1 6170 136 THE HDAC INHIBITOR SAHA IMPROVES DEPRESSIVE-LIKE BEHAVIOR OF CRTC1-DEFICIENT MICE: POSSIBLE RELEVANCE FOR TREATMENT-RESISTANT DEPRESSION. MAJOR DEPRESSION IS A HIGHLY COMPLEX DISABLING PSYCHIATRIC DISORDER AFFECTING MILLIONS OF PEOPLE WORLDWIDE. DESPITE THE AVAILABILITY OF SEVERAL CLASSES OF ANTIDEPRESSANTS, A SUBSTANTIAL PERCENTAGE OF PATIENTS ARE UNRESPONSIVE TO THESE MEDICATIONS. A BETTER UNDERSTANDING OF THE NEUROBIOLOGY OF DEPRESSION AND THE MECHANISMS UNDERLYING ANTIDEPRESSANT RESPONSE IS THUS CRITICALLY NEEDED. WE PREVIOUSLY REPORTED THAT MICE LACKING CREB-REGULATED TRANSCRIPTION COACTIVATOR 1 (CRTC1) EXHIBIT A DEPRESSIVE-LIKE PHENOTYPE AND A BLUNTED ANTIDEPRESSANT RESPONSE TO THE SELECTIVE SEROTONIN REUPTAKE INHIBITOR FLUOXETINE. IN THIS STUDY, WE SIMILARLY SHOW THAT CRTC1(-/-) MICE ARE RESISTANT TO THE ANTIDEPRESSANT EFFECT OF CHRONIC DESIPRAMINE IN A BEHAVIORAL DESPAIR PARADIGM. SUPPORTING THE BLUNTED RESPONSE TO THIS TRICYCLIC ANTIDEPRESSANT, WE FOUND THAT DESIPRAMINE DOES NOT SIGNIFICANTLY INCREASE THE EXPRESSION OF BDNF AND NR4A1-3 IN THE HIPPOCAMPUS AND PREFRONTAL CORTEX OF CRTC1(-/-) MICE. EPIGENETIC REGULATION OF NEUROPLASTICITY GENE EXPRESSION HAS BEEN ASSOCIATED WITH DEPRESSION AND ANTIDEPRESSANT RESPONSE, AND HISTONE DEACETYLASE (HDAC) INHIBITORS HAVE BEEN SHOWN TO HAVE ANTIDEPRESSANT-LIKE PROPERTIES. HERE, WE SHOW THAT UNLIKE CONVENTIONAL ANTIDEPRESSANTS, CHRONIC SYSTEMIC ADMINISTRATION OF THE HDAC INHIBITOR SAHA PARTIALLY RESCUES THE DEPRESSIVE-LIKE BEHAVIOR OF CRTC1(-/-) MICE. THIS BEHAVIORAL EFFECT IS ACCOMPANIED BY AN INCREASED EXPRESSION OF BDNF, BUT NOT NR4A1-3, IN THE PREFRONTAL CORTEX OF THESE MICE, SUGGESTING THAT THIS EPIGENETIC INTERVENTION RESTORES THE EXPRESSION OF A SUBSET OF GENES BY ACTING DOWNSTREAM OF CRTC1. THESE FINDINGS SUGGEST THAT CRTC1 ALTERATIONS MAY BE ASSOCIATED WITH TREATMENT-RESISTANT DEPRESSION, AND SUPPORT THE INTERESTING POSSIBILITY THAT TARGETING HDACS MAY BE A USEFUL THERAPEUTIC STRATEGY IN ANTIDEPRESSANT DEVELOPMENT. 2016 2 4544 36 MUSCLE HYPERTROPHY IN HYPOXIA WITH INFLAMMATION IS CONTROLLED BY BROMODOMAIN AND EXTRA-TERMINAL DOMAIN PROTEINS. SOME OF THE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) PATIENTS ENGAGED IN EXERCISE-BASED MUSCLE REHABILITATION PROGRAMS ARE UNRESPONSIVE. TO UNRAVEL THE RESPECTIVE ROLE OF CHRONIC HYPOXIA AND PULMONARY INFLAMMATION ON SOLEUS MUSCLE HYPERTROPHIC CAPACITIES, WE CHALLENGED MALE WISTAR RATS TO REPEATED LIPOPOLYSACCHARIDE INSTILLATIONS, ASSOCIATED OR NOT WITH A CHRONIC HYPOXIA EXPOSURE. MUSCLE HYPERTROPHY WAS INITIATED BY BILATERAL ABLATION OF SOLEUS AGONISTS 1 WEEK BEFORE SACRIFICE. TO UNDERSTAND THE ROLE PLAYED BY THE HISTONE ACETYLATION, WE ALSO TREATED OUR ANIMALS WITH AN INHIBITOR OF BROMODOMAINS AND EXTRA TERMINAL PROTEINS (I-BET) DURING THE WEEK AFTER SURGERY. PULMONARY INFLAMMATION TOTALLY INHIBITED THIS HYPERTROPHY RESPONSE UNDER BOTH NORMOXIC AND HYPOXIC CONDITIONS (26% LOWER THAN CONTROL SURGERY, P < 0.05), CONSISTENT WITH THE S6K1 AND MYOGENIN MEASUREMENTS. CHANGES IN HISTONE ACETYLATION AND CLASS IIA HISTONE DEACETYLASES EXPRESSION, FOLLOWING PULMONARY INFLAMMATION, SUGGESTED A PUTATIVE ROLE FOR HISTONE ACETYLATION SIGNALING IN THE ALTERED HYPERTROPHY RESPONSE. THE I-BET DRUG RESTORED THE HYPERTROPHY RESPONSE SUGGESTING THAT THE NON-RESPONSE OF MUSCLE TO A HYPERTROPHIC STIMULUS COULD BE MODULATED BY EPIGENETIC MECHANISMS, INCLUDING HISTONE-ACETYLATION DEPENDANT PATHWAYS. DRUGS TARGETING SUCH EPIGENETIC MECHANISMS MAY OPEN THERAPEUTIC PERSPECTIVES FOR COPD PATIENTS WITH SYSTEMIC INFLAMMATION WHO ARE UNRESPONSIVE TO REHABILITATION. 2017 3 2454 33 EPIGENETIC TARGETING OF HISTONE DEACETYLASES IN DIAGNOSTICS AND TREATMENT OF DEPRESSION. DEPRESSION IS A HIGHLY PREVALENT, DISABLING, AND OFTEN CHRONIC ILLNESS THAT PLACES SUBSTANTIAL BURDENS ON PATIENTS, FAMILIES, HEALTHCARE SYSTEMS, AND THE ECONOMY. A SUBSTANTIAL MINORITY OF PATIENTS ARE UNRESPONSIVE TO CURRENT THERAPIES, SO THERE IS AN URGENT NEED TO DEVELOP MORE BROADLY EFFECTIVE, ACCESSIBLE, AND TOLERABLE THERAPIES. PHARMACOLOGICAL REGULATION OF HISTONE ACETYLATION LEVEL HAS BEEN INVESTIGATED AS ONE POTENTIAL CLINICAL STRATEGY. HISTONE ACETYLATION STATUS IS CONSIDERED A POTENTIAL DIAGNOSTIC BIOMARKER FOR DEPRESSION, WHILE INHIBITORS OF HISTONE DEACETYLASES (HDACS) HAVE GARNERED INTEREST AS NOVEL THERAPEUTICS. THIS REVIEW DESCRIBES RECENT ADVANCES IN OUR KNOWLEDGE OF HISTONE ACETYLATION STATUS IN DEPRESSION AND THE THERAPEUTIC POTENTIAL OF HDAC INHIBITORS. 2021 4 6093 34 THE EFFECTS OF HIGH GLUCOSE EXPOSURE ON GLOBAL GENE EXPRESSION AND DNA METHYLATION IN HUMAN PANCREATIC ISLETS. BACKGROUND: TYPE 2 DIABETES (T2D) IS A COMPLEX DISEASE CHARACTERISED BY CHRONIC HYPERGLYCAEMIA. THE EFFECTS OF ELEVATED GLUCOSE ON GLOBAL GENE EXPRESSION IN COMBINATION WITH DNA METHYLATION PATTERNS HAVE NOT YET BEEN STUDIED IN HUMAN PANCREATIC ISLETS. OUR AIM WAS TO STUDY THE IMPACT OF 48 H EXPOSURE TO HIGH (19 MM) VERSUS CONTROL (5.6 MM) GLUCOSE LEVELS ON GLUCOSE-STIMULATED INSULIN SECRETION, GENE EXPRESSION AND DNA METHYLATION IN HUMAN PANCREATIC ISLETS. RESULTS: WHILE ISLETS KEPT AT 5.6 MM GLUCOSE SECRETED SIGNIFICANTLY MORE INSULIN IN RESPONSE TO SHORT TERM GLUCOSE-STIMULATION (P = 0.0067), ISLETS EXPOSED TO HIGH GLUCOSE FOR 48 H WERE DESENSITISED AND UNRESPONSIVE TO SHORT TERM GLUCOSE-STIMULATION WITH RESPECT TO INSULIN SECRETION (P = 0.32). MOREOVER, THE EXPOSURE OF HUMAN ISLETS TO 19 MM GLUCOSE RESULTED IN SIGNIFICANTLY ALTERED EXPRESSION OF EIGHT GENES (FDR<5%), WITH FIVE OF THESE (GLRA1, RASD1, VAC14, SLCO5A1, CHRNA5) ALSO EXHIBITING CHANGES IN DNA METHYLATION (P < 0.05). A GENE SET ENRICHMENT ANALYSIS OF THE EXPRESSION DATA SHOWED SIGNIFICANT ENRICHMENT OF E.G. TGF-BETA SIGNALLING PATHWAY, NOTCH SIGNALLING PATHWAY AND SNARE INTERACTIONS IN VESICULAR TRANSPORT; THESE PATHWAYS ARE OF RELEVANCE FOR ISLET FUNCTION AND POSSIBLY ALSO DIABETES. WE ALSO FOUND INCREASED DNA METHYLATION OF CPG SITES ANNOTATED TO PDX1 IN HUMAN ISLETS EXPOSED TO 19 MM GLUCOSE FOR 48 H. FINALLY, WE COULD FUNCTIONALLY VALIDATE A ROLE FOR GLRA1 IN INSULIN SECRETION. CONCLUSION: OUR DATA DEMONSTRATE THAT HIGH GLUCOSE LEVELS AFFECT HUMAN PANCREATIC ISLET GENE EXPRESSION AND SEVERAL OF THESE GENES ALSO EXHIBIT EPIGENETIC CHANGES. THIS MIGHT CONTRIBUTE TO THE IMPAIRED INSULIN SECRETION SEEN IN T2D. 2018 5 2455 29 EPIGENETIC TARGETS FOR NOVEL THERAPIES OF LUNG DISEASES. IN SPITE OF SUBSTANTIAL ADVANCES IN DEFINING THE IMMUNOBIOLOGY AND FUNCTION OF STRUCTURAL CELLS IN LUNG DISEASES THERE IS STILL INSUFFICIENT KNOWLEDGE TO DEVELOP FUNDAMENTALLY NEW CLASSES OF DRUGS TO TREAT MANY LUNG DISEASES. FOR EXAMPLE, THERE IS A COMPELLING NEED FOR NEW THERAPEUTIC APPROACHES TO ADDRESS SEVERE PERSISTENT ASTHMA THAT IS INSENSITIVE TO INHALED CORTICOSTEROIDS. ALTHOUGH THE PREVALENCE OF STEROID-RESISTANT ASTHMA IS 5-10%, SEVERE ASTHMATICS REQUIRE A DISPROPORTIONATE LEVEL OF HEALTH CARE SPENDING AND CONSTITUTE A MAJORITY OF FATAL ASTHMA EPISODES. NONE OF THE ESTABLISHED DRUG THERAPIES INCLUDING LONG-ACTING BETA AGONISTS OR INHALED CORTICOSTEROIDS REVERSE ESTABLISHED AIRWAY REMODELING. OBSTRUCTIVE AIRWAYS REMODELING IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), RESTRICTIVE REMODELING IN IDIOPATHIC PULMONARY FIBROSIS (IPF) AND OCCLUSIVE VASCULAR REMODELING IN PULMONARY HYPERTENSION ARE SIMILARLY UNRESPONSIVE TO CURRENT DRUG THERAPY. THEREFORE, DRUGS ARE NEEDED TO ACHIEVE LONG-ACTING SUPPRESSION AND REVERSAL OF PATHOLOGICAL AIRWAY AND VASCULAR REMODELING. NOVEL DRUG CLASSES ARE EMERGING FROM ADVANCES IN EPIGENETICS. NOVEL MECHANISMS ARE EMERGING BY WHICH CELLS ADAPT TO ENVIRONMENTAL CUES, WHICH INCLUDE CHANGES IN DNA METHYLATION, HISTONE MODIFICATIONS AND REGULATION OF TRANSCRIPTION AND TRANSLATION BY NONCODING RNAS. IN THIS REVIEW WE WILL SUMMARIZE CURRENT EPIGENETIC APPROACHES BEING APPLIED TO PRECLINICAL DRUG DEVELOPMENT ADDRESSING IMPORTANT THERAPEUTIC CHALLENGES IN LUNG DISEASES. THESE CHALLENGES ARE BEING ADDRESSED BY ADVANCES IN LUNG DELIVERY OF OLIGONUCLEOTIDES AND SMALL MOLECULES THAT MODIFY THE HISTONE CODE, DNA METHYLATION PATTERNS AND MIRNA FUNCTION. 