXPERIMENTAL CONDITIONS. HERE, WE DEMONSTRATE THIS USING THE EXAMPLE OF DNA METHYLTRANSFERASES (DNMTS) - A GROUP OF EPIGENETIC MODIFIERS CONSISTING OF DNMT1, DNMT3A, AND DNMT3B IN MAMMALIAN CELLS. WE USED SENSORY NEURON-SPECIFIC KNOCKOUT MICE FOR DNMT3A/3B AS WELL AS PHARMACOLOGICAL BLOCKADE OF DNMT1 TO STUDY THEIR ROLE IN NOCICEPTION. IN CONTRAST TO PREVIOUS ANALYSES ON WHOLE TISSUE, WE FIND THAT DNMT3A AND 3B PROTEIN IS NOT EXPRESSED IN ADULT DRG NEURONS, THAT NONE OF THE DNA METHYLTRANSFERASES ARE REGULATED WITH INJURY AND THAT INTERFERING WITH THEIR FUNCTION HAS NO EFFECT ON NOCICEPTION. OUR RESULTS THEREFORE CURRENTLY DO NOT SUPPORT A ROLE FOR NEURONAL DNA METHYLTRANSFERASES IN PAIN PROCESSING IN ADULT ANIMALS. 2018 18 3587 37 IMPACT OF TLR4 ON BEHAVIORAL AND COGNITIVE DYSFUNCTIONS ASSOCIATED WITH ALCOHOL-INDUCED NEUROINFLAMMATORY DAMAGE. TOLL-LIKE RECEPTORS (TLRS) PLAY AN IMPORTANT ROLE IN THE INNATE IMMUNE RESPONSE, AND EMERGING EVIDENCE INDICATES THEIR ROLE IN BRAIN INJURY AND NEURODEGENERATION. OUR RECENT RESULTS HAVE DEMONSTRATED THAT ETHANOL IS CAPABLE OF ACTIVATING GLIAL TLR4 RECEPTORS AND THAT THE ELIMINATION OF THESE RECEPTORS IN MICE PROTECTS AGAINST ETHANOL-INDUCED GLIAL ACTIVATION, INDUCTION OF INFLAMMATORY MEDIATORS AND APOPTOSIS. THIS STUDY WAS DESIGNED TO ASSESS WHETHER ETHANOL-INDUCED INFLAMMATORY DAMAGE CAUSES BEHAVIORAL AND COGNITIVE CONSEQUENCES, AND IF BEHAVIORAL ALTERATIONS ARE DEPENDENT OF TLR4 FUNCTIONS. HERE WE SHOW IN MICE DRINKING ALCOHOL FOR 5MONTHS, FOLLOWED BY A 15-DAY WITHDRAWAL PERIOD, THAT ACTIVATION OF THE ASTROGLIAL AND MICROGLIAL CELLS IN FRONTAL CORTEX AND STRIATUM IS MAINTAINED AND THAT THESE EVENTS ARE ASSOCIATED WITH COGNITIVE AND ANXIETY-RELATED BEHAVIORAL IMPAIRMENTS IN WILD-TYPE (WT) MICE, AS DEMONSTRATED BY TESTING THE ANIMALS WITH OBJECT MEMORY RECOGNITION, CONDITIONED TASTE AVERSION AND DARK AND LIGHT BOX ANXIETY TASKS. MICE LACKING TLR4 RECEPTORS ARE PROTECTED AGAINST ETHANOL-INDUCED INFLAMMATORY DAMAGE, AND BEHAVIORAL ASSOCIATED EFFECTS. WE FURTHER ASSESS THE POSSIBILITY OF THE EPIGENETIC MODIFICATIONS PARTICIPATING IN SHORT- OR LONG-TERM BEHAVIORAL EFFECTS ASSOCIATED WITH NEUROINFLAMMATORY DAMAGE. WE SHOW THAT CHRONIC ALCOHOL TREATMENT DECREASES H4 HISTONE ACETYLATION AND HISTONE ACETYLTRANSFERASES ACTIVITY IN FRONTAL CORTEX, STRIATUM AND HIPPOCAMPUS OF WT MICE. ALTERATIONS IN CHROMATIN STRUCTURE WERE NOT OBSERVED IN TLR4(-/-) MICE. THESE RESULTS PROVIDE THE FIRST EVIDENCE OF THE ROLE THAT TLR4 FUNCTIONS PLAY IN THE BEHAVIORAL CONSEQUENCES OF ALCOHOL-INDUCED INFLAMMATORY DAMAGE AND SUGGEST THAT THE EPIGENETIC MODIFICATIONS MEDIATED BY TLR4 COULD CONTRIBUTE TO SHORT- OR LONG-TERM ALCOHOL-INDUCED BEHAVIORAL OR COGNITIVE DYSFUNCTIONS. 