1 4398 138 MODULATION OF DNA METHYLTRANSFERASE PROFILE BY METHYL DONOR STARVATION FOLLOWED BY GAMMA IRRADIATION. DNA METHYLATION IS AN IMPORTANT EPIGENETIC MECHANISM OF TRANSCRIPTIONAL CONTROL, WHICH PLAYS AN ESSENTIAL ROLE IN MAINTAINING CELLULAR FUNCTION. ROLE OF ONE-CARBON TRANSFER AGENTS/METHYL DONORS NAMELY FOLATE, CHOLINE AND METHIONINE IN DNA METHYLATION HAS BEEN THE SUBJECT OF EXTENSIVE INVESTIGATION. THE METHYLATION PATTERN OF DNA IS ESTABLISHED DURING EMBRYOGENESIS BY DNA METHYLTRANSFERASE 3 (DNMT3) AND IS SUBSEQUENTLY MAINTAINED BY MAINTENANCE METHYLATION ACTIVITY OF THE ENZYME DNA METHYLTRANSFERASE 1 (DNMT1). IONIZING RADIATION IS KNOWN TO EXTENSIVELY DAMAGE THE DNA. SUFFICIENT DIETARY AVAILABILITY OF METHYL DONORS IS KNOWN TO CONTRIBUTE TOWARDS ONE-CARBON TRANSFER MEDIATED REPAIR OF DAMAGED DNA WHERE FOLATE IS INVOLVED IN NUCLEOTIDE BASE SYNTHESIS. IN THE PRESENT STUDY, MODIFICATION IN ACTIVITIES OF DNMT1 AND DNMT3 BY METHYL DONOR STARVATION FOLLOWED BY GAMMA-IRRADIATION WAS OBSERVED. ASSAYS WERE BASED ON THE CATALYTIC TRANSFER OF (3)H-METHYL GROUPS FROM S-ADENOSYL-L: -METHIONINE TO A DNA SUBSTRATE. EXPERIMENTS SHOWED A DOSE AND METHYL DONORS STARVATION DEPENDENT ATTENUATION IN DNMT1 ACTIVITY. ATTENUATION OF DNMT1 ACTIVITY WAS MOST SIGNIFICANT FOR DIET DEPRIVED OF ALL THE THREE-METHYL DONORS. NO SIGNIFICANT CHANGE IN NUCLEAR OR CYTOPLASMIC DNMT3 ACTIVITY WAS OBSERVED WHEN EITHER OR ALL THE THREE POSSIBLE SOURCE OF DIETARY METHYL GROUP SUPPLY WERE REMOVED. IONIZING RADIATION AND METHYL DONOR DEFICIENCY WERE OBSERVED TO ACT SYNERGISTICALLY TOWARDS INHIBITING DNMT1 ACTIVITY. PRESENT RESULTS SUGGESTED POSSIBILITY OF INTERACTION AMONG FOLATE, METHIONINE AND CHOLINE DEFICIENCY TO POTENTIATE SYMPTOMS OF IONIZING RADIATION STRESS. THESE ENZYMATIC MODIFICATIONS MIGHT CONTRIBUTE TO ALTERED DNA METHYLATION AFTER CHRONIC FEEDING OF METHYL DONOR FREE DIETS FOLLOWED BY GAMMA IRRADIATION. THESE RESULTS SUGGESTED THAT DIETARY AVAILABILITY OF METHYL DONORS AND GAMMA-RADIATION STRESS MIGHT SIGNIFICANTLY ALTER THE DNMT1 PROFILE. 2007 2 482 28 ARSENITE BINDS TO THE ZINC FINGER MOTIF OF TIP60 HISTONE ACETYLTRANSFERASE AND INDUCES ITS DEGRADATION VIA THE 26S PROTEASOME. ARSENIC IS A UBIQUITOUS ENVIRONMENTAL CONTAMINANT WITH WIDESPREAD PUBLIC HEALTH CONCERN. EPIDEMIOLOGICAL STUDIES HAVE REVEALED THAT CHRONIC HUMAN EXPOSURE TO ARSENIC IN DRINKING WATER IS ASSOCIATED WITH THE PREVALENCE OF SKIN, LUNG, AND BLADDER CANCERS. ABERRANT HISTONE MODIFICATIONS (E.G., METHYLATION, ACETYLATION, AND UBIQUITINATION) WERE PREVIOUSLY FOUND TO BE ACCOMPANIED BY ARSENIC EXPOSURE; THUS, PERTURBATION OF EPIGENETIC PATHWAYS IS THOUGHT TO CONTRIBUTE TO ARSENIC CARCINOGENESIS. ARSENITE IS KNOWN TO INTERACT WITH ZINC FINGER MOTIFS OF PROTEINS, AND ZINC FINGER MOTIF IS PRESENT IN AND INDISPENSABLE FOR THE ENZYMATIC ACTIVITIES OF CRUCIAL HISTONE-MODIFYING ENZYMES ESPECIALLY THE MYST FAMILY OF HISTONE ACETYLTRANSFERASES (E.G., TIP60). HENCE, WE REASONED THAT TRIVALENT ARSENIC MAY TARGET THE ZINC FINGER MOTIF OF THESE ENZYMES, DISTURB THEIR ENZYMATIC ACTIVITIES, AND ALTER HISTONE ACETYLATION. HEREIN, WE FOUND THAT AS(3+) COULD BIND DIRECTLY TO THE ZINC-FINGER MOTIF OF TIP60 IN VITRO AND IN CELLS. IN ADDITION, EXPOSURE TO AS(3+) COULD LEAD TO A DOSE-DEPENDENT DECREASE IN TIP60 PROTEIN LEVEL VIA THE UBIQUITIN-PROTEASOME PATHWAY. THUS, THE RESULTS FROM THE PRESENT STUDY REVEALED, FOR THE FIRST TIME, THAT ARSENITE MAY TARGET CYSTEINE RESIDUES IN THE ZINC-FINGER MOTIF OF THE TIP60 HISTONE ACETYLTRANSFERASE, THEREBY ALTERING THE H4K16AC HISTONE EPIGENETIC MARK. OUR RESULTS ALSO SHED SOME NEW LIGHT ON THE MECHANISMS UNDERLYING THE ARSENIC-INDUCED EPIGENOTOXICITY AND CARCINOGENESIS IN HUMANS. 2017 3 2280 36 EPIGENETIC REGULATION IN DRUG ADDICTION. THE INTERACTION BETWEEN ENVIRONMENTAL SIGNALS AND GENES HAS NOW TAKEN ON A CLEAR MOLECULAR FORM AS DEMONSTRATED BY STABLE CHANGES IN CHROMATIN STRUCTURE. THESE CHANGES OCCUR THROUGH ACTIVATION OR REPRESSION OF SPECIFIC GENE PROGRAMMES BY A COMBINATION OF CHROMATIN REMODELLING, ACTIVATION AND ENZYMATIC MODIFICATION OF DNA AND HISTONES AS WELL AS NUCLEOSOMAL SUBUNIT EXCHANGE. RECENT RESEARCH INVESTIGATING THE MOLECULAR MECHANISMS CONTROLLING DRUG-INDUCED TRANSCRIPTIONAL, BEHAVIOURAL AND SYNAPTIC ACTIVITY HAS SHOWN A DIRECT ROLE FOR CHROMATIN REMODELLING--TERMED AS EPIGENETIC REGULATION--OF NEURONAL GENE PROGRAMMES AND SUBSEQUENT ADDICTIVE BEHAVIOUR ARISING FROM IT. RECENT DATA SUGGEST THAT REPEATED EXPOSURE TO CERTAIN DRUGS PROMOTES CHANGES IN LEVELS OF HISTONE ACETYLATION, PHOSPHORYLATION AND METHYLATION, TOGETHER WITH ALTERATIONS IN DNA METHYLATION LEVELS IN THE NEURONS OF THE BRAIN REWARD CENTRE, LOCALISED IN THE NUCLEUS ACCUMBENS (NAC) REGION OF THE LIMBIC SYSTEM. THE COMBINATION OF ACETYLATING, PHOSPHORYLATING AND METHYLATING H3 AND H4 HISTONE TAILS ALTER CHROMATIN COMPACTION THEREBY PROMOTING ALTERED LEVELS OF CELLULAR GENE EXPRESSION. HISTONE MODIFICATIONS, WHICH WEAKEN HISTONE INTERACTION WITH DNA OR THAT PROMOTE RECRUITMENT OF TRANSCRIPTIONAL ACTIVATING COMPLEXES, CORRELATE WITH PERMISSIVE GENE EXPRESSION. HISTONE DEACETYLATION, (WHICH STRENGTHEN HISTONE: DNA CONTACTS), OR HISTONE METHYLATION, (WHICH RECRUITS REPRESSIVE COMPLEXES TO CHROMATIN), PROMOTE A STATE OF TRANSCRIPTIONAL REPRESSION. USING ANIMAL MODELS, ACUTE COCAINE TREATMENT INCREASES H4 ACETYLATION AT ACUTELY REGULATED GENE PROMOTERS, WHEREAS H3 ACETYLATION APPEARS TO PREDOMINATE AT CHRONICALLY INDUCED PROMOTERS. CHRONIC COCAINE AND ALCOHOL TREATMENT ACTIVATE AND REPRESS MANY GENES SUCH AS FOSB, CDK5, AND BDNF, WHERE THEIR DYSREGULATION, AT THE CHROMATIN LEVEL, CONTRIBUTE TO THE DEVELOPMENT AND MAINTENANCE OF ADDICTION. FOLLOWING DRUG EXPOSURE, IT IS STILL UNKNOWN, HOWVER, HOW LONG THESE CHANGES IN CHROMATIN STRUCTURE PERSIST IN AFFECTING NEURONAL FUNCTION, BUT SOME DO SO FOR LIFE. 2012 4 5010 33 PEROXIDATION OF LINOLEIC, ARACHIDONIC AND OLEIC ACID IN RELATION TO THE INDUCTION OF OXIDATIVE DNA DAMAGE AND CYTOGENETIC EFFECTS. IN THE PRESENT STUDY, THE POSSIBLE ROLE OF THE POLYUNSATURATED FATTY ACIDS LINOLEIC AND ARACHIDONIC ACID IN THE CHEMICAL INDUCTION OF CARCINOGENESIS HAS BEEN INVESTIGATED. ANALYSIS OF 7,8-DIHYDRO-8-OXO-2'-DEOXYGUANOSINE (8-OXODG) LEVELS IN 2'-DEOXYGUANOSINE (DG) AND ISOLATED DNA HAS DEMONSTRATED THAT LINOLEIC AND ARACHIDONIC ACID ARE CAPABLE OF INDUCING THIS SPECIFIC GENOTOXIC DAMAGE. THIS EFFECT APPEARS TO BE RELATED TO THE DEGREE OF FATTY ACID UNSATURATION, SINCE IT WAS NOT INDUCED BY MONOUNSATURATED OLEIC ACID. ENZYMATIC PEROXIDATION OF LINOLEIC AND ARACHIDONIC ACID RESULTED IN A SIGNIFICANT INCREASE IN OXIDATIVE DNA DAMAGE. STUDIES ON THE INTERFERENCE OF RADICAL SCAVENGERS WITH THE INDUCTION OF 8-OXODG IN COMBINATION WITH ELECTRON SPIN RESONANCE SPECTROSCOPY DEMONSTRATED THAT THE SUPEROXIDE ANION WAS GENERATED DURING PEROXIDATION OF THESE FATTY ACIDS AND THAT SINGLET OXYGEN IS MOST LIKELY INVOLVED IN THE FORMATION OF OXIDATIVE DNA DAMAGE. THE LEVEL OF OXIDATIVE DAMAGE IN DG AND SINGLE-STRANDED DNA WAS HIGHER AS COMPARED TO THAT IN NATIVE DNA AFTER EQUIMOLAR TREATMENT. EXPOSURE OF HUMAN LYMPHOCYTES TO LINOLEIC OR ARACHIDONIC ACID DID NOT RESULT IN A SIGNIFICANT INCREASE IN LEVELS OF 8-OXODG. THIS MAY INDICATE THAT THE RATE OF INTRACELLULAR PEROXIDATION IS RELATIVELY LOW AND/OR THAT NUCLEAR DNA IN INTACT CELLS IS EFFECTIVELY PROTECTED AGAINST GENETIC DAMAGE INDUCED BY REACTIVE OXYGEN SPECIES. IT IS THEREFORE CONCLUDED THAT RELATIVELY SHORT PERIODS OF LINOLEIC OR ARACHIDONIC ACID ADMINISTRATION ARE NOT LIKELY TO IMPOSE A DIRECT GENOTOXIC RISK. IT CAN, HOWEVER, NOT BE EXCLUDED THAT CHRONIC EXPOSURE TO POLYUNSATURATED FATTY ACIDS INDUCES OXIDATIVE DNA DAMAGE OR IS RELATED TO CANCER RISK BY EPIGENETIC MECHANISMS, AS IS ALSO INDICATED BY THE OBSERVED CYTOTOXIC EFFECTS OF LINOLEIC AND ARACHIDONIC ACID. 1994 5 3840 31 IRON DEFICIENCY REPROGRAMS PHOSPHORYLATION SIGNALING AND REDUCES O-GLCNAC PATHWAYS IN NEURONAL CELLS. MICRONUTRIENT SENSING IS CRITICAL FOR CELLULAR GROWTH AND DIFFERENTIATION. DEFICIENCIES IN ESSENTIAL NUTRIENTS SUCH AS IRON STRONGLY AFFECT NEURONAL CELL DEVELOPMENT AND MAY LEAD TO DEFECTS IN NEURONAL FUNCTION THAT CANNOT BE REMEDIED BY SUBSEQUENT IRON SUPPLEMENTATION. TO UNDERSTAND THE ADAPTIVE INTRACELLULAR RESPONSES TO IRON DEFICIENCY IN NEURONAL CELLS, WE DEVELOPED AND UTILIZED A STABLE ISOTOPIC LABELING OF AMINO ACIDS IN CELL CULTURE (SILAC)-BASED QUANTITATIVE PHOSPHOPROTEOMICS WORKFLOW. OUR INTEGRATED APPROACH WAS DESIGNED TO COMPREHENSIVELY ELUCIDATE THE CHANGES IN PHOSPHORYLATION SIGNALING UNDER BOTH ACUTE AND CHRONIC IRON-DEFICIENT CELL MODELS. IN ADDITION, WE ANALYZED THE DIFFERENTIAL CELLULAR RESPONSES BETWEEN IRON DEFICIENCY AND HYPOXIA (OXYGEN-DEPRIVED) IN NEURONAL CELLS. OUR ANALYSIS IDENTIFIED NEARLY 16,000 PHOSPHORYLATION SITES IN HT-22 CELLS, A HIPPOCAMPAL-DERIVED NEURONAL CELL LINE, MORE THAN TEN PERCENT OF WHICH SHOWED AT LEAST 2-FOLD CHANGES IN RESPONSE TO EITHER HYPOXIA OR ACUTE/CHRONIC IRON DEFICIENCY. BIOINFORMATIC ANALYSIS REVEALED THAT IRON DEFICIENCY ALTERED KEY METABOLIC AND EPIGENETIC PATHWAYS INCLUDING THE PHOSPHORYLATION OF PROTEINS INVOLVED IN IRON SEQUESTRATION, GLUTAMATE METABOLISM, AND HISTONE METHYLATION. IN PARTICULAR, IRON DEFICIENCY INCREASED GLUTAMINE-FRUCTOSE-6-PHOSPHATE TRANSAMINASE (GFPT1) PHOSPHORYLATION, WHICH IS A KEY ENZYME IN THE GLUCOSAMINE BIOSYNTHESIS PATHWAY AND A TARGET OF 5' AMP-ACTIVATED PROTEIN KINASE (AMPK), LEADING TO REDUCED GFPT1 ENZYMATIC ACTIVITY AND CONSEQUENTLY LOWER GLOBAL O-GLCNAC MODIFICATION IN NEURONAL CELLS. TAKEN TOGETHER, OUR ANALYSIS OF THE PHOSPHOPROTEOME DYNAMICS IN RESPONSE TO IRON AND OXYGEN DEPRIVATION DEMONSTRATED AN ADAPTIVE CELLULAR RESPONSE BY MOUNTING POST-TRANSLATIONAL MODIFICATIONS THAT ARE CRITICAL FOR INTRACELLULAR SIGNALING AND EPIGENETIC PROGRAMMING IN NEURONAL CELLS. 2021 6 313 27 ALCOHOL METABOLISM AND EPIGENETICS CHANGES. METABOLITES, INCLUDING THOSE GENERATED DURING ETHANOL METABOLISM, CAN IMPACT DISEASE STATES BY BINDING TO TRANSCRIPTION FACTORS AND/OR MODIFYING CHROMATIN STRUCTURE, THEREBY ALTERING GENE EXPRESSION PATTERNS. FOR EXAMPLE, THE ACTIVITIES OF ENZYMES INVOLVED IN EPIGENETIC MODIFICATIONS SUCH AS DNA AND HISTONE METHYLATION AND HISTONE ACETYLATION, ARE INFLUENCED BY THE LEVELS OF METABOLITES SUCH AS NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD), ADENOSINE TRIPHOSPHATE (ATP), AND S-ADENOSYLMETHIONINE (SAM). CHRONIC ALCOHOL CONSUMPTION LEADS TO SIGNIFICANT REDUCTIONS IN SAM LEVELS, THEREBY CONTRIBUTING TO DNA HYPOMETHYLATION. SIMILARLY, ETHANOL METABOLISM ALTERS THE RATIO OF NAD+ TO REDUCED NAD (NADH) AND PROMOTES THE FORMATION OF REACTIVE OXYGEN SPECIES AND ACETATE, ALL OF WHICH IMPACT EPIGENETIC REGULATORY MECHANISMS. IN ADDITION TO ALTERED CARBOHYDRATE METABOLISM, INDUCTION OF CELL DEATH, AND CHANGES IN MITOCHONDRIAL PERMEABILITY TRANSITION, THESE METABOLISM-RELATED CHANGES CAN LEAD TO MODULATION OF EPIGENETIC REGULATION OF GENE EXPRESSION. UNDERSTANDING THE NATURE OF THESE EPIGENETIC CHANGES WILL HELP RESEARCHERS DESIGN NOVEL MEDICATIONS TO TREAT OR AT LEAST AMELIORATE ALCOHOL-INDUCED ORGAN DAMAGE. 2013 7 3203 29 HDAC3 ACTIVITY WITHIN THE NUCLEUS ACCUMBENS REGULATES COCAINE-INDUCED PLASTICITY AND BEHAVIOR IN A CELL-TYPE-SPECIFIC MANNER. EPIGENETIC MECHANISMS REGULATE PROCESSES OF NEUROPLASTICITY CRITICAL TO COCAINE-INDUCED BEHAVIORS. THIS INCLUDES THE CLASS I HISTONE DEACETYLASE (HDAC) HDAC3, KNOWN TO ACT AS A NEGATIVE REGULATOR OF COCAINE-ASSOCIATED MEMORY FORMATION WITHIN THE NUCLEUS ACCUMBENS (NAC). DESPITE THIS, IT REMAINS UNKNOWN HOW COCAINE ALTERS HDAC3-DEPENDENT MECHANISMS. HERE, WE PROFILED HDAC3 EXPRESSION AND ACTIVITY IN TOTAL NAC MOUSE TISSUE FOLLOWING COCAINE EXPOSURE. ALTHOUGH CHRONIC COCAINE DID NOT AFFECT EXPRESSION OF HDAC3 WITHIN THE NAC, CHRONIC COCAINE DID AFFECT PROMOTER-SPECIFIC CHANGES IN HDAC3 AND H4K8AC OCCUPANCY. THESE CHANGES IN PROMOTER OCCUPANCY CORRELATED WITH COCAINE-INDUCED CHANGES IN EXPRESSION OF PLASTICITY-RELATED GENES. TO CAUSALLY DETERMINE WHETHER COCAINE-INDUCED PLASTICITY IS MEDIATED BY HDAC3'S DEACETYLASE ACTIVITY, WE OVEREXPRESSED A DEACETYLASE-DEAD HDAC3 POINT MUTANT (HDAC3-Y298H-V5) WITHIN THE NAC OF ADULT MALE MICE. WE FOUND THAT DISRUPTING HDAC3'S ENZYMATIC ACTIVITY ALTERED SELECTIVE CHANGES IN GENE EXPRESSION AND SYNAPTIC PLASTICITY FOLLOWING COCAINE EXPOSURE, DESPITE HAVING NO EFFECTS ON COCAINE-INDUCED BEHAVIORS. IN FURTHER ASSESSING HDAC3'S ROLE WITHIN THE NAC, WE OBSERVED THAT CHRONIC COCAINE INCREASES HDAC3 EXPRESSION IN DRD1 BUT NOT DRD2-CELLS OF THE NAC. MOREOVER, WE DISCOVERED THAT HDAC3 ACTS SELECTIVELY WITHIN D1R CELL-TYPES TO REGULATE COCAINE-ASSOCIATED MEMORY FORMATION AND COCAINE-SEEKING. OVERALL, THESE RESULTS SUGGEST THAT COCAINE INDUCES CELL-TYPE-SPECIFIC CHANGES IN EPIGENETIC MECHANISMS TO PROMOTE PLASTICITY IMPORTANT FOR DRIVING COCAINE-RELATED BEHAVIORS.SIGNIFICANCE STATEMENT DRUGS OF ABUSE ALTER MOLECULAR MECHANISMS THROUGHOUT THE REWARD CIRCUITRY THAT CAN LEAD TO PERSISTENT DRUG-ASSOCIATED BEHAVIORS. EPIGENETIC REGULATORS ARE CRITICAL DRIVERS OF DRUG-INDUCED CHANGES IN GENE EXPRESSION. HERE, WE DEMONSTRATE THAT THE ACTIVITY OF AN EPIGENETIC ENZYME PROMOTES NEUROPLASTICITY WITHIN THE NUCLEUS ACCUMBENS (NAC) CRITICAL TO COCAINE ACTION. IN ADDITION, WE DEMONSTRATE THAT THESE CHANGES IN EPIGENETIC ACTIVITY DRIVE COCAINE-SEEKING BEHAVIORS IN A CELL-TYPE-SPECIFIC MANNER. THESE FINDINGS ARE KEY IN UNDERSTANDING AND TARGETING COCAINE'S IMPACT OF NEURAL CIRCUITRY AND BEHAVIOR. 2021 8 651 29 BISPHENOL A AND PHTHALATES MODULATE PERITONEAL MACROPHAGE FUNCTION IN FEMALE MICE INVOLVING SYMD2-H3K36 DIMETHYLATION. AMPLE EVIDENCE SUGGESTS THAT ENVIRONMENTAL AND OCCUPATIONAL EXPOSURE TO BISPHENOL A (BPA) AND PHTHALATE, TWO CHEMICALS WIDELY USED IN THE PLASTICS INDUSTRY, DISTURBS HOMEOSTASIS OF INNATE IMMUNITY AND CAUSES INFLAMMATORY DISEASES. HOWEVER, THE UNDERLYING MOLECULAR MECHANISMS OF THESE TOXICANTS IN THE REGULATION OF MACROPHAGE INFLAMMATORY FUNCTIONS REMAIN POORLY UNDERSTOOD. IN THIS STUDY, WE ADDRESSED THE EFFECT OF CHRONIC EXPOSURE TO BPA OR PHTHALATE AT LEVELS RELEVANT TO HUMAN EXPOSURE, EITHER IN VITRO OR IN VIVO, ON THE INFLAMMATORY REPROGRAMING OF PERITONEAL MACROPHAGES. OUR STUDIES REVEALED THAT BPA AND PHTHALATES ADVERSELY AFFECTED EXPRESSION LEVELS OF THE PROINFLAMMATORY CYTOKINES AND MEDIATORS IN RESPONSE TO LIPOPOLYSACCHARIDE STIMULATION. EXPOSURE TO THESE TOXICANTS ALSO AFFECTED GENE EXPRESSION OF SCAVENGER RECEPTORS AND PHAGOCYTIC CAPACITY OF PERITONEAL MACROPHAGES. OUR STUDIES REVEALED THAT THE EPIGENETIC INHIBITORS DIFFERENTIALLY MODULATED TARGET GENE EXPRESSION IN THESE CELLS. FURTHER ANALYSIS REVEALED THAT CERTAIN HISTONE MODIFICATION ENZYMES WERE ABERRANTLY EXPRESSED IN RESPONSE TO BPA OR PHTHALATE EXPOSURE, LEADING TO ALTERATION IN THE LEVELS OF H3K36 ACETYLATION AND DIMETHYLATION, TWO CHROMATIN MODIFICATIONS THAT ARE CRITICAL FOR TRANSCRIPTIONAL EFFICACY AND ACCURACY. OUR RESULTS FURTHER REVEALED THAT SILENCING OF H3K36-SPECIFIC METHYLTRANSFERASE SMYD2 EXPRESSION OR INHIBITION OF SMYD2 ENZYMATIC ACTIVITY ATTENUATED H3K36 DIMETHYLATION AND ENHANCED INTERLEUKIN-6 AND TUMOR NECROSIS FACTOR-ALPHA EXPRESSION BUT DAMPENED THE PHAGOCYTIC CAPACITY OF PERITONEAL MACROPHAGES. IN SUMMARY, OUR RESULTS INDICATE THAT PERITONEAL MACROPHAGES ARE VULNERABLE TO BPA OR PHTHALATE AT LEVELS RELEVANT TO HUMAN EXPOSURE. THESE ENVIRONMENTAL TOXICANTS AFFECT PHENOTYPIC PROGRAMMING OF MACROPHAGES VIA EPIGENETIC MECHANISMS INVOLVING SMYD2-MEDIATED H3K36 MODIFICATION. 2018 9 4898 27 OXIDATIVE STRESS INDUCED LUNG CANCER AND COPD: OPPORTUNITIES FOR EPIGENETIC THERAPY. REACTIVE OXYGEN SPECIES (ROS) FORM AS A NATURAL BY-PRODUCT OF THE NORMAL METABOLISM OF OXYGEN AND PLAY IMPORTANT ROLES WITHIN THE CELL. UNDER NORMAL CIRCUMSTANCES THE CELL IS ABLE TO MAINTAIN AN ADEQUATE HOMEOSTASIS BETWEEN THE FORMATION OF ROS AND ITS REMOVAL THROUGH PARTICULAR ENZYMATIC PATHWAYS OR VIA ANTIOXIDANTS. IF HOWEVER, THIS BALANCE IS DISTURBED A SITUATION CALLED OXIDATIVE STRESS OCCURS. CRITICALLY, OXIDATIVE STRESS PLAYS IMPORTANT ROLES IN THE PATHOGENESIS OF MANY DISEASES, INCLUDING CANCER. EPIGENETICS IS A PROCESS WHERE GENE EXPRESSION IS REGULATED BY HERITABLE MECHANISMS THAT DO NOT CAUSE ANY DIRECT CHANGES TO THE DNA SEQUENCE ITSELF, AND DISRUPTION OF EPIGENETIC MECHANISMS HAS IMPORTANT IMPLICATIONS IN DISEASE. EVIDENCE IS EMERGING THAT HISTONE DEACETYLASES (HDACS) PLAY DECISIVE ROLES IN REGULATING IMPORTANT CELLULAR OXIDATIVE STRESS PATHWAYS INCLUDING THOSE INVOLVED WITH SENSING OXIDATIVE STRESS AND THOSE INVOLVED WITH REGULATING THE CELLULAR RESPONSE TO OXIDATIVE STRESS. IN PARTICULAR ABERRANT REGULATION OF THESE PATHWAYS BY HDACS MAY PLAY CRITICAL ROLES IN CANCER PROGRESSION. IN THIS REVIEW WE DISCUSS THE CURRENT EVIDENCE LINKING EPIGENETICS AND OXIDATIVE STRESS AND CANCER, USING CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND NON-SMALL CELL LUNG CANCER TO ILLUSTRATE THE IMPORTANCE OF EPIGENETICS ON THESE PATHWAYS WITHIN THESE DISEASE SETTINGS. 2009 10 4768 29 NUCLEAR EFFECTS OF ETHANOL-INDUCED PROTEASOME INHIBITION IN LIVER CELLS. ALCOHOL INGESTION CAUSES ALTERATION IN SEVERAL CELLULAR MECHANISMS, AND LEADS TO INFLAMMATION, APOPTOSIS, IMMUNOLOGICAL RESPONSE DEFECTS, AND FIBROSIS. THESE PHENOMENA ARE ASSOCIATED WITH SIGNIFICANT CHANGES IN THE EPIGENETIC MECHANISMS, AND SUBSEQUENTLY, TO LIVER CELL MEMORY. THE UBIQUITIN-PROTEASOME PATHWAY IS ONE OF THE VITAL PATHWAYS IN THE CELL THAT BECOMES DYSFUNCTIONAL AS A RESULT OF CHRONIC ETHANOL CONSUMPTION. INHIBITION OF THE PROTEASOME ACTIVITY IN THE NUCLEUS CAUSES CHANGES IN THE TURNOVER OF TRANSCRIPTIONAL FACTORS, HISTONE MODIFYING ENZYMES, AND THEREFORE, AFFECTS EPIGENETIC MECHANISMS. ALCOHOL CONSUMPTION HAS BEEN ASSOCIATED WITH AN INCREASE IN HISTONE ACETYLATION AND A DECREASE IN HISTONE METHYLATION, WHICH LEADS TO GENE EXPRESSION CHANGES. DNA AND HISTONE MODIFICATIONS THAT RESULT FROM ETHANOL-INDUCED PROTEASOME INHIBITION ARE KEY PLAYERS IN REGULATING GENE EXPRESSION, ESPECIALLY GENES INVOLVED IN THE CELL CYCLE, IMMUNOLOGICAL RESPONSES, AND METABOLISM OF ETHANOL. THE PRESENT REVIEW HIGHLIGHTS THE CONSEQUENCES OF ETHANOL-INDUCED PROTEASOME INHIBITION IN THE NUCLEUS OF LIVER CELLS THAT ARE CHRONICALLY EXPOSED TO ETHANOL. 2009 11 4374 36 MISMATCH REPAIR PROTEINS RECRUIT DNA METHYLTRANSFERASE 1 TO SITES OF OXIDATIVE DNA DAMAGE. AT SITES OF CHRONIC INFLAMMATION, EPITHELIAL CELLS ARE EXPOSED TO HIGH LEVELS OF REACTIVE OXYGEN SPECIES AND UNDERGO CANCER-ASSOCIATED DNA METHYLATION CHANGES, SUGGESTING THAT INFLAMMATION MAY INITIATE EPIGENETIC ALTERATIONS. PREVIOUSLY, WE DEMONSTRATED THAT OXIDATIVE DAMAGE CAUSES EPIGENETIC SILENCING PROTEINS TO BECOME PART OF A LARGE COMPLEX THAT IS LOCALIZED TO GC-RICH REGIONS OF THE GENOME, INCLUDING PROMOTER CPG ISLANDS THAT ARE EPIGENETICALLY SILENCED IN CANCER. HOWEVER, WHETHER THESE PROTEINS WERE RECRUITED DIRECTLY TO DAMAGED DNA OR DURING THE DNA REPAIR PROCESS WAS UNKNOWN. HERE WE DEMONSTRATE THAT THE MISMATCH REPAIR PROTEIN HETERODIMER MSH2-MSH6 PARTICIPATES IN THE OXIDATIVE DAMAGE-INDUCED RECRUITMENT OF DNA METHYLTRANSFERASE 1 (DNMT1) TO CHROMATIN. HYDROGEN PEROXIDE TREATMENT INDUCES THE INTERACTION OF MSH2-MSH6 WITH DNMT1, SUGGESTING THAT THE RECRUITMENT IS THROUGH A PROTEIN-PROTEIN INTERACTION. IMPORTANTLY, THE REDUCTION IN TRANSCRIPTION FOR GENES WITH CPG ISLAND-CONTAINING PROMOTERS CAUSED BY OXIDATIVE DAMAGE IS ABROGATED BY KNOCKDOWN OF MSH6 AND/OR DNMT1. OUR FINDINGS PROVIDE EVIDENCE THAT THE ROLE OF DNMT1 AT SITES OF OXIDATIVE DAMAGE IS TO REDUCE TRANSCRIPTION, POTENTIALLY PREVENTING TRANSCRIPTION FROM INTERFERING WITH THE REPAIR PROCESS. THIS STUDY UNIQUELY BRINGS TOGETHER SEVERAL FACTORS THAT ARE KNOWN TO CONTRIBUTE TO COLON CANCER, NAMELY INFLAMMATION, MISMATCH REPAIR PROTEINS, AND EPIGENETIC CHANGES. 2016 12 6086 31 THE EFFECTS OF ACETALDEHYDE EXPOSURE ON HISTONE MODIFICATIONS AND CHROMATIN STRUCTURE IN HUMAN LUNG BRONCHIAL EPITHELIAL CELLS. AS THE PRIMARY METABOLITE OF ALCOHOL AND THE MOST ABUNDANT CARCINOGEN IN TOBACCO SMOKE, ACETALDEHYDE IS LINKED TO A NUMBER OF HUMAN DISEASES ASSOCIATED WITH CHRONIC ALCOHOL CONSUMPTION AND SMOKING INCLUDING CANCERS. IN ADDITION TO DIRECT DNA DAMAGE AS A RESULT OF THE FORMATION OF ACETALDEHYDE-DNA ADDUCTS, ACETALDEHYDE MAY ALSO INDIRECTLY IMPACT PROPER GENOME FUNCTION THROUGH THE FORMATION OF PROTEIN ADDUCTS. HISTONE PROTEINS ARE THE MAJOR COMPONENT OF THE CHROMATIN. POST-TRANSLATIONAL HISTONE MODIFICATIONS (PTMS) ARE CRITICALLY IMPORTANT FOR THE MAINTENANCE OF GENETIC AND EPIGENETIC STABILITY. HOWEVER, LITTLE IS KNOWN ABOUT HOW ACETALDEHYDE-HISTONE ADDUCTS AFFECT HISTONE MODIFICATIONS AND CHROMATIN STRUCTURE. THE RESULTS OF PROTEIN CARBONYL ASSAYS SUGGEST THAT ACETALDEHYDE FORMS ADDUCTS WITH HISTONE PROTEINS IN HUMAN BRONCHIAL EPITHELIAL BEAS-2B CELLS. THE LEVEL OF ACETYLATION FOR N-TERMINAL TAILS OF CYTOSOLIC HISTONES H3 AND H4, AN IMPORTANT MODIFICATION FOR HISTONE NUCLEAR IMPORT AND CHROMATIN ASSEMBLY, IS SIGNIFICANTLY DOWNREGULATED FOLLOWING ACETALDEHYDE EXPOSURE IN BEAS-2B CELLS, POSSIBLY DUE TO THE FORMATION OF HISTONE ADDUCTS AND/OR THE DECREASE IN THE EXPRESSION OF HISTONE ACETYLTRANSFERASES. NOTABLY, THE LEVEL OF NUCLEOSOMAL HISTONES IN THE CHROMATIN FRACTION AND AT MOST OF THE GENOMIC LOCI WE TESTED ARE LOW IN ACETALDEHYDE-TREATED CELLS AS COMPARED WITH THE CONTROL CELLS, WHICH IS SUGGESTIVE OF INHIBITION OF CHROMATIN ASSEMBLY. MOREOVER, ACETALDEHYDE EXPOSURE PERTURBS CHROMATIN STRUCTURE AS EVIDENCED BY THE INCREASE IN GENERAL CHROMATIN ACCESSIBILITY AND THE DECREASE IN NUCLEOSOME OCCUPANCY AT GENOMIC LOCI FOLLOWING ACETALDEHYDE TREATMENT. OUR RESULTS INDICATE THAT REGULATION OF HISTONE MODIFICATIONS AND CHROMATIN ACCESSIBILITY MAY PLAY IMPORTANT ROLES IN ACETALDEHYDE-INDUCED PATHOGENESIS. ENVIRON. MOL. MUTAGEN. 59:375-385, 2018. (C) 2018 WILEY PERIODICALS, INC. 2018 13 3207 28 HDACI: CELLULAR EFFECTS, OPPORTUNITIES FOR RESTORATIVE DENTISTRY. ACETYLATION OF HISTONE AND NON-HISTONE PROTEINS ALTERS GENE EXPRESSION AND INDUCES A HOST OF CELLULAR EFFECTS. THE ACETYLATION PROCESS IS HOMEOSTATICALLY BALANCED BY TWO GROUPS OF CELLULAR ENZYMES, HISTONE ACETYLTRANSFERASES (HATS) AND HISTONE DEACETYLASES (HDACS). HAT ACTIVITY RELAXES THE STRUCTURE OF THE HUMAN CHROMATIN, RENDERING IT TRANSCRIPTIONALLY ACTIVE, THEREBY INCREASING GENE EXPRESSION. IN CONTRAST, HDAC ACTIVITY LEADS TO GENE SILENCING. THE ENZYMATIC BALANCE CAN BE 'TIPPED' BY HISTONE DEACETYLASE INHIBITORS (HDACI), LEADING TO AN ACCUMULATION OF ACETYLATED PROTEINS, WHICH SUBSEQUENTLY MODIFY CELLULAR PROCESSES INCLUDING STEM CELL DIFFERENTIATION, CELL CYCLE, APOPTOSIS, GENE EXPRESSION, AND ANGIOGENESIS. THERE IS A VARIETY OF NATURAL AND SYNTHETIC HDACI AVAILABLE, AND THEIR PLEIOTROPIC EFFECTS HAVE CONTRIBUTED TO DIVERSE CLINICAL APPLICATIONS, NOT ONLY IN CANCER BUT ALSO IN NON-CANCER AREAS, SUCH AS CHRONIC INFLAMMATORY DISEASE, BONE ENGINEERING, AND NEURODEGENERATIVE DISEASE. INDEED, IT APPEARS THAT HDACI-MODULATED EFFECTS MAY DIFFER BETWEEN 'NORMAL' AND TRANSFORMED CELLS, PARTICULARLY WITH REGARD TO REACTIVE OXYGEN SPECIES ACCUMULATION, APOPTOSIS, PROLIFERATION, AND CELL CYCLE ARREST. THE POTENTIAL BENEFICIAL EFFECTS OF HDACI FOR HEALTH, RESULTING FROM THEIR ABILITY TO REGULATE GLOBAL GENE EXPRESSION BY EPIGENETIC MODIFICATION OF DNA-ASSOCIATED PROTEINS, ALSO OFFER POTENTIAL FOR APPLICATION WITHIN RESTORATIVE DENTISTRY, WHERE THEY MAY PROMOTE DENTAL TISSUE REGENERATION FOLLOWING PULPAL DAMAGE. 2011 14 6166 32 THE GLUTATHIONE SYSTEM: A NEW DRUG TARGET IN NEUROIMMUNE DISORDERS. GLUTATHIONE (GSH) HAS A CRUCIAL ROLE IN CELLULAR SIGNALING AND ANTIOXIDANT DEFENSES EITHER BY REACTING DIRECTLY WITH REACTIVE OXYGEN OR NITROGEN SPECIES OR BY ACTING AS AN ESSENTIAL COFACTOR FOR GSH S-TRANSFERASES AND GLUTATHIONE PEROXIDASES. GSH ACTING IN CONCERT WITH ITS DEPENDENT ENZYMES, KNOWN AS THE GLUTATHIONE SYSTEM, IS RESPONSIBLE FOR THE DETOXIFICATION OF REACTIVE OXYGEN AND NITROGEN SPECIES (ROS/RNS) AND ELECTROPHILES PRODUCED BY XENOBIOTICS. ADEQUATE LEVELS OF GSH ARE ESSENTIAL FOR THE OPTIMAL FUNCTIONING OF THE IMMUNE SYSTEM IN GENERAL AND T CELL ACTIVATION AND DIFFERENTIATION IN PARTICULAR. GSH IS A UBIQUITOUS REGULATOR OF THE CELL CYCLE PER SE. GSH ALSO HAS CRUCIAL FUNCTIONS IN THE BRAIN AS AN ANTIOXIDANT, NEUROMODULATOR, NEUROTRANSMITTER, AND ENABLER OF NEURON SURVIVAL. DEPLETION OF GSH LEADS TO EXACERBATION OF DAMAGE BY OXIDATIVE AND NITROSATIVE STRESS; HYPERNITROSYLATION; INCREASED LEVELS OF PROINFLAMMATORY MEDIATORS AND INFLAMMATORY POTENTIAL; DYSFUNCTIONS OF INTRACELLULAR SIGNALING NETWORKS, E.G., P53, NUCLEAR FACTOR-KAPPAB, AND JANUS KINASES; DECREASED CELL PROLIFERATION AND DNA SYNTHESIS; INACTIVATION OF COMPLEX I OF THE ELECTRON TRANSPORT CHAIN; ACTIVATION OF CYTOCHROME C AND THE APOPTOTIC MACHINERY; BLOCKADE OF THE METHIONINE CYCLE; AND COMPROMISED EPIGENETIC REGULATION OF GENE EXPRESSION. AS SUCH, GSH DEPLETION HAS MARKED CONSEQUENCES FOR THE HOMEOSTATIC CONTROL OF THE IMMUNE SYSTEM, OXIDATIVE AND NITROSATIVE STRESS (O&NS) PATHWAYS, REGULATION OF ENERGY PRODUCTION, AND MITOCHONDRIAL SURVIVAL AS WELL. GSH DEPLETION AND CONCOMITANT INCREASE IN O&NS AND MITOCHONDRIAL DYSFUNCTIONS PLAY A ROLE IN THE PATHOPHYSIOLOGY OF DIVERSE NEUROIMMUNE DISORDERS, INCLUDING DEPRESSION, MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME AND PARKINSON'S DISEASE, SUGGESTING THAT DEPLETED GSH IS AN INTEGRAL PART OF THESE DISEASES. THERAPEUTICAL INTERVENTIONS THAT AIM TO INCREASE GSH CONCENTRATIONS IN VIVO INCLUDE N-ACETYL CYSTEINE; NRF-2 ACTIVATION VIA HYPERBARIC OXYGEN THERAPY; DIMETHYL FUMARATE; PHYTOCHEMICALS, INCLUDING CURCUMIN, RESVERATROL, AND CINNAMON; AND FOLATE SUPPLEMENTATION. 2014 15 3952 27 LOCUS-SPECIFIC EPIGENETIC REMODELING CONTROLS ADDICTION- AND DEPRESSION-RELATED BEHAVIORS. CHRONIC EXPOSURE TO DRUGS OF ABUSE OR STRESS REGULATES TRANSCRIPTION FACTORS, CHROMATIN-MODIFYING ENZYMES AND HISTONE POST-TRANSLATIONAL MODIFICATIONS IN DISCRETE BRAIN REGIONS. GIVEN THE PROMISCUITY OF THE ENZYMES INVOLVED, IT HAS NOT YET BEEN POSSIBLE TO OBTAIN DIRECT CAUSAL EVIDENCE TO IMPLICATE THE REGULATION OF TRANSCRIPTION AND CONSEQUENT BEHAVIORAL PLASTICITY BY CHROMATIN REMODELING THAT OCCURS AT A SINGLE GENE. WE INVESTIGATED THE MECHANISM LINKING CHROMATIN DYNAMICS TO NEUROBIOLOGICAL PHENOMENA BY APPLYING ENGINEERED TRANSCRIPTION FACTORS TO SELECTIVELY MODIFY CHROMATIN AT A SPECIFIC MOUSE GENE IN VIVO. WE FOUND THAT HISTONE METHYLATION OR ACETYLATION AT THE FOSB LOCUS IN NUCLEUS ACCUMBENS, A BRAIN REWARD REGION, WAS SUFFICIENT TO CONTROL DRUG- AND STRESS-EVOKED TRANSCRIPTIONAL AND BEHAVIORAL RESPONSES VIA INTERACTIONS WITH THE ENDOGENOUS TRANSCRIPTIONAL MACHINERY. THIS APPROACH ALLOWED US TO RELATE THE EPIGENETIC LANDSCAPE AT A GIVEN GENE DIRECTLY TO REGULATION OF ITS EXPRESSION AND TO ITS SUBSEQUENT EFFECTS ON REWARD BEHAVIOR. 2014 16 2067 33 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 17 4836 27 ONCOGENIC FUNCTIONS OF THE TRANSCRIPTION FACTOR NRF2. NUCLEAR FACTOR E2-RELATED FACTOR 2 (NRF2) IS A TRANSCRIPTION FACTOR THAT CONTROLS THE EXPRESSION OF A LARGE POOL OF ANTIOXIDANT AND CYTOPROTECTIVE GENES REGULATING THE CELLULAR RESPONSE TO OXIDATIVE AND ELECTROPHILIC STRESS. NRF2 IS NEGATIVELY REGULATED BY KELCH-LIKE ECH-ASSOCIATED PROTEIN 1 (KEAP1) AND, UPON STIMULATION BY AN OXIDATIVE OR ELECTROPHILIC INSULT, IS RAPIDLY ACTIVATED BY PROTEIN STABILIZATION. OWING TO ITS CYTOPROTECTIVE FUNCTIONS, NRF2 HAS BEEN TRADITIONALLY STUDIED IN THE FIELD OF CHEMOPREVENTION; HOWEVER, THERE IS ACCUMULATED EVIDENCE THAT KEAP1/NRF2 MUTATIONS OR UNBALANCED REGULATION THAT LEADS TO OVEREXPRESSION OR HYPERACTIVATION OF NRF2 MAY PARTICIPATE IN TUMORIGENESIS AND BE INVOLVED IN CHEMORESISTANCE OF A WIDE NUMBER OF SOLID CANCERS AND LEUKEMIAS. IN ADDITION TO PROTECTING CELLS FROM REACTIVE OXYGEN SPECIES, NRF2 SEEMS TO PLAY A DIRECT ROLE IN CELL GROWTH CONTROL AND IS RELATED TO APOPTOSIS-REGULATING PATHWAYS. MOREOVER, NRF2 ACTIVITY IS CONNECTED WITH ONCOGENIC KINASE PATHWAYS, STRUCTURAL PROTEINS, HORMONAL REGULATION, OTHER TRANSCRIPTION FACTORS, AND EPIGENETIC ENZYMES INVOLVED IN THE PATHOGENESIS OF VARIOUS TYPES OF TUMORS. THE AIM OF THIS REVIEW IS TO COMPILE AND SUMMARIZE EXISTING KNOWLEDGE OF THE ONCOGENIC FUNCTIONS OF NRF2 TO PROVIDE A SOLID BASIS FOR ITS POTENTIAL USE AS A MOLECULAR MARKER AND PHARMACOLOGICAL TARGET IN CANCER. 2013 18 1406 26 DIETARY HISTONE DEACETYLASE INHIBITORS: FROM CELLS TO MICE TO MAN. SULFORAPHANE (SFN) IS AN ISOTHIOCYANATE FOUND IN CRUCIFEROUS VEGETABLES, SUCH AS BROCCOLI AND BROCCOLI SPROUTS. THIS ANTICARCINOGEN WAS FIRST IDENTIFIED AS A POTENT INDUCER OF PHASE 2 DETOXIFICATION ENZYMES, BUT EVIDENCE IS MOUNTING THAT SFN ALSO ACTS THROUGH EPIGENETIC MECHANISMS. SFN HAS BEEN SHOWN TO INHIBIT HISTONE DEACETYLASE (HDAC) ACTIVITY IN HUMAN COLON AND PROSTATE CANCER LINES, WITH AN INCREASE IN GLOBAL AND LOCAL HISTONE ACETYLATION STATUS, SUCH AS ON THE PROMOTER REGIONS OF P21 AND BAX GENES. SFN ALSO INHIBITED THE GROWTH OF PROSTATE CANCER XENOGRAFTS AND SPONTANEOUS INTESTINAL POLYPS IN MOUSE MODELS, WITH EVIDENCE FOR ALTERED HISTONE ACETYLATION AND HDAC ACTIVITIES IN VIVO. IN HUMAN SUBJECTS, A SINGLE INGESTION OF 68 G BROCCOLI SPROUTS INHIBITED HDAC ACTIVITY IN CIRCULATING PERIPHERAL BLOOD MONONUCLEAR CELLS 3-6 H AFTER CONSUMPTION, WITH CONCOMITANT INDUCTION OF HISTONE H3 AND H4 ACETYLATION. THESE FINDINGS PROVIDE EVIDENCE THAT ONE MECHANISM OF CANCER CHEMOPREVENTION BY SFN IS VIA EPIGENETIC CHANGES ASSOCIATED WITH INHIBITION OF HDAC ACTIVITY. OTHER DIETARY AGENTS SUCH AS BUTYRATE, BIOTIN, LIPOIC ACID, GARLIC ORGANOSULFUR COMPOUNDS, AND METABOLITES OF VITAMIN E HAVE STRUCTURAL FEATURES COMPATIBLE WITH HDAC INHIBITION. THE ABILITY OF DIETARY COMPOUNDS TO DE-REPRESS EPIGENETICALLY SILENCED GENES IN CANCER CELLS, AND TO ACTIVATE THESE GENES IN NORMAL CELLS, HAS IMPORTANT IMPLICATIONS FOR CANCER PREVENTION AND THERAPY. IN A BROADER CONTEXT, THERE IS GROWING INTEREST IN DIETARY HDAC INHIBITORS AND THEIR IMPACT ON EPIGENETIC MECHANISMS AFFECTING OTHER CHRONIC CONDITIONS, SUCH AS CARDIOVASCULAR DISEASE, NEURODEGENERATION AND AGING. 2007 19 6801 33 [EPIGENETIC MECHANISMS AND ALCOHOL USE DISORDERS: A POTENTIAL THERAPEUTIC TARGET]. ALCOHOL USE DISORDER IS A DEVASTATING ILLNESS WITH A PROFOUND HEALTH IMPACT, AND ITS DEVELOPMENT IS DEPENDENT ON BOTH GENETIC AND ENVIRONMENTAL FACTORS. THIS DISEASE OCCURS OVER TIME AND REQUIRES CHANGES IN BRAIN GENE EXPRESSION. THERE IS CONVERGING EVIDENCE SUGGESTING THAT THE EPIGENETIC PROCESSES MAY PLAY A ROLE IN THE ALCOHOL-INDUCED GENE REGULATIONS AND BEHAVIOR SUCH AS THE INTERVENTION OF DNA METHYLATION AND HISTONE ACETYLATION. HISTONE ACETYLATION, LIKE HISTONE METHYLATION, IS A HIGHLY DYNAMIC PROCESS REGULATED BY TWO CLASSES OF ENZYMES: HISTONE ACETYLTRANSFERASES AND HISTONE DEACETYLASES (HDACS). TO DATE, 18 HUMAN HDAC ISOFORMS HAVE BEEN CHARACTERIZED, AND BASED ON THEIR SEQUENCE HOMOLOGIES AND COFACTOR DEPENDENCIES, THEY HAVE BEEN PHYLOGENETICALLY CATEGORIZED INTO 4 MAIN CLASSES: CLASSES I, II (A AND B), III, AND IV. IN THE BRAIN, EXPRESSION OF THE DIFFERENT CLASSES OF HDACS VARIES BETWEEN CELL TYPES AND ALSO IN THEIR SUBCELLULAR LOCALIZATION (NUCLEUS AND/OR CYTOSOL). FURTHERMORE, WE RECENTLY SHOWED THAT A SINGLE ETHANOL EXPOSURE INHIBITS HDAC ACTIVITY AND INCREASES BOTH H3 AND H4 HISTONE ACETYLATION WITHIN THE AMYGDALA OF RATS. IN THE BRAIN OF ALCOHOLIC PATIENTS, ETHANOL HAS BEEN SHOWN TO INDUCE HISTONE-RELATED AND DNA METHYLATION EPIGENETIC CHANGES IN SEVERAL REWARD REGIONS INVOLVED IN REWARD PROCESSES SUCH AS HIPPOCAMPUS, PREFRONTAL CORTEX, AND AMYGDALA. WE RECENTLY DEMONSTRATED ALTERATION OF HISTONE H3 ACETYLATION LEVELS IN SEVERAL BRAIN REGIONS FROM THE REWARD CIRCUIT OF RATS MADE DEPENDENT TO ALCOHOL AFTER CHRONIC AND INTERMITTENT EXPOSURE TO ETHANOL VAPOR. IN NEURONAL CELL LINE CULTURE, ETHANOL WAS SHOWN TO INDUCE HDAC EXPRESSION. IN MOUSE AND RAT BRAIN, NUMEROUS STUDIES REPORTED EPIGENETIC ALTERATIONS FOLLOWING ETHANOL EXPOSURE. WE ALSO DEMONSTRATED THAT BOTH THE EXPRESSION OF GENES AND THE ACTIVITY OF ENZYMES INVOLVED IN EPIGENETIC MECHANISMS ARE CHANGED AFTER REPEATED ADMINISTRATIONS OF ETHANOL IN MICE SENSITIZED TO THE MOTOR STIMULANT EFFECT OF ETHANOL (A MODEL OF DRUG-INDUCED NEUROPLASTICITY). NUMEROUS STUDIES HAVE SHOWN THAT HDAC INHIBITORS ARE ABLE TO COUNTER ETHANOL-INDUCED BEHAVIORS AND THE ETHANOL-INDUCED CHANGES IN THE LEVELS OF HDAC AND/OR LEVELS OF ACETYLATED HDAC. FOR EXAMPLE, TRICHOSTATIN A (TSA) TREATMENT CAUSED THE REVERSAL OF ETHANOL-INDUCED TOLERANCE, ANXIETY, AND ETHANOL DRINKING BY INHIBITING HDAC ACTIVITY, THEREBY INCREASING HISTONE ACETYLATION IN THE AMYGDALA OF RATS. ANOTHER STUDY DEMONSTRATED THAT TSA PREVENTED THE DEVELOPMENT OF ETHANOL WITHDRAWAL INDUCED ANXIETY IN RATS BY RESCUING DEFICITS IN HISTONE ACETYLATION INDUCED BY INCREASED HDAC ACTIVITY IN THE AMYGDALA. WE HAVE DEMONSTRATED THAT TREATMENT WITH THE HDAC INHIBITOR SODIUM BUTYRATE BLOCKS BOTH THE DEVELOPMENT AND THE EXPRESSION OF ETHANOL-INDUCED BEHAVIORAL SENSITIZATION IN MICE. IN THIS CONTEXT, CONVERGING EVIDENCE INDICATES THAT HDAC INHIBITORS COULD BE USEFUL IN COUNTERACTING ETHANOL-INDUCED GENE REGULATIONS VIA EPIGENETIC MECHANISMS, THAT IS, HDAC INHIBITORS COULD AFFECT DIFFERENT ACETYLATION SITES AND MAY ALSO ALTER THE EXPRESSION OF DIFFERENT GENES THAT COULD IN TURN COUNTERACT THE EFFECT OF ETHANOL. RECENT WORK IN RODENTS HAS SHOWN THAT SYSTEMIC ADMINISTRATION OF PAN HDAC CLASS I AND II INHIBITORS, TSA AND N-HYDROXY-N-PHENYL-OCTANEDIAMIDE [SUBEROYLANILIDE HYDROXAMIC ACID] (SAHA), AND OF THE MORE SELECTIVE INHIBITOR (MAINLY HDAC1 AND HDAC9) MS-275, DECREASE BINGE-LIKE ALCOHOL DRINKING IN MICE. SAHA SELECTIVELY REDUCED ETHANOL OPERANT SELF-ADMINISTRATION AND SEEKING IN RATS. OUR PREVIOUS STUDY REVEALED THAT MS-275 STRONGLY DECREASED OPERANT ETHANOL SELF-ADMINISTRATION IN ALCOHOL-DEPENDENT RATS WHEN ADMINISTERED 30 MINUTES BEFORE THE SESSION AT THE SECOND DAY OF INJECTION. WE ALSO DEMONSTRATED THAT INTRA-CEREBRO-VENTRICULAR INFUSION OF MS-275 INCREASES ACETYLATION OF HISTONE 4 WITHIN THE NUCLEUS ACCUMBENS AND THE DORSOLATERAL STRIATUM, ASSOCIATED TO A DECREASE IN ETHANOL SELF-ADMINISTRATION BY ABOUT 75%. MS-275 ALSO DIMINISHED BOTH THE MOTIVATION TO CONSUME ETHANOL (25% DECREASE), RELAPSE (BY ABOUT 50%) AND POSTPONED REACQUISITION AFTER ABSTINENCE. BOTH LITERATURE AND SEVERAL OF OUR STUDIES STRONGLY SUPPORT THE POTENTIAL THERAPEUTIC INTEREST OF TARGETING EPIGENETIC MECHANISMS IN EXCESSIVE ALCOHOL DRINKING AND STRENGTHEN THEINTEREST OF FOCUSING ON SPECIFIC ISOFORMS OF HISTONE DEACETYLASES. 2017 20 5943 25 TARGETING OXIDATIVE STRESS IN CANCER. IMPORTANCE OF THE FIELD: REACTIVE OXYGEN SPECIES (ROS) OCCUR AS NATURAL BY-PRODUCTS OF OXYGEN METABOLISM AND HAVE IMPORTANT CELLULAR FUNCTIONS. NORMALLY, THE CELL IS ABLE TO MAINTAIN AN ADEQUATE BALANCE BETWEEN THE FORMATION AND REMOVAL OF ROS EITHER VIA ANTI-OXIDANTS OR THROUGH THE USE SPECIFIC ENZYMATIC PATHWAYS. HOWEVER, IF THIS BALANCE IS DISTURBED, OXIDATIVE STRESS MAY OCCUR IN THE CELL, A SITUATION LINKED TO THE PATHOGENESIS OF MANY DISEASES, INCLUDING CANCER. AREAS COVERED IN THIS REVIEW: HDACS ARE IMPORTANT REGULATORS OF MANY OXIDATIVE STRESS PATHWAYS INCLUDING THOSE INVOLVED WITH BOTH SENSING AND COORDINATING THE CELLULAR RESPONSE TO OXIDATIVE STRESS. IN PARTICULAR ABERRANT REGULATION OF THESE PATHWAYS BY HISTONE DEACETYLASES MAY PLAY CRITICAL ROLES IN CANCER PROGRESSION. WHAT THE READER WILL GAIN: IN THIS REVIEW WE DISCUSS THE NOTION THAT TARGETING HDACS MAY BE A USEFUL THERAPEUTIC AVENUE IN THE TREATMENT OF OXIDATIVE STRESS IN CANCER, USING CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), NSCLC AND HEPATOCELLULAR CARCINOMA (HCC) AS EXAMPLES TO ILLUSTRATE THIS POSSIBILITY. TAKE HOME MESSAGE: EPIGENETIC MECHANISMS MAY BE AN IMPORTANT NEW THERAPEUTIC AVENUE FOR TARGETING OXIDATIVE STRESS IN CANCER. 2010