2015 6 3721 42 INHIBITION OF CLASS II HISTONE DEACETYLASES IN THE SPINAL CORD ATTENUATES INFLAMMATORY HYPERALGESIA. BACKGROUND: SEVERAL CLASSES OF HISTONE DEACETYLASES (HDACS) ARE EXPRESSED IN THE SPINAL CORD THAT IS A CRITICAL STRUCTURE OF THE NOCICEPTIVE PATHWAY. HDAC-REGULATED HISTONE ACETYLATION IS AN IMPORTANT COMPONENT OF CHROMATIN REMODELING LEADING TO EPIGENETIC REGULATION OF GENE TRANSCRIPTION. TO UNDERSTAND THE ROLE OF HISTONE ACETYLATION IN EPIGENETIC REGULATION OF PATHOLOGICAL PAIN, WE HAVE STUDIED THE IMPACT OF DIFFERENT CLASSES OF HDACS IN THE SPINAL CORD ON INFLAMMATORY HYPERALGESIA INDUCED BY COMPLETE FREUND'S ADJUVANT (CFA). RESULTS: WE INTRATHECALLY APPLIED INHIBITORS SPECIFIC TO DIFFERENT CLASSES OF HDACS AND EVALUATED THEIR IMPACT ON INFLAMMATORY HYPERALGESIA. PRE-INJECTED INHIBITORS TARGETING CLASS I AS WELL AS II (SAHA, TSA, LAQ824) OR IIA (VPA, 4-PB) HDACS SIGNIFICANTLY DELAYED THE THERMAL HYPERALGESIA INDUCED BY UNILATERAL CFA INJECTION IN THE HINDPAW. EXISTING HYPERALGESIA INDUCED BY CFA WAS ALSO ATTENUATED BY THE HDAC INHIBITORS (HDACIS). IN CONTRAST, THESE INHIBITORS DID NOT INTERFERE WITH THE THERMAL RESPONSE EITHER IN NAIVE ANIMALS, OR ON THE CONTRALATERAL SIDE OF INFLAMED ANIMALS. INTERESTINGLY, MS-275 THAT SPECIFICALLY INHIBITS CLASS I HDACS FAILED TO ALTER THE HYPERALGESIA ALTHOUGH IT INCREASED HISTONE 3 ACETYLATION IN THE SPINAL CORD AS SAHA DID. USING IMMUNOBLOT ANALYSIS, WE FURTHER FOUND THAT THE LEVELS OF CLASS IIA HDAC MEMBERS (HDAC4, 5, 7, 9) IN THE SPINAL DORSAL HORN WERE UPREGULATED FOLLOWING CFA INJECTION WHILE THOSE OF CLASS I HDAC MEMBERS (HDAC1, 2, 3) REMAINED STABLE OR WERE SLIGHTLY REDUCED. CONCLUSIONS: OUR DATA SUGGEST THAT ACTIVITY OF CLASS II HDACS IN THE SPINAL CORD IS CRITICAL TO THE INDUCTION AND MAINTENANCE OF INFLAMMATORY HYPERALGESIA INDUCED BY CFA, WHILE ACTIVITY OF CLASS I HDACS MAY BE UNNECESSARY. COMPARISON OF THE EFFECTS OF HDACIS SPECIFIC TO CLASS II AND IIA AS WELL AS THE EXPRESSION PATTERN OF DIFFERENT HDACS IN THE SPINAL CORD IN RESPONSE TO CFA SUGGESTS THAT THE MEMBERS OF CLASS IIA HDACS MAY BE POTENTIAL TARGETS FOR ATTENUATING PERSISTENT INFLAMMATORY PAIN. 2010 7 5713 41 SIRT2 INHIBITION REVERSES ANHEDONIA IN THE VGLUT1+/- DEPRESSION MODEL. SOME HISTONE DEACETYLASE (HDACS) ENZYMES HAVE BEEN PROPOSED AS EPIGENETIC TARGETS INVOLVED IN THE PATHOPHYSIOLOGY OF DEPRESSION AND ANTIDEPRESSANT-LIKE ACTION. AMONG THEM, WE HAVE RECENTLY IDENTIFIED SIRT2, A CLASS III NAD(+)-DEPENDENT HDAC, AS BEING OPPOSITELY REGULATED BY STRESS AND ANTIDEPRESSANTS. MOREOVER, SIRT2 INHIBITION HAS SHOWN ANTIANHEDONIC-LIKE ACTION IN THE CHRONIC MILD STRESS MODEL OF DEPRESSION. HERE WE HAVE EXTENDED THE STUDY USING AN ALTERNATIVE MODEL OF DEPRESSION BASED IN A GENETIC MANIPULATION OF GLUTAMATE FUNCTION. SPECIFICALLY, MICE HETEROZYGOUS FOR THE VESICULAR GLUTAMATE TRANSPORTER 1 (VGLUT1+/-) WERE USED. FIRSTLY, MRNA EXPRESSION OF THE DIFFERENT MEMBERS OF THE HDAC SUPERFAMILY IN THE PREFRONTAL CORTEX (PFC) OF VGLUT1+/- MICE AND WT LITTERMATES WERE STUDIED BY RT-PCR. SECONDLY, THE EFFECT OF REPEATED TREATMENT WITH THE SELECTIVE SIRT2 INHIBITOR 33I AND THE ANTIDEPRESSANT IMIPRAMINE ON ANHEDONIC BEHAVIOUR OF VGLUT1+/- MICE WAS STUDIED BY WEEKLY MONITORING OF SUCROSE INTAKE. FURTHER, THE INTERACTION OF 33I TOWARDS SPECIFIC MONOAMINERGIC TARGETS SUCH AS SEROTONIN OR NORADRENALINE TRANSPORTERS AS WELL AS THE MONOAMINOOXIDASE ENZYME WAS STUDIED. THE MRNA OCCURANCE OF THE DIFFERENT MEMBERS OF HDAC SUPERFAMILY WAS NOT ALTERED IN THE PFC OF VGLUT1+/- MICE. WHILE REPEATED IMIPRAMINE SHOWED AN ANTI-ANHEDONIC ACTION IN BOTH VGLUT1+/- AND WT, THE SELECTIVE SIRT2 INHIBITOR 33I FULLY REVERSED ANHEDONIA OF VGLUT1+/-. FURTHER, 33I SHOWED NO INTERACTION WITH THE ABOVE MENTIONED MONOAMINERGIC MOLECULAR TARGETS. THESE RESULTS CONFIRM THAT SIRT2 INHIBITION IS ABLE TO REVERSE ANHEDONIA IN DIFFERENT ANIMAL MODELS AND HIGHLIGHT THE NEED TO FURTHER INVESTIGATE THE ROLE OF SIRT2 INHIBITORS AS NEW ANTIDEPRESSANT AGENTS. 2017 8 3719 30 INHIBITION OF BET PROTEINS REDUCES RIGHT VENTRICLE HYPERTROPHY AND PULMONARY HYPERTENSION RESULTING FROM COMBINED HYPOXIA AND PULMONARY INFLAMMATION. PULMONARY HYPERTENSION IS A CO-MORBIDITY, WHICH STRONGLY PARTICIPATES IN MORBI-MORTALITY IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). RECENT FINDINGS SHOWED THAT BROMODOMAIN-CONTAINING PROTEINS, IN CHARGE OF READING HISTONE ACETYLATION, COULD BE INVOLVED IN PULMONARY ARTERIAL HYPERTENSION. OUR AIM WAS TO STUDY THE EFFECT OF I-BET151, AN INHIBITOR OF BROMODOMAIN AND EXTRA-TERMINAL DOMAIN (BET), ON THE RIGHT VENTRICLE HYPERTROPHY AND PULMONARY HYPERTENSION, INDUCED BY A COMBINATION OF CHRONIC HYPOXIA AND PULMONARY INFLAMMATION, AS THE TWO MAIN STIMULI ENCOUNTERED IN COPD. ADULT WISTAR MALE RATS, EXPOSED TO CHRONIC HYPOXIA PLUS PULMONARY INFLAMMATION (CHPI), SHOWED A SIGNIFICANT RIGHT VENTRICLE HYPERTROPHY (+57%, P < 0.001), AN INCREASE IN SYSTOLIC PRESSURE (+46%, P < 0.001) AND IN CONTRACTION SPEED (+36%, P < 0.001), WHEN COMPARED TO CONTROL ANIMALS. I-BET151 TREATED ANIMALS (CHPI-IB) SHOWED RESTORED HEMODYNAMIC PARAMETERS TO LEVELS SIMILAR TO CONTROL ANIMALS, DESPITE CHRONIC HYPOXIA PLUS EXPOSURE TO PULMONARY INFLAMMATION. THEY DISPLAYED LOWER RIGHT VENTRICLE HYPERTROPHY AND HEMATOCRIT COMPARED TO THE CHPI GROUP (RESPECTIVELY -16%, P < 0.001; AND -9%, P < 0.05). OUR DESCRIPTIVE STUDY SHOWS A VALUABLE EFFECT OF THE INHIBITION OF BROMODOMAIN AND EXTRA-TERMINAL DOMAIN PROTEINS ON HEMODYNAMIC PARAMETERS, DESPITE THE PRESENCE OF CHRONIC HYPOXIA AND PULMONARY INFLAMMATION. THIS SUGGESTS THAT SUCH INHIBITION COULD BE OF POTENTIAL INTEREST FOR COPD PATIENTS WITH PULMONARY HYPERTENSION. FURTHER STUDIES ARE NEEDED TO UNRAVEL THE UNDERLYING MECHANISMS INVOLVED AND THE NET BENEFITS OF INHIBITING ADAPTATIONS TO CHRONIC HYPOXIA. 2018 9 850 30 CHILDREN WITH CHRONIC IMMUNE THROMBOCYTOPENIA EXHIBIT HIGH EXPRESSION OF HUMAN ENDOGENOUS RETROVIRUSES TRIM28 AND SETDB1. CHRONIC IMMUNE THROMBOCYTOPENIA (CITP) IS AN AUTOIMMUNE DISEASE WHOSE UNDERLYING BIOLOGIC MECHANISMS REMAIN ELUSIVE. HUMAN ENDOGENOUS RETROVIRUSES (HERVS) DERIVE FROM ANCESTRAL INFECTIONS AND CONSTITUTE ABOUT 8% OF OUR GENOME. A WEALTH OF CLINICAL AND EXPERIMENTAL STUDIES HIGHLIGHTS THEIR PIVOTAL PATHOGENETIC ROLE IN AUTOIMMUNE DISEASES. EPIGENETIC MECHANISMS, SUCH AS THOSE MODULATED BY TRIM28 AND SETDB1, ARE INVOLVED IN HERV ACTIVATION AND REGULATION OF IMMUNE RESPONSE. WE ASSESSED, THROUGH A POLYMERASE CHAIN REACTION REAL-TIME TAQMAN AMPLIFICATION ASSAY, THE TRANSCRIPTION LEVELS OF POL GENES OF HERV-H, HERV-K, AND HERV-W; ENV GENES OF SYNCYTIN (SYN)1, SYN2, AND HERV-W; AS WELL AS TRIM28 AND SETDB1 IN WHOLE BLOOD FROM 34 CHILDREN WITH CITP AND AGE-MATCHED HEALTHY CONTROLS (HC). THE TRANSCRIPTIONAL LEVELS OF ALL HERV SEQUENCES, WITH THE EXCEPTION OF HERV-W-ENV, WERE SIGNIFICANTLY ENHANCED IN CHILDREN WITH CITP AS COMPARED TO HC. PATIENTS ON ELTROMBOPAG TREATMENT EXHIBITED LOWER EXPRESSION OF SYN1, SYN2, AND HERV-W-ENV AS COMPARED TO UNTREATED PATIENTS. THE MRNA CONCENTRATIONS OF TRIM28 AND SETDB1 WERE SIGNIFICANTLY HIGHER AND WERE POSITIVELY CORRELATED WITH THOSE OF HERVS IN CITP PATIENTS. THE OVER-EXPRESSIONS OF HERVS AND TRIM28/SETDB1 AND THEIR POSITIVE CORRELATIONS IN PATIENTS WITH CITP ARE SUGGESTIVE CLUES OF THEIR CONTRIBUTION TO THE PATHOGENESIS OF THE DISEASE AND SUPPORT INNOVATIVE INTERVENTIONS TO INHIBIT HERV AND TRIM28/SETDB1 EXPRESSIONS IN PATIENTS UNRESPONSIVE TO STANDARD THERAPIES. 2023 10 113 55 A SELECTIVE HDAC 1/2 INHIBITOR MODULATES CHROMATIN AND GENE EXPRESSION IN BRAIN AND ALTERS MOUSE BEHAVIOR IN TWO MOOD-RELATED TESTS. PSYCHIATRIC DISEASES, INCLUDING SCHIZOPHRENIA, BIPOLAR DISORDER AND MAJOR DEPRESSION, ARE PROJECTED TO LEAD GLOBAL DISEASE BURDEN WITHIN THE NEXT DECADE. PHARMACOTHERAPY, THE PRIMARY--ALBEIT OFTEN INEFFECTIVE--TREATMENT METHOD, HAS REMAINED LARGELY UNCHANGED OVER THE PAST 50 YEARS, HIGHLIGHTING THE NEED FOR NOVEL TARGET DISCOVERY AND IMPROVED MECHANISM-BASED TREATMENTS. HERE, WE EXAMINED IN WILD TYPE MICE THE IMPACT OF CHRONIC, SYSTEMIC TREATMENT WITH COMPOUND 60 (CPD-60), A SLOW-BINDING, BENZAMIDE-BASED INHIBITOR OF THE CLASS I HISTONE DEACETYLASE (HDAC) FAMILY MEMBERS, HDAC1 AND HDAC2, IN MOOD-RELATED BEHAVIORAL ASSAYS RESPONSIVE TO CLINICALLY EFFECTIVE DRUGS. CPD-60 TREATMENT FOR ONE WEEK WAS ASSOCIATED WITH ATTENUATED LOCOMOTOR ACTIVITY FOLLOWING ACUTE AMPHETAMINE CHALLENGE. FURTHER, TREATED MICE DEMONSTRATED DECREASED IMMOBILITY IN THE FORCED SWIM TEST. THESE CHANGES ARE CONSISTENT WITH ESTABLISHED EFFECTS OF CLINICAL MOOD STABILIZERS AND ANTIDEPRESSANTS, RESPECTIVELY. WHOLE-GENOME EXPRESSION PROFILING OF SPECIFIC BRAIN REGIONS (PREFRONTAL CORTEX, NUCLEUS ACCUMBENS, HIPPOCAMPUS) FROM MICE TREATED WITH CPD-60 IDENTIFIED GENE EXPRESSION CHANGES, INCLUDING A SMALL SUBSET OF TRANSCRIPTS THAT SIGNIFICANTLY OVERLAPPED THOSE PREVIOUSLY REPORTED IN LITHIUM-TREATED MICE. HDAC INHIBITION IN BRAIN WAS CONFIRMED BY INCREASED HISTONE ACETYLATION BOTH GLOBALLY AND, USING CHROMATIN IMMUNOPRECIPITATION, AT THE PROMOTER REGIONS OF UPREGULATED TRANSCRIPTS, A FINDING CONSISTENT WITH IN VIVO ENGAGEMENT OF HDAC TARGETS. IN CONTRAST, TREATMENT WITH SUBEROYLANILIDE HYDROXAMIC ACID (SAHA), A NON-SELECTIVE FAST-BINDING, HYDROXAMIC ACID HDAC 1/2/3/6 INHIBITOR, WAS SUFFICIENT TO INCREASE HISTONE ACETYLATION IN BRAIN, BUT DID NOT ALTER MOOD-RELATED BEHAVIORS AND HAD DISSIMILAR TRANSCRIPTIONAL REGULATORY EFFECTS COMPARED TO CPD-60. THESE RESULTS PROVIDE EVIDENCE THAT SELECTIVE INHIBITION OF HDAC1 AND HDAC2 IN BRAIN MAY PROVIDE AN EPIGENETIC-BASED TARGET FOR DEVELOPING IMPROVED TREATMENTS FOR MOOD DISORDERS AND OTHER BRAIN DISORDERS WITH ALTERED CHROMATIN-MEDIATED NEUROPLASTICITY. 2013 11 1251 32 CURRENT PERSPECTIVES ON ROLE OF CHROMATIN MODIFICATIONS AND DEACETYLASES IN LUNG INFLAMMATION IN COPD. CHROMATIN MODIFICATIONS AND EPIGENETIC REGULATION ARE CRITICAL FOR SUSTAINED AND ABNORMAL INFLAMMATORY RESPONSE SEEN IN LUNGS OF PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) BECAUSE THE ACTIVITIES OF ENZYMES THAT REGULATE THESE EPIGENETIC MODIFICATIONS ARE ALTERED IN RESPONSE TO CIGARETTE SMOKE. CIGARETTE SMOKE INDUCES CHROMATIN MODIFICATIONS AND EPIGENETIC CHANGES BY CAUSING POST-TRANSLATIONAL MODIFICATIONS OF HISTONE ACETYLTRANSFERASES, AND HISTONE/NON-HISTONE DEACETYLASES (HDACS), SUCH AS HDAC2 AND SIRTUIN 1 (SIRT1), WHICH LEADS TO CHROMATIN REMODELING. IN THIS REVIEW, WE DISCUSSED THE CURRENT KNOWLEDGE ON CIGARETTE SMOKE/OXIDANTS-INDUCED POST-TRANSLATIONAL MODIFICATIONS OF DEACETYLASES (HDAC2 AND SIRT1), DISRUPTION OF HDAC2/SIRT1-RELA/P65 COREPRESSOR COMPLEX ASSOCIATED WITH ACETYLATION OF RELA/P65, AND CHROMATIN MODIFICATIONS (HISTONE H3 PHOSPHO-ACETYLATION) LEADING TO SUSTAINED PRO-INFLAMMATORY GENE TRANSCRIPTION. KNOWLEDGE ON MOLECULAR MECHANISMS OF EPIGENETIC CHANGES IN ABNORMAL LUNG INFLAMMATION WILL HELP IN UNDERSTANDING THE PATHOPHYSIOLOGY OF COPD WHICH MAY LEAD TO THE DEVELOPMENT OF NOVEL EPIGENETIC THERAPIES IN THE NEAR FUTURE. 2009 12 6138 35 THE ETIOLOGICAL CHANGES OF ACETYLATION IN PERIPHERAL NERVE INJURY-INDUCED NEUROPATHIC HYPERSENSITIVITY. NEUROPATHIC PAIN IS A COMMON CHRONIC PAIN CONDITION WITH MECHANISMS FAR CLEARLY BEEN ELUCIDATED. MOUNTING PRECLINICAL AND CLINICAL STUDIES HAVE SHOWN NEUROPATHIC PAIN IS HIGHLY ASSOCIATED WITH HISTONE ACETYLATION MODIFICATION, WHICH FOLLOWS EXPRESSION REGULATION OF VARIOUS PAIN-RELATED MOLECULES SUCH AS MGLUR1/5, GLUTAMATE ASPARTATE TRANSPORTER, GLUTAMATE TRANSPORTER-1, GAD65, NA(V)1.8, KV4.3, MU-OPIOID RECEPTOR, BRAIN-DERIVED NEUROTROPHIC FACTOR, AND CERTAIN CHEMOKINES. AS TWO TYPES OF PIVOTAL ENZYMES INVOLVED IN HISTONE ACETYLATION, HISTONE DEACETYLASES INDUCE HISTONE DEACETYLATION TO SILENCE GENE EXPRESSION; IN CONTRAST, HISTONE ACETYL TRANSFERASES FACILITATE HISTONE ACETYLATION TO POTENTIATE GENE TRANSCRIPTION. ACCORDINGLY, UPREGULATION OR BLOCKADE OF ACETYLATION MAY BE A PROMISING INTERVENTION DIRECTION FOR NEUROPATHIC PAIN TREATMENT. IN FACT, NUMEROUS ANIMAL STUDIES HAVE SUGGESTED VARIOUS HISTONE DEACETYLASE INHIBITORS, SIRT (CLASS III HISTONE DEACETYLASES) ACTIVATORS, AND HISTONE ACETYL TRANSFERASES INHIBITORS ARE EFFECTIVE IN NEUROPATHIC PAIN TREATMENT VIA TARGETING SPECIFIC EPIGENETIC SITES. IN THIS REVIEW, WE SUMMARIZE THE CHARACTERISTICS OF THE MOLECULES AND MECHANISMS OF NEUROPATHY-RELATED ACETYLATION, AS WELL AS THE ACETYLATION UPREGULATION AND BLOCKADE FOR NEUROPATHIC PAIN THERAPY. FINALLY, WE WILL DISCUSS THE CURRENT DRUG ADVANCES FOCUSING ON NEUROPATHY-RELATED ACETYLATION ALONG WITH THE UNDERLYING TREATMENT MECHANISMS. 2018 13 3197 37 HDAC INHIBITORS: TARGETS FOR TUMOR THERAPY, IMMUNE MODULATION AND LUNG DISEASES. HISTONE DEACETYLASES (HDACS) ARE ENZYMES THAT PLAY A KEY ROLE IN THE EPIGENETIC REGULATION OF GENE EXPRESSION BY REMODELING CHROMATIN. INHIBITION OF HDACS IS A PROSPECTIVE THERAPEUTIC APPROACH FOR REVERSING EPIGENETIC ALTERATION IN SEVERAL DISEASES. IN PRECLINICAL RESEARCH, NUMEROUS TYPES OF HDAC INHIBITORS WERE DISCOVERED TO EXHIBIT POWERFUL AND SELECTIVE ANTICANCER PROPERTIES. HOWEVER, SUCH RESEARCH HAS REVEALED THAT THE EFFECTS OF HDAC INHIBITORS MAY BE FAR BROADER AND MORE INTRICATE THAN PREVIOUSLY THOUGHT. THIS REVIEW WILL PROVIDE INSIGHT INTO THE HDAC INHIBITORS AND THEIR MECHANISM OF ACTION WITH SPECIAL EMPHASIS ON THE SIGNIFICANCE OF HDAC INHIBITORS IN THE TREATMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND LUNG CANCER. NANOCARRIER-MEDIATED HDAC INHIBITOR DELIVERY AND NEW APPROACHES FOR TARGETING HDACS ARE ALSO DISCUSSED. 2022 14 2116 35 EPIGENETIC HISTONE DEACETYLATION INHIBITION PREVENTS THE DEVELOPMENT AND PERSISTENCE OF TEMPORAL LOBE EPILEPSY. EPILEPSY IS A CHRONIC BRAIN DISEASE CHARACTERIZED BY REPEATED UNPROVOKED SEIZURES. CURRENTLY, NO DRUG THERAPY EXISTS FOR CURING EPILEPSY OR DISEASE MODIFICATION IN PEOPLE AT RISK. DESPITE SEVERAL EMERGING MECHANISMS, THERE HAVE BEEN FEW STUDIES OF EPIGENETIC SIGNALING IN EPILEPTOGENESIS, THE PROCESS WHEREBY A NORMAL BRAIN BECOMES PROGRESSIVELY EPILEPTIC BECAUSE OF PRECIPITATING FACTORS. HERE, WE REPORT A NOVEL ROLE OF HISTONE DEACETYLATION AS A CRITICAL EPIGENETIC MECHANISM IN EPILEPTOGENESIS. EXPERIMENTS WERE CONDUCTED USING THE HISTONE DEACETYLASE (HDAC) INHIBITOR SODIUM BUTYRATE IN THE HIPPOCAMPUS KINDLING MODEL OF TEMPORAL LOBE EPILEPSY (TLE), A CLASSIC MODEL HEAVILY USED TO APPROVE DRUGS FOR TREATMENT OF EPILEPSY. DAILY TREATMENT WITH BUTYRATE SIGNIFICANTLY INHIBITED HDAC ACTIVITY AND RETARDED THE DEVELOPMENT OF LIMBIC EPILEPTOGENESIS WITHOUT AFFECTING AFTER-DISCHARGE SIGNAL. HDAC INHIBITION MARKEDLY IMPAIRED THE PERSISTENCE OF SEIZURE EXPRESSION MANY WEEKS AFTER EPILEPSY DEVELOPMENT. MOREOVER, SUBCHRONIC HDAC INHIBITION FOR 2 WEEKS RESULTED IN A STRIKING RETARDATION OF EPILEPTOGENESIS. HDAC INHIBITION, UNEXPECTEDLY, ALSO SHOWED ERASURE OF THE EPILEPTOGENIC STATE IN EPILEPTIC ANIMALS. FINALLY, BUTYRATE-TREATED ANIMALS EXHIBITED A POWERFUL REDUCTION IN MOSSY FIBER SPROUTING, A MORPHOLOGIC INDEX OF EPILEPTOGENESIS. TOGETHER THESE RESULTS UNDERSCORE THAT HDAC INHIBITION PREVENTS THE DEVELOPMENT OF TLE, INDICATING HDAC'S CRITICAL SIGNALING ROLE IN EPILEPTOGENESIS. THESE FINDINGS, THEREFORE, ENVISAGE A UNIQUE NOVEL THERAPY FOR PREVENTING OR CURING EPILEPSY BY TARGETING THE EPIGENETIC HDAC PATHWAY. 2018 15 5867 34 SUPPRESSIVE EFFECT OF THE HISTONE DEACETYLASE INHIBITOR SUBEROYLANILIDE HYDROXAMIC ACID (SAHA) ON HEPATITIS C VIRUS REPLICATION. THE HISTONE DEACETYLASE (HDAC) INHIBITOR SUBEROYLANILIDE HYDROXAMIC ACID (SAHA) HAS A CLINICAL PROMISE FOR TREATMENT OF CANCER INCLUDING HEPATOCELLULAR CARCINOMA (HCC). TO INVESTIGATE EFFECT OF SAHA ON HEPATITIS C VIRUS (HCV) REPLICATION, WE TREATED THE HCV REPLICON CELL OR6 WITH SAHA. HCV REPLICATION WAS SIGNIFICANTLY INHIBITED BY SAHA AT CONCENTRATIONS BELOW 1 MUM WITH NO CELLULAR TOXICITY. ANOTHER HDAC INHIBITOR, TRICOSTATIN A, ALSO SHOWED REDUCTION OF HCV REPLICATION. THE MICROARRAY ANALYSIS AND QUANTITATIVE RT-PCR DEMONSTRATED UP-REGULATION OF OSTEOPONTIN (OPN) AND DOWN-REGULATION OF APOLIPOPROTEIN-A1 (APO-A1) AFTER SAHA TREATMENT. DIRECT GENE INDUCTION OF OPN AND KNOCKDOWN OF APO-A1 ALSO SHOWED REDUCTION OF HCV REPLICATION. THE LIVER SPECIFIC MICRORNA-122, WHICH IS INVOLVED IN HCV REPLICATION, WAS NOT AFFECTED BY SAHA TREATMENT. THESE RESULTS SUGGEST THAT SAHA HAS SUPPRESSIVE EFFECT ON HCV REPLICATION THROUGH ALTERATIONS OF GENE EXPRESSION SUCH AS OPN AND APO-A1 IN HOST CELLS. EPIGENETIC TREATMENT WITH HDAC INHIBITORS MAY BE A NOVEL THERAPEUTIC APPROACH FOR DISEASES ASSOCIATED WITH HCV INFECTION SUCH AS CHRONIC HEPATITIS, LIVER CIRRHOSIS, AND HCC. 2013 16 3193 43 HDAC INHIBITION REGULATES OXIDATIVE STRESS IN CD4(+)THELPER CELLS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND NON-SMALL CELL LUNG CANCER PATIENTS VIA MITOCHONDRIAL TRANSCRIPTION FACTOR A (MTTFA) MODULATING NF-KAPPAB/HIF1ALPHA AXIS. HISTONE DEACETYLASES (HDACS) PLAY A CRUCIAL ROLE IN THE EPIGENETIC REGULATION OF GENE EXPRESSION BY REMODELLING CHROMATIN. ISOENZYMES OF THE HDAC FAMILY EXHIBIT ABERRANT REGULATION IN A WIDE VARIETY OF CANCERS AS WELL AS SEVERAL INFLAMMATORY LUNG DISORDERS LIKE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). INHIBITION OF HDACS IS A POTENTIAL THERAPEUTIC STRATEGY THAT COULD BE USED TO REVERSE EPIGENETIC MODIFICATION. TRICHOSTATIN A (TSA), A POWERFUL HISTONE DEACETYLASE (HDAC) INHIBITOR, HAS ANTI-CANCER EFFECTS IN NUMEROUS CANCER TYPES. HOWEVER, IT IS NOT YET APPARENT HOW HDAC INHIBITORS AFFECT HUMAN NON-SMALL CELL LUNG CANCER CELLS (NSCLC) AND COPD. THIS STUDY AIMS TO INVESTIGATE TSA'S ROLE IN RESTORING MITOCHONDRIAL DYSFUNCTION AND ITS EFFECT ON HYPOXIA AND INFLAMMATION IN CD4(+)T CELLS OBTAINED FROM PATIENTS WITH COPD AND LUNG CANCER. AS A RESULT OF TREATMENT WITH TSA, THERE IS A REDUCTION IN THE EXPRESSION OF INFLAMMATORY CYTOKINES AND A DECREASED ENRICHMENT OF TRANSCRIPTIONAL FACTORS ASSOCIATED WITH INFLAMMATION AT VEGFA GENE LOCI. WE HAVE SEEN A SUBSTANTIAL DECREASE IN THE EXPRESSION OF NF-KAPPAB AND HIF1ALPHA, WHICH ARE THE CRITICAL MEDIATORS OF INFLAMMATION AND HYPOXIA, RESPECTIVELY. FOLLOWING TSA TREATMENT, MTTFA EXPRESSION WAS INCREASED, FACILITATING PATIENTS WITH COPD AND NSCLC IN THE RECOVERY OF THEIR DYSFUNCTIONAL MITOCHONDRIA. FURTHERMORE, WE HAVE DISCOVERED THAT TSA TREATMENT IN PATIENTS WITH COPD AND NSCLC MAY LEAD TO IMMUNOPROTECTIVE NESS BY INDUCING TH1NESS. OUR FINDING GIVES A NEW INSIGHT INTO THE EXISTING BODY OF KNOWLEDGE REGARDING TSA-BASED THERAPEUTIC METHODS AND HIGHLIGHTS THE NECESSITY OF EPIGENETIC THERAPY FOR THESE DEVASTATING LUNG DISORDERS. 2023 17 3321 34 HISTONE ACETYLATION OF THE HTR3A GENE IN THE PREFRONTAL CORTEX OF WISTAR RATS REGULATES ETHANOL-SEEKING BEHAVIOR. PREVIOUS REPORTS SHOWED THAT DECREASED HISTONE DEACETYLASE ACTIVITY SIGNIFICANTLY POTENTIATED THE REWARDING EFFECTS OF PSYCHOSTIMULANTS, AND THAT ENCODING OF THE 5-HT3 RECEPTOR BY THE HTR3A GENE WAS RELATED TO ETHANOL-SEEKING BEHAVIOR. HOWEVER, THE EFFECTS OF A HISTONE DEACETYLASE INHIBITOR ON ETHANOL-SEEKING BEHAVIOR AND EPIGENETIC REGULATION OF HTR3A MRNA EXPRESSION AFTER CHRONIC ETHANOL EXPOSURE ARE NOT FULLY UNDERSTOOD. USING QUANTITATIVE REVERSE TRANSCRIPTION-POLYMERASE CHAIN REACTION AND CHROMATIN IMMUNOPRECIPITATION ANALYSIS, WE INVESTIGATED THE EFFECTS OF CHRONIC ETHANOL EXPOSURE AND ITS INTERACTION WITH A HISTONE DEACETYLASE INHIBITOR ON HISTONE-ACETYLATION-MEDIATED CHANGES IN HTR3A MRNA EXPRESSION IN THE HTR3A PROMOTER REGION. THE CONDITIONED PLACE PREFERENCE PROCEDURE WAS USED TO EVALUATE ETHANOL-SEEKING BEHAVIOR. CHRONIC EXPOSURE TO ETHANOL EFFECTIVELY ELICITED PLACE CONDITIONING. IN THE PREFRONTAL CORTEX, THE ACETYLATION OF H3K9 AND HTR3A MRNA EXPRESSION IN THE HTR3A PROMOTER REGION WERE SIGNIFICANTLY HIGHER IN THE ETHANOL GROUP THAN IN THE SALINE GROUP. THE HISTONE DEACETYLASE INHIBITOR SODIUM BUTYRATE POTENTIATED THE EFFECTS OF ETHANOL ON HTR3A MRNA EXPRESSION AND ENHANCED ETHANOL-INDUCED CONDITIONED PLACE PREFERENCES. THESE RESULTS SUGGEST THAT ETHANOL UPREGULATES HTR3A LEVELS THROUGH MECHANISMS INVOLVING H3K9 ACETYLATION, AND THAT HISTONE ACETYLATION MAY BE A THERAPEUTIC TARGET FOR TREATING ETHANOL ABUSE. 2012 18 2068 30 EPIGENETIC CONTROL OF MICROSOMAL PROSTAGLANDIN E SYNTHASE-1 BY HDAC-MEDIATED RECRUITMENT OF P300. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS ARE THE MOST WIDELY USED MEDICINE TO TREAT PAIN AND INFLAMMATION, AND TO INHIBIT PLATELET FUNCTION. UNDERSTANDING THE EXPRESSION REGULATION OF ENZYMES OF THE PROSTANOID PATHWAY IS OF GREAT MEDICAL RELEVANCE. HISTONE ACETYLATION CRUCIALLY CONTROLS GENE EXPRESSION. WE SET OUT TO IDENTIFY THE IMPACT OF HISTONE DEACETYLASES (HDACS) ON THE GENERATION OF PROSTANOIDS AND EXAMINE THE CONSEQUENCES ON VASCULAR FUNCTION. HDAC INHIBITION (HDACI) WITH THE PAN-HDAC INHIBITOR, VORINOSTAT, ATTENUATED PROSTAGLANDIN (PG)E(2) GENERATION IN THE MURINE VASCULATURE AND IN HUMAN VASCULAR SMOOTH MUSCLE CELLS. IN LINE WITH THIS, THE EXPRESSION OF THE KEY ENZYME FOR PGE(2) SYNTHESIS, MICROSOMAL PGE SYNTHASE-1 (PTGES1), WAS REDUCED BY HDACI. ACCORDINGLY, THE RELAXATION TO ARACHIDONIC ACID WAS DECREASED AFTER EX VIVO INCUBATION OF MURINE VESSELS WITH HDACI. TO IDENTIFY THE UNDERLYING MECHANISM, CHROMATIN IMMUNOPRECIPITATION (CHIP) AND CHIP-SEQUENCING ANALYSIS WERE PERFORMED. THESE RESULTS SUGGEST THAT HDACS ARE INVOLVED IN THE RECRUITMENT OF THE TRANSCRIPTIONAL ACTIVATOR P300 TO THE PTGES1 GENE AND THAT HDACI PREVENTED THIS EFFECT. IN LINE WITH THE ACETYLTRANSFERASE ACTIVITY OF P300, H3K27 ACETYLATION WAS REDUCED AFTER HDACI AND RESULTED IN THE FORMATION OF HETEROCHROMATIN IN THE PTGES1 GENE. IN CONCLUSION, HDAC ACTIVITY MAINTAINS PTGES1 EXPRESSION BY RECRUITING P300 TO ITS GENE. 2017 19 434 43 ANTIDEPRESSANT-LIKE EFFECT OF SODIUM BUTYRATE IS ASSOCIATED WITH AN INCREASE IN TET1 AND IN 5-HYDROXYMETHYLATION LEVELS IN THE BDNF GENE. BACKGROUND: EPIGENETIC DRUGS LIKE SODIUM BUTYRATE (NAB) SHOW ANTIDEPRESSANT-LIKE EFFECTS IN PRECLINICAL STUDIES, BUT THE EXACT MOLECULAR MECHANISMS OF THE ANTIDEPRESSANT EFFECTS REMAIN UNKNOWN. WHILE RESEARCH USING NAB HAS MAINLY FOCUSED ON ITS ROLE AS A HISTONE DEACETYLASE INHIBITOR (HDACI), THERE IS ALSO EVIDENCE THAT NAB AFFECTS DNA METHYLATION. METHODS: THE PURPOSE OF THIS STUDY WAS TO EXAMINE NAB'S PUTATIVE ANTIDEPRESSANT-LIKE EFFICACY IN RELATION TO DNA METHYLATION CHANGES IN THE PREFRONTAL CORTEX OF AN ESTABLISHED GENETIC RAT MODEL OF DEPRESSION (THE FLINDERS SENSITIVE LINE [FSL]) AND ITS CONTROLS (THE FLINDERS RESISTANT LINE). RESULTS: THE FSL RATS HAD LOWER LEVELS OF TEN-ELEVEN TRANSLOCATION METHYLCYTOSINE DIOXYGENASE 1 (TET1), WHICH CATALYZES THE CONVERSION OF DNA METHYLATION TO HYDROXYMETHYLATION. AS INDICATED BY THE BEHAVIORAL DESPAIR TEST, CHRONIC ADMINISTRATION OF NAB HAD ANTIDEPRESSANT-LIKE EFFECTS IN THE FSL AND WAS ACCOMPANIED BY INCREASED LEVELS OF TET1. THE TET1 UPREGULATION WAS ALSO ASSOCIATED WITH AN INCREASE OF HYDROXYMETHYLATION AND A DECREASE OF METHYLATION IN BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), A GENE ASSOCIATED WITH NEUROGENESIS AND SYNAPTIC PLASTICITY. THESE EPIGENETIC CHANGES WERE ASSOCIATED WITH A CORRESPONDING BDNF OVEREXPRESSION. CONCLUSIONS: OUR DATA SUPPORT THE ANTIDEPRESSANT EFFICACY OF HDACIS AND SUGGEST THAT THEIR EPIGENETIC EFFECTS MAY ALSO INCLUDE DNA METHYLATION CHANGES THAT ARE MEDIATED BY DEMETHYLATION-FACILITATING ENZYMES LIKE TET1. 2014 20 5474 33 RESTORATION OF HISTONE ACETYLATION AMELIORATES DISEASE AND METABOLIC ABNORMALITIES IN A FUS MOUSE MODEL. DYSREGULATION OF EPIGENETIC MECHANISMS IS EMERGING AS A CENTRAL EVENT IN NEURODEGENERATIVE DISORDERS, INCLUDING AMYOTROPHIC LATERAL SCLEROSIS (ALS). IN MANY MODELS OF NEURODEGENERATION, GLOBAL HISTONE ACETYLATION IS DECREASED IN THE AFFECTED NEURONAL TISSUES. HISTONE ACETYLATION IS CONTROLLED BY THE ANTAGONISTIC ACTIONS OF TWO PROTEIN FAMILIES -THE HISTONE ACETYLTRANSFERASES (HATS) AND THE HISTONE DEACETYLASES (HDACS). DRUGS INHIBITING HDAC ACTIVITY ARE ALREADY USED IN THE CLINIC AS ANTI-CANCER AGENTS. THE AIM OF THIS STUDY WAS TO EXPLORE THE THERAPEUTIC POTENTIAL OF HDAC INHIBITION IN THE CONTEXT OF ALS. WE DISCOVERED THAT TRANSGENIC MICE OVEREXPRESSING WILD-TYPE FUS ("TG FUS+/+"), WHICH RECAPITULATE MANY ASPECTS OF HUMAN ALS, SHOWED REDUCED GLOBAL HISTONE ACETYLATION AND ALTERATIONS IN METABOLIC GENE EXPRESSION, RESULTING IN A DYSREGULATED METABOLIC HOMEOSTASIS. CHRONIC TREATMENT OF TG FUS+/+ MICE WITH ACY-738, A POTENT HDAC INHIBITOR THAT CAN CROSS THE BLOOD-BRAIN BARRIER, AMELIORATED THE MOTOR PHENOTYPE AND SUBSTANTIALLY EXTENDED THE LIFE SPAN OF THE TG FUS+/+ MICE. AT THE MOLECULAR LEVEL, ACY-738 RESTORED GLOBAL HISTONE ACETYLATION AND METABOLIC GENE EXPRESSION, THEREBY RE-ESTABLISHING METABOLITE LEVELS IN THE SPINAL CORD. TAKEN TOGETHER, OUR FINDINGS LINK EPIGENETIC ALTERATIONS TO METABOLIC DYSREGULATION IN ALS PATHOLOGY, AND HIGHLIGHT ACY-738 AS A POTENTIAL THERAPEUTIC STRATEGY TO TREAT THIS DEVASTATING DISEASE. 2019