2011 19 5624 33 SELECTIVE BOOSTING OF TRANSCRIPTIONAL AND BEHAVIORAL RESPONSES TO DRUGS OF ABUSE BY HISTONE DEACETYLASE INHIBITION. HISTONE ACETYLATION AND OTHER MODIFICATIONS OF THE CHROMATIN ARE IMPORTANT REGULATORS OF GENE EXPRESSION AND, CONSEQUENTLY, MAY CONTRIBUTE TO DRUG-INDUCED BEHAVIORS AND NEUROPLASTICITY. EARLIER STUDIES HAVE SHOWN THAT A REDUCTION IN HISTONE DEACETYLASE (HDAC) ACTIVITY RESULTS IN THE ENHANCEMENT OF SOME PSYCHOSTIMULANT-INDUCED BEHAVIORS. IN THIS STUDY, WE EXTEND THOSE SEMINAL FINDINGS BY SHOWING THAT THE ADMINISTRATION OF THE HDAC INHIBITOR SODIUM BUTYRATE ENHANCES MORPHINE-INDUCED LOCOMOTOR SENSITIZATION AND CONDITIONED PLACE PREFERENCE. IN CONTRAST, THIS COMPOUND HAS NO EFFECTS ON THE DEVELOPMENT OF MORPHINE TOLERANCE AND DEPENDENCE. SIMILAR EFFECTS WERE OBSERVED FOR COCAINE AND ETHANOL-INDUCED BEHAVIORS. THESE BEHAVIORAL CHANGES WERE ACCOMPANIED BY A SELECTIVE BOOSTING OF A COMPONENT OF THE TRANSCRIPTIONAL PROGRAM ACTIVATED BY CHRONIC MORPHINE ADMINISTRATION THAT INCLUDED CIRCADIAN CLOCK GENES AND OTHER GENES RELEVANT TO ADDICTIVE BEHAVIOR. OUR RESULTS SUPPORT A SPECIFIC FUNCTION FOR HISTONE ACETYLATION AND THE EPIGENETIC MODULATION OF TRANSCRIPTION AT A REDUCED NUMBER OF BIOLOGICALLY RELEVANT LOCI ON NON-HOMEOSTATIC, LONG-LASTING, DRUG-INDUCED BEHAVIORAL PLASTICITY. 2009 20 1994 40 EPIGENETIC AND GENE EXPRESSION ALTERATIONS OF FOXP3 IN THE T CELLS OF EAE MOUSE MODEL OF MULTIPLE SCLEROSIS. MULTIPLE SCLEROSIS (MS) IS A CHRONIC AUTOIMMUNE DISEASE WITH DEMYELINATION AND NEURODEGENERATION OF THE CENTRAL NERVOUS SYSTEM. IT HAS BEEN SHOWN THAT THE REGULATORY T (TREG) CELLS ARE RESPONSIBLE FOR MAINTAINING TOLERANCE TO SELF-ANTIGENS AND CAN SUPPRESS THE AUTOIMMUNE PROCESS IN SEVERAL ANIMAL MODELS SUCH AS EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS (EAE), A MOUSE MODEL OF MS. RECENT BASIC STUDIES HAVE DEMONSTRATED THAT FORKHEAD BOX P (FOXP3) AND BTB DOMAIN AND CNC HOMOLOG 2 (BACH2) ARE THE MASTER TRANSCRIPTION FACTORS OF THESE CELLS PLAYING A PIVOTAL ROLE IN THE POLARIZATION OF NAIVE T CELLS INTO TREG CELLS. IN THE CURRENT STUDY, THE EXPRESSION OF FOXP3 AND BACH2 GENES AND FOXP3 PROMOTER METHYLATION WERE EVALUATED IN T CELLS OF THE EAE-INDUCED MICE. THE RESULTS OF THIS STUDY SHOWED A PROMINENT AND SIGNIFICANT HYPERMETHYLATION OF THE FOXP3 GENE PROMOTER IN THE EAE-INDUCED MICE COMPARED TO THE SHAM AND CONTROL GROUPS. THE EXPRESSION OF FOXP3 AND BACH2 GENES WAS SIGNIFICANTLY DECREASED IN THE EAE GROUP IN COMPARISON WITH THE SHAM AND CONTROL GROUPS. THIS STUDY SUGGESTS THAT THE EPIGENETIC MODIFICATION OF FOXP3 GENE IS INVOLVED IN THE PATHOGENESIS OF EAE AND THIS COULD BE IMPORTANT IN THERAPY IN AN APPROPRIATE AND LOGICAL STATEMENT. 2017