1 4768 89 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 2 3398 26 HOW ALCOHOL DRINKING AFFECTS OUR GENES: AN EPIGENETIC POINT OF VIEW. THIS WORK HIGHLIGHTS RECENT STUDIES IN EPIGENETIC MECHANISMS THAT PLAY A ROLE IN ALCOHOLISM, WHICH IS A COMPLEX MULTIFACTORIAL DISORDER. THERE IS A LARGE BODY OF EVIDENCE SHOWING THAT ALCOHOL CAN MODIFY GENE EXPRESSION THROUGH EPIGENETIC PROCESSES, NAMELY DNA METHYLATION AND NUCLEOSOMAL REMODELING VIA HISTONE MODIFICATIONS. IN THAT REGARD, CHRONIC EXPOSURE TO ETHANOL MODIFIES DNA AND HISTONE METHYLATION, HISTONE ACETYLATION, AND MICRORNA EXPRESSION. THE ALCOHOL-MEDIATED CHROMATIN REMODELING IN THE BRAIN PROMOTES THE TRANSITION FROM USE TO ABUSE AND ADDICTION. UNRAVELLING THE MULTIPLEX PATTERN OF MOLECULAR MODIFICATIONS INDUCED BY ETHANOL COULD SUPPORT THE DEVELOPMENT OF NEW THERAPIES FOR ALCOHOLISM AND DRUG ADDICTION TARGETING EPIGENETIC PROCESSES. 2019 3 2104 36 EPIGENETIC EVENTS IN LIVER CANCER RESULTING FROM ALCOHOLIC LIVER DISEASE. EPIGENETIC MECHANISMS PLAY AN EXTENSIVE ROLE IN THE DEVELOPMENT OF LIVER CANCER (I.E., HEPATOCELLULAR CARCINOMA [HCC]) ASSOCIATED WITH ALCOHOLIC LIVER DISEASE (ALD) AS WELL AS IN LIVER DISEASE ASSOCIATED WITH OTHER CONDITIONS. FOR EXAMPLE, EPIGENETIC MECHANISMS, SUCH AS CHANGES IN THE METHYLATION AND/OR ACETYLATION PATTERN OF CERTAIN DNA REGIONS OR OF THE HISTONE PROTEINS AROUND WHICH THE DNA IS WRAPPED, CONTRIBUTE TO THE REVERSION OF NORMAL LIVER CELLS INTO PROGENITOR AND STEM CELLS THAT CAN DEVELOP INTO HCC. CHRONIC EXPOSURE TO BEVERAGE ALCOHOL (I.E., ETHANOL) CAN INDUCE ALL OF THESE EPIGENETIC CHANGES. THUS, ETHANOL METABOLISM RESULTS IN THE FORMATION OF COMPOUNDS THAT CAN CAUSE CHANGES IN DNA METHYLATION AND INTERFERE WITH OTHER COMPONENTS OF THE NORMAL PROCESSES REGULATING DNA METHYLATION. ALCOHOL EXPOSURE ALSO CAN ALTER HISTONE ACETYLATION/DEACETYLATION AND METHYLATION PATTERNS THROUGH A VARIETY OF MECHANISMS AND SIGNALING PATHWAYS. ALCOHOL ALSO ACTS INDIRECTLY ON ANOTHER MOLECULE CALLED TOLL-LIKE RECEPTOR 4 (TLR4) THAT IS A KEY COMPONENT IN A CRUCIAL REGULATORY PATHWAY IN THE CELLS AND WHOSE DYSREGULATION IS INVOLVED IN THE DEVELOPMENT OF HCC. FINALLY, ALCOHOL USE REGULATES AN EPIGENETIC MECHANISM INVOLVING SMALL MOLECULES CALLED MIRNAS THAT CONTROL TRANSCRIPTIONAL EVENTS AND THE EXPRESSION OF GENES IMPORTANT TO ALD. 2013 4 2493 39 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 5 6100 34 THE EMERGING ROLE OF EPIGENETIC MODIFIERS IN REPAIR OF DNA DAMAGE ASSOCIATED WITH CHRONIC INFLAMMATORY DISEASES. AT SITES OF CHRONIC INFLAMMATION EPITHELIAL CELLS ARE EXPOSED TO HIGH LEVELS OF REACTIVE OXYGEN SPECIES (ROS), WHICH CAN CONTRIBUTE TO THE INITIATION AND DEVELOPMENT OF MANY DIFFERENT HUMAN CANCERS. ABERRANT EPIGENETIC ALTERATIONS THAT CAUSE TRANSCRIPTIONAL SILENCING OF TUMOR SUPPRESSOR GENES ARE ALSO IMPLICATED IN MANY DISEASES ASSOCIATED WITH INFLAMMATION, INCLUDING CANCER. HOWEVER, IT IS NOT CLEAR HOW ALTERED EPIGENETIC GENE SILENCING IS INITIATED DURING CHRONIC INFLAMMATION. THE HIGH LEVEL OF ROS AT SITES OF INFLAMMATION IS KNOWN TO INDUCE OXIDATIVE DNA DAMAGE IN SURROUNDING EPITHELIAL CELLS. FURTHERMORE, DNA DAMAGE IS KNOWN TO TRIGGER SEVERAL RESPONSES, INCLUDING RECRUITMENT OF DNA REPAIR PROTEINS, TRANSCRIPTIONAL REPRESSION, CHROMATIN MODIFICATIONS AND OTHER CELL SIGNALING EVENTS. RECRUITMENT OF EPIGENETIC MODIFIERS TO CHROMATIN IN RESPONSE TO DNA DAMAGE RESULTS IN TRANSIENT COVALENT MODIFICATIONS TO CHROMATIN SUCH AS HISTONE UBIQUITINATION, ACETYLATION AND METHYLATION AND DNA METHYLATION. DNA DAMAGE ALSO ALTERS NON-CODING RNA EXPRESSION. ALL OF THESE ALTERATIONS HAVE THE POTENTIAL TO ALTER GENE EXPRESSION AT SITES OF DAMAGE. TYPICALLY, THESE MODIFICATIONS AND GENE TRANSCRIPTION ARE RESTORED BACK TO NORMAL ONCE THE REPAIR OF THE DNA DAMAGE IS COMPLETED. HOWEVER, CHRONIC INFLAMMATION MAY INDUCE SUSTAINED DNA DAMAGE AND DNA DAMAGE RESPONSES THAT RESULT IN THESE TRANSIENT COVALENT CHROMATIN MODIFICATIONS BECOMING MITOTICALLY STABLE EPIGENETIC ALTERATIONS. UNDERSTANDING HOW EPIGENETIC ALTERATIONS ARE INITIATED DURING CHRONIC INFLAMMATION WILL ALLOW US TO DEVELOP PHARMACEUTICAL STRATEGIES TO PREVENT OR TREAT CHRONIC INFLAMMATION-INDUCED CANCER. THIS REVIEW WILL FOCUS ON TYPES OF DNA DAMAGE AND EPIGENETIC ALTERATIONS ASSOCIATED WITH CHRONIC INFLAMMATORY DISEASES, THE TYPES OF DNA DAMAGE AND TRANSIENT COVALENT CHROMATIN MODIFICATIONS INDUCED BY INFLAMMATION AND OXIDATIVE DNA DAMAGE AND HOW THESE MODIFICATIONS MAY RESULT IN EPIGENETIC ALTERATIONS. 2019 6 2606 34 EPIGENETICS-BEYOND THE GENOME IN ALCOHOLISM. GENETIC AND ENVIRONMENTAL FACTORS PLAY A ROLE IN THE DEVELOPMENT OF ALCOHOLISM. WHOLE-GENOME EXPRESSION PROFILING HAS HIGHLIGHTED THE IMPORTANCE OF SEVERAL GENES THAT MAY CONTRIBUTE TO ALCOHOL ABUSE DISORDERS. IN ADDITION, MORE RECENT FINDINGS HAVE ADDED YET ANOTHER LAYER OF COMPLEXITY TO THE OVERALL MOLECULAR MECHANISMS INVOLVED IN A PREDISPOSITION TO ALCOHOLISM AND ADDICTION BY DEMONSTRATING THAT PROCESSES RELATED TO GENETIC FACTORS THAT DO NOT MANIFEST AS DNA SEQUENCE CHANGES (I.E., EPIGENETIC PROCESSES) PLAY A ROLE. BOTH ACUTE AND CHRONIC ETHANOL EXPOSURE CAN ALTER GENE EXPRESSION LEVELS IN SPECIFIC NEURONAL CIRCUITS THAT GOVERN THE BEHAVIORAL CONSEQUENCES RELATED TO TOLERANCE AND DEPENDENCE. THE UNREMITTING CYCLE OF ALCOHOL CONSUMPTION OFTEN INCLUDES SATIATION AND SELF-MEDICATION WITH ALCOHOL, FOLLOWED BY EXCRUCIATING WITHDRAWAL SYMPTOMS AND THE RESULTANT RELAPSE, WHICH REFLECTS BOTH THE POSITIVE AND NEGATIVE AFFECTIVE STATES OF ALCOHOL ADDICTION. RECENT STUDIES HAVE INDICATED THAT BEHAVIORAL CHANGES INDUCED BY ACUTE AND CHRONIC ETHANOL EXPOSURE MAY INVOLVE CHROMATIN REMODELING RESULTING FROM COVALENT HISTONE MODIFICATIONS AND DNA METHYLATION IN THE NEURONAL CIRCUITS INVOLVING A BRAIN REGION CALLED THE AMYGDALA. THESE FINDINGS HAVE HELPED IDENTIFY ENZYMES INVOLVED IN EPIGENETIC MECHANISMS, SUCH AS THE HISTONE DEACETYLASE, HISTONE ACETYLTRANSFERASE, AND DNA METHYLTRANSFERASE ENZYMES, AS NOVEL THERAPEUTIC TARGETS FOR THE DEVELOPMENT OF FUTURE PHARMACOTHERAPIES FOR THE TREATMENT OF ALCOHOLISM. 2012 7 315 37 ALCOHOL, DNA METHYLATION, AND CANCER. CANCER IS ONE OF THE MOST SIGNIFICANT DISEASES ASSOCIATED WITH CHRONIC ALCOHOL CONSUMPTION, AND CHRONIC DRINKING IS A STRONG RISK FACTOR FOR CANCER, PARTICULARLY OF THE UPPER AERODIGESTIVE TRACT, LIVER, COLORECTUM, AND BREAST. SEVERAL FACTORS CONTRIBUTE TO ALCOHOL-INDUCED CANCER DEVELOPMENT (I.E., CARCINOGENESIS), INCLUDING THE ACTIONS OF ACETALDEHYDE, THE FIRST AND PRIMARY METABOLITE OF ETHANOL, AND OXIDATIVE STRESS. HOWEVER, INCREASING EVIDENCE SUGGESTS THAT ABERRANT PATTERNS OF DNA METHYLATION, AN IMPORTANT EPIGENETIC MECHANISM OF TRANSCRIPTIONAL CONTROL, ALSO COULD BE PART OF THE PATHOGENETIC MECHANISMS THAT LEAD TO ALCOHOL-INDUCED CANCER DEVELOPMENT. THE EFFECTS OF ALCOHOL ON GLOBAL AND LOCAL DNA METHYLATION PATTERNS LIKELY ARE MEDIATED BY ITS ABILITY TO INTERFERE WITH THE AVAILABILITY OF THE PRINCIPAL BIOLOGICAL METHYL DONOR, S-ADENOSYLMETHIONINE (SAME), AS WELL AS PATHWAYS RELATED TO IT. SEVERAL MECHANISMS MAY MEDIATE THE EFFECTS OF ALCOHOL ON DNA METHYLATION, INCLUDING REDUCED FOLATE LEVELS AND INHIBITION OF KEY ENZYMES IN ONE-CARBON METABOLISM THAT ULTIMATELY LEAD TO LOWER SAME LEVELS, AS WELL AS INHIBITION OF ACTIVITY AND EXPRESSION OF ENZYMES INVOLVED IN DNA METHYLATION (I.E., DNA METHYLTRANSFERASES). FINALLY, VARIATIONS (I.E., POLYMORPHISMS) OF SEVERAL GENES INVOLVED IN ONE-CARBON METABOLISM ALSO MODULATE THE RISK OF ALCOHOL-ASSOCIATED CARCINOGENESIS. 2013 8 318 42 ALCOHOL-INDUCED EPIGENETIC CHANGES IN CANCER. CHRONIC, HEAVY ALCOHOL CONSUMPTION IS ASSOCIATED WITH SERIOUS NEGATIVE HEALTH EFFECTS, INCLUDING THE DEVELOPMENT OF SEVERAL CANCER TYPES. ONE OF THE PATHWAYS AFFECTED BY ALCOHOL TOXICITY IS THE ONE-CARBON METABOLISM. THE ALCOHOL-INDUCED IMPAIRMENT OF THIS METABOLIC PATHWAY RESULTS IN EPIGENETIC CHANGES ASSOCIATED WITH CANCER DEVELOPMENT. THESE EPIGENETIC CHANGES ARE INDUCED BY FOLATE DEFICIENCY AND BY PRODUCTS OF THE ETHANOL METABOLISM. THE CHANGES INDUCED BY LONG-TERM HEAVY ETHANOL CONSUMPTION RESULT IN ELEVATIONS OF HOMOCYSTEINE AND S-ADENOSYL-HOMOCYSTEINE (SAH) AND REDUCTIONS IN S-ADENOSYLMETHIONINE (SAM) AND ANTIOXIDANT GLUTATHIONE (GSH) LEVELS, LEADING TO ABNORMAL PROMOTER GENE HYPERMETHYLATION, GLOBAL HYPOMETHYLATION, AND METABOLIC INSUFFICIENCY OF ANTIOXIDANT DEFENSE MECHANISMS. IN ADDITION, REACTIVE OXYGEN SPECIES (ROS) GENERATED DURING THE ETHANOL METABOLISM INDUCE ALTERATIONS IN DNA METHYLATION PATTERNS THAT PLAY A CRITICAL ROLE IN CANCER DEVELOPMENT. SPECIFIC EPIGENETIC CHANGES IN ESOPHAGEAL, HEPATIC, AND COLORECTAL CANCERS HAVE BEEN DETECTED IN BLOOD SAMPLES AND PROPOSED TO BE USED CLINICALLY AS EPIGENETIC BIOMARKERS FOR DIAGNOSIS AND PROGNOSIS OF THESE CANCERS. ALSO, GENETIC VARIANTS OF GENES INVOLVED IN ONE-CARBON METABOLISM AND ETHANOL METABOLISM WERE FOUND TO MODULATE THE RELATIONSHIP BETWEEN ALCOHOL-INDUCED EPIGENETIC CHANGES AND CANCER RISK. FURTHERMORE, ALCOHOL METABOLISM PRODUCTS HAVE BEEN ASSOCIATED WITH AN INCREASE IN NADH LEVELS, WHICH LEAD TO HISTONE MODIFICATIONS AND CHANGES IN GENE EXPRESSION THAT IN TURN INFLUENCE CANCER SUSCEPTIBILITY. CHRONIC EXCESSIVE USE OF ALCOHOL ALSO AFFECTS SELECTED MEMBERS OF THE FAMILY OF MICRORNAS, AND AS MIRNAS COULD ACT AS EPIGENETIC REGULATORS, THIS MAY PLAY AN IMPORTANT ROLE IN CARCINOGENESIS. IN CONCLUSION, TARGETING ALCOHOL-INDUCED EPIGENETIC CHANGES IN SEVERAL CANCER TYPES COULD MAKE AVAILABLE CLINICAL TOOLS FOR THE DIAGNOSIS, PROGNOSIS, AND TREATMENT OF THESE CANCERS, WITH AN IMPORTANT ROLE IN PRECISION MEDICINE. 2018 9 313 34 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 10 5550 34 ROLE OF EPIGENETICS IN INFLAMMATION-ASSOCIATED DISEASES. THERE IS CONSIDERABLE EVIDENCE SUGGESTING THAT EPIGENETIC MECHANISMS MAY MEDIATE DEVELOPMENT OF CHRONIC INFLAMMATION BY MODULATING THE EXPRESSION OF PRO-INFLAMMATORY CYTOKINE TNF-ALPHA, INTERLEUKINS, TUMOR SUPPRESSOR GENES, ONCOGENES AND AUTOCRINE AND PARACRINE ACTIVATION OF THE TRANSCRIPTION FACTOR NF-KAPPAB. THESE MOLECULES ARE CONSTITUTIVELY PRODUCED BY A VARIETY OF CELLS UNDER CHRONIC INFLAMMATORY CONDITIONS, WHICH IN TURN LEADS TO THE DEVELOPMENT OF MAJOR DISEASES SUCH AS AUTOIMMUNE DISORDERS, CHRONIC OBSTRUCTIVE PULMONARY DISEASES, NEURODEGENERATIVE DISEASES AND CANCER. DISTINCT OR GLOBAL CHANGES IN THE EPIGENETIC LANDSCAPE ARE HALLMARKS OF CHRONIC INFLAMMATION DRIVEN DISEASES. EPIGENETICS INCLUDE CHANGES TO DISTINCT MARKERS ON THE GENOME AND ASSOCIATED CELLULAR TRANSCRIPTIONAL MACHINERY THAT ARE COPIED DURING CELL DIVISION (MITOSIS AND MEIOSIS). THESE CHANGES APPEAR FOR A SHORT SPAN OF TIME AND THEY NECESSARILY DO NOT MAKE PERMANENT CHANGES TO THE PRIMARY DNA SEQUENCE ITSELF. HOWEVER, THE MOST FREQUENTLY OBSERVED EPIGENETIC CHANGES INCLUDE ABERRANT DNA METHYLATION, AND HISTONE ACETYLATION AND DEACETYLATION. IN THIS CHAPTER, WE FOCUS ON PRO-INFLAMMATORY MOLECULES THAT ARE REGULATED BY ENZYMES INVOLVED IN EPIGENETIC MODIFICATIONS SUCH AS ARGININE AND LYSINE METHYL TRANSFERASES, DNA METHYLTRANSFERASE, HISTONE ACETYLTRANSFERASES AND HISTONE DEACETYLASES AND THEIR ROLE IN INFLAMMATION DRIVEN DISEASES. AGENTS THAT MODULATE OR INHIBIT THESE EPIGENETIC MODIFICATIONS, SUCH AS HAT OR HDAC INHIBITORS HAVE SHOWN GREAT POTENTIAL IN INHIBITING THE PROGRESSION OF THESE DISEASES. GIVEN THE PLASTICITY OF THESE EPIGENETIC CHANGES AND THEIR READINESS TO RESPOND TO INTERVENTION BY SMALL MOLECULE INHIBITORS, THERE IS A TREMENDOUS POTENTIAL FOR THE DEVELOPMENT OF NOVEL THERAPEUTICS THAT WILL SERVE AS DIRECT OR ADJUVANT THERAPEUTIC COMPOUNDS IN THE TREATMENT OF THESE DISEASES. 2013 11 6533 39 TRANSCRIPTIONAL REGULATION OF INFLAMMATORY GENES ASSOCIATED WITH SEVERE ASTHMA. THE 10% OF PATIENTS WITH THE MOST SEVERE ASTHMA ARE RESPONSIBLE FOR A LARGE PART OF HEALTHCARE EXPENDITURE AND MORBIDITY. UNDERSTANDING THE PROCESSES INVOLVED IS KEY IF NEW THERAPEUTIC APPROACHES ARE TO BE DEVELOPED. EVIDENCE IS ACCUMULATING THAT CHRONIC DISEASES SUCH AS ASTHMA ARE ASSOCIATED WITH TEMPORAL AND SPATIAL ALTERATIONS IN THE PATTERN OF INFLAMMATORY GENE EXPRESSION WITHIN THE AIRWAYS. EXPRESSION OF THESE GENES CAN BE REGULATED BY TRANSCRIPTIONAL, POSTTRANSCRIPTIONAL, TRANSLATIONAL AND EPIGENETIC MECHANISMS. IT IS WELL ESTABLISHED THAT BINDING OF ACTIVATED TRANSCRIPTION FACTORS TO SPECIFIC INDUCIBLE GENE PROMOTER SITES IS TIGHTLY CONTROLLED BY CHROMATIN STATE AS A RESULT OF HISTONE MODIFICATIONS, PARTICULARLY THE BALANCE BETWEEN HISTONE ACETYLATION AND DEACETYLATION [1]. THE INTERACTION BETWEEN TRANSCRIPTION FACTORS AND THE PROMOTER IS KEY TO THE DIVERSIFICATION OF GENE EXPRESSION IN A TIME DEPENDENT MANNER LEADING TO ALTERED GENE EXPRESSION PROFILES. ALTERATIONS OF THE ACCESSIBILITY OF TRANSCRIPTION FACTORS TO THE DNA CAN HAVE RESIDING EFFECTS UPON GENE TRANSCRIPTION. THIS REVIEW WILL FOCUS ON THE REGULATION OF SEVERAL GROUPS OF KEY GENES WHICH ARE INVOLVED IN CHRONIC AIRWAY INFLAMMATION AND REMODELLING IN ASTHMA DRAWING MAINLY FROM OUR EXPERIENCE OF STUDYING THESE PROCESSES IN AIRWAY SMOOTH MUSCLE CELLS. AN OVERVIEW IS SHOWN IN FIGURE 1. 2011 12 6527 36 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 13 4897 38 OXIDATIVE STRESS IN ALCOHOL-RELATED LIVER DISEASE. ALCOHOL CONSUMPTION IS ONE OF THE LEADING CAUSES OF THE GLOBAL BURDEN OF DISEASE AND RESULTS IN HIGH HEALTHCARE AND ECONOMIC COSTS. HEAVY ALCOHOL MISUSE LEADS TO ALCOHOL-RELATED LIVER DISEASE, WHICH IS RESPONSIBLE FOR A SIGNIFICANT PROPORTION OF ALCOHOL-ATTRIBUTABLE DEATHS GLOBALLY. OTHER THAN REDUCING ALCOHOL CONSUMPTION, THERE ARE CURRENTLY NO EFFECTIVE TREATMENTS FOR ALCOHOL-RELATED LIVER DISEASE. OXIDATIVE STRESS REFERS TO AN IMBALANCE IN THE PRODUCTION AND ELIMINATION OF REACTIVE OXYGEN SPECIES AND ANTIOXIDANTS. IT PLAYS IMPORTANT ROLES IN SEVERAL ASPECTS OF ALCOHOL-RELATED LIVER DISEASE PATHOGENESIS. HERE, WE REVIEW HOW CHRONIC ALCOHOL USE RESULTS IN OXIDATIVE STRESS THROUGH INCREASED METABOLISM VIA THE CYTOCHROME P450 2E1 SYSTEM PRODUCING REACTIVE OXYGEN SPECIES, ACETALDEHYDE AND PROTEIN AND DNA ADDUCTS. THESE TRIGGER INFLAMMATORY SIGNALING PATHWAYS WITHIN THE LIVER LEADING TO EXPRESSION OF PRO-INFLAMMATORY MEDIATORS CAUSING HEPATOCYTE APOPTOSIS AND NECROSIS. REACTIVE OXYGEN SPECIES EXPOSURE ALSO RESULTS IN MITOCHONDRIAL STRESS WITHIN HEPATOCYTES CAUSING STRUCTURAL AND FUNCTIONAL DYSREGULATION OF MITOCHONDRIA AND UPREGULATING APOPTOTIC SIGNALING. THERE IS ALSO EVIDENCE THAT OXIDATIVE STRESS AS WELL AS THE DIRECT EFFECT OF ALCOHOL INFLUENCES EPIGENETIC REGULATION. INCREASED GLOBAL HISTONE METHYLATION AND ACETYLATION AND SPECIFIC HISTONE ACETYLATION INHIBITS ANTIOXIDANT RESPONSES AND PROMOTES EXPRESSION OF KEY PRO-INFLAMMATORY GENES. THIS REVIEW HIGHLIGHTS ASPECTS OF THE ROLE OF OXIDATIVE STRESS IN DISEASE PATHOGENESIS THAT WARRANT FURTHER STUDY INCLUDING MITOCHONDRIAL STRESS AND EPIGENETIC REGULATION. IMPROVED UNDERSTANDING OF THESE PROCESSES MAY IDENTIFY NOVEL TARGETS FOR THERAPY. 2020 14 2306 32 EPIGENETIC REGULATION OF CELL-FATE CHANGES THAT DETERMINE ADULT LIVER REGENERATION AFTER INJURY. THE ADULT LIVER HAS EXCELLENT REGENERATIVE POTENTIAL FOLLOWING INJURY. IN CONTRAST TO OTHER ORGANS OF THE BODY THAT HAVE HIGH CELLULAR TURNOVER DURING HOMEOSTASIS (E.G., INTESTINE, STOMACH, AND SKIN), THE ADULT LIVER IS A SLOWLY SELF-RENEWING ORGAN AND DOES NOT CONTAIN A DEFINED STEM-CELL COMPARTMENT THAT MAINTAINS HOMEOSTASIS. HOWEVER, TISSUE DAMAGE INDUCES SIGNIFICANT PROLIFERATION ACROSS THE LIVER AND CAN TRIGGER CELL-FATE CHANGES, SUCH AS TRANS-DIFFERENTIATION AND DE-DIFFERENTIATION INTO LIVER PROGENITORS, WHICH CONTRIBUTE TO EFFICIENT TISSUE REGENERATION AND RESTORATION OF LIVER FUNCTIONS. EPIGENETIC MECHANISMS HAVE BEEN SHOWN TO REGULATE CELL-FATE DECISIONS IN BOTH EMBRYONIC AND ADULT TISSUES IN RESPONSE TO ENVIRONMENTAL CUES. UNDERLYING THEIR RELEVANCE IN LIVER BIOLOGY, EXPRESSION LEVELS AND EPIGENETIC ACTIVITY OF CHROMATIN MODIFIERS ARE OFTEN ALTERED IN CHRONIC LIVER DISEASE AND LIVER CANCER. IN THIS REVIEW, I EXAMINE THE ROLE OF SEVERAL CHROMATIN MODIFIERS IN THE REGULATION OF CELL-FATE CHANGES THAT DETERMINE EFFICIENT ADULT LIVER EPITHELIAL REGENERATION IN RESPONSE TO TISSUE INJURY IN MOUSE MODELS. SPECIFICALLY, I FOCUS ON EPIGENETIC MECHANISMS SUCH AS CHROMATIN REMODELLING, DNA METHYLATION AND HYDROXYMETHYLATION, AND HISTONE METHYLATION AND DEACETYLATION. FINALLY, I ADDRESS HOW ALTERED EPIGENETIC MECHANISMS AND THE INTERPLAY BETWEEN EPIGENETICS AND METABOLISM MAY CONTRIBUTE TO THE INITIATION AND PROGRESSION OF LIVER DISEASE AND CANCER. 2021 15 2058 28 EPIGENETIC CONTROL OF GENE EXPRESSION IN THE ALCOHOLIC BRAIN. CHRONIC ALCOHOL EXPOSURE CAUSES WIDESPREAD CHANGES IN BRAIN GENE EXPRESSION IN HUMANS AND ANIMAL MODELS. MANY OF THESE CONTRIBUTE TO CELLULAR ADAPTATIONS THAT ULTIMATELY LEAD TO BEHAVIORAL TOLERANCE AND ALCOHOL DEPENDENCE. THERE IS AN EMERGING APPRECIATION FOR THE ROLE OF EPIGENETIC PROCESSES IN ALCOHOL-INDUCED CHANGES IN BRAIN GENE EXPRESSION AND BEHAVIOR. FOR EXAMPLE, CHRONIC ALCOHOL EXPOSURE PRODUCES CHANGES IN DNA AND HISTONE METHYLATION, HISTONE ACETYLATION, AND MICRORNA EXPRESSION THAT AFFECT EXPRESSION OF MULTIPLE GENES IN VARIOUS TYPES OF BRAIN CELLS (I.E., NEURONS AND GLIA) AND CONTRIBUTE TO BRAIN PATHOLOGY AND BRAIN PLASTICITY ASSOCIATED WITH ALCOHOL ABUSE AND DEPENDENCE. DRUGS TARGETING THE EPIGENETIC "MASTER REGULATORS" ARE EMERGING AS POTENTIAL THERAPEUTICS FOR NEURODEGENERATIVE DISORDERS AND DRUG ADDICTION. 2013 16 3659 33 INDUCTION OF EPIGENETIC ALTERATIONS BY CHRONIC INFLAMMATION AND ITS SIGNIFICANCE ON CARCINOGENESIS. CHRONIC INFLAMMATION IS DEEPLY INVOLVED IN DEVELOPMENT OF HUMAN CANCERS, SUCH AS GASTRIC AND LIVER CANCERS. INDUCTION OF CELL PROLIFERATION, PRODUCTION OF REACTIVE OXYGEN SPECIES, AND DIRECT STIMULATION OF EPITHELIAL CELLS BY INFLAMMATION-INDUCING FACTORS HAVE BEEN CONSIDERED AS MECHANISMS INVOLVED. INFLAMMATION-RELATED CANCERS ARE KNOWN FOR THEIR MULTIPLE OCCURRENCES, AND ABERRANT DNA METHYLATION IS KNOWN TO BE PRESENT EVEN IN NONCANCEROUS TISSUES. IMPORTANTLY, FOR SOME CANCERS, THE DEGREE OF ACCUMULATION HAS BEEN DEMONSTRATED TO BE CORRELATED WITH RISK OF DEVELOPING CANCERS. THIS INDICATES THAT INFLAMMATION INDUCES ABERRANT EPIGENETIC ALTERATIONS IN A TISSUE EARLY IN THE PROCESS OF CARCINOGENESIS, AND ACCUMULATION OF SUCH ALTERATIONS FORMS "AN EPIGENETIC FIELD FOR CANCERIZATION." THIS ALSO SUGGESTS THAT INHIBITION OF INDUCTION OF EPIGENETIC ALTERATIONS AND REMOVAL OF THE ACCUMULATED ALTERATIONS ARE NOVEL APPROACHES TO CANCER PREVENTION. DISTURBANCES IN CYTOKINE AND CHEMOKINE SIGNALS AND INDUCTION OF CELL PROLIFERATIONS ARE IMPORTANT MECHANISMS OF HOW INFLAMMATION INDUCES ABERRANT DNA METHYLATION. ABERRANT DNA METHYLATION IS INDUCED IN SPECIFIC GENES, AND GENE EXPRESSION LEVELS, THE PRESENCE OF RNA POLYMERASE II (ACTIVE OR STALLED), AND TRIMETHYLATION OF H3K4 ARE INVOLVED IN THE SPECIFICITY. EXPRESSION OF DNA METHYLTRANSFERASES (DNMTS) IS NOT NECESSARILY INDUCED BY INFLAMMATION, AND LOCAL IMBALANCE BETWEEN DNMTS AND FACTORS THAT PROTECT GENES FROM DNA METHYLATION SEEMS TO BE IMPORTANT. 2010 17 2228 23 EPIGENETIC MODIFICATIONS OF HISTONES IN PERIODONTAL DISEASE. PERIODONTITIS IS A CHRONIC INFECTIOUS DISEASE DRIVEN BY DYSBIOSIS, AN IMBALANCE BETWEEN COMMENSAL BACTERIA AND THE HOST ORGANISM. PERIODONTITIS IS A LEADING CAUSE OF TOOTH LOSS IN ADULTS AND OCCURS IN ABOUT 50% OF THE US POPULATION. IN ADDITION TO THE CLINICAL CHALLENGES ASSOCIATED WITH TREATING PERIODONTITIS, THE PROGRESSION AND CHRONIC NATURE OF THIS DISEASE SERIOUSLY AFFECT HUMAN HEALTH. EMERGING EVIDENCE SUGGESTS THAT PERIODONTITIS IS ASSOCIATED WITH MECHANISMS BEYOND BACTERIA-INDUCED PROTEIN AND TISSUE DEGRADATION. HERE, WE HYPOTHESIZE THAT BACTERIA ARE ABLE TO INDUCE EPIGENETIC MODIFICATIONS IN ORAL EPITHELIAL CELLS MEDIATED BY HISTONE MODIFICATIONS. IN THIS STUDY, WE FOUND THAT DYSBIOSIS IN VIVO LED TO EPIGENETIC MODIFICATIONS, INCLUDING ACETYLATION OF HISTONES AND DOWNREGULATION OF DNA METHYLTRANSFERASE 1. IN ADDITION, IN VITRO EXPOSURE OF ORAL EPITHELIAL CELLS TO LIPOPOLYSACCHARIDES RESULTED IN HISTONE MODIFICATIONS, ACTIVATION OF TRANSCRIPTIONAL COACTIVATORS, SUCH AS P300/CBP, AND ACCUMULATION OF NUCLEAR FACTOR-KAPPAB (NF-KAPPAB). GIVEN THAT ORAL EPITHELIAL CELLS ARE THE FIRST LINE OF DEFENSE FOR THE PERIODONTIUM AGAINST BACTERIA, WE ALSO EVALUATED WHETHER ACTIVATION OF PATHOGEN RECOGNITION RECEPTORS INDUCED HISTONE MODIFICATIONS. WE FOUND THAT ACTIVATION OF THE TOLL-LIKE RECEPTORS 1, 2, AND 4 AND THE NUCLEOTIDE-BINDING OLIGOMERIZATION DOMAIN PROTEIN 1 INDUCED HISTONE ACETYLATION IN ORAL EPITHELIAL CELLS. OUR FINDINGS CORROBORATE THE EMERGING CONCEPT THAT EPIGENETIC MODIFICATIONS PLAY A ROLE IN THE DEVELOPMENT OF PERIODONTITIS. 2016 18 834 28 CHEMICAL BIOLOGY OF LYSINE DEMETHYLASES. ABNORMAL LEVELS OF DNA METHYLATION AND/OR HISTONE MODIFICATIONS ARE OBSERVED IN PATIENTS WITH A WIDE VARIETY OF CHRONIC DISEASES. METHYLATION OF LYSINES WITHIN HISTONE TAILS IS A KEY MODIFICATION THAT CONTRIBUTES TO INCREASED GENE EXPRESSION OR REPRESSION DEPENDING ON THE SPECIFIC RESIDUE AND DEGREE OF METHYLATION, WHICH IS IN TURN CONTROLLED BY THE INTERPLAY OF LYSINE METHYL TRANSFERASES AND DEMETHYLASES. DRUGS THAT TARGET THESE AND OTHER ENZYMES CONTROLLING CHROMATIN MODIFICATIONS CAN MODULATE THE EXPRESSION OF CLUSTERS OF GENES, POTENTIALLY OFFERING HIGHER THERAPEUTIC EFFICACY THAN CLASSICAL AGENTS ACTING ON DOWNSTREAM BIOCHEMICAL PATHWAYS THAT ARE SUSCEPTIBLE TO DEGENERACY. LYSINE DEMETHYLASES, FIRST DISCOVERED IN 2004, ARE THE SUBJECT OF INCREASING INTEREST AS THERAPEUTIC TARGETS. THIS REVIEW PROVIDES AN OVERVIEW OF RECENT FINDINGS IMPLICATING LYSINE DEMETHYLASES IN A RANGE OF THERAPEUTIC AREAS INCLUDING ONCOLOGY, IMMUNOINFLAMMATION, METABOLIC DISORDERS, NEUROSCIENCE, VIROLOGY AND REGENERATIVE MEDICINE, TOGETHER WITH A SUMMARY OF RECENT ADVANCES IN STRUCTURAL BIOLOGY AND SMALL MOLECULE INHIBITOR DISCOVERY, SUPPORTING THE TRACTABILITY OF THE PROTEIN FAMILY FOR THE DEVELOPMENT OF SELECTIVE DRUGLIKE INHIBITORS. 2011 19 860 33 CHROMATIN MODIFICATIONS DURING REPAIR OF ENVIRONMENTAL EXPOSURE-INDUCED DNA DAMAGE: A POTENTIAL MECHANISM FOR STABLE EPIGENETIC ALTERATIONS. EXPOSURES TO ENVIRONMENTAL TOXICANTS AND TOXINS CAUSE EPIGENETIC CHANGES THAT LIKELY PLAY A ROLE IN THE DEVELOPMENT OF DISEASES ASSOCIATED WITH EXPOSURE. THE MECHANISM BEHIND THESE EXPOSURE-INDUCED EPIGENETIC CHANGES IS CURRENTLY UNKNOWN. ONE COMMONALITY BETWEEN MOST ENVIRONMENTAL EXPOSURES IS THAT THEY CAUSE DNA DAMAGE EITHER DIRECTLY OR THROUGH CAUSING AN INCREASE IN REACTIVE OXYGEN SPECIES, WHICH CAN DAMAGE DNA. LIKE TRANSCRIPTION, DNA DAMAGE REPAIR MUST OCCUR IN THE CONTEXT OF CHROMATIN REQUIRING BOTH HISTONE MODIFICATIONS AND ATP-DEPENDENT CHROMATIN REMODELING. THESE CHROMATIN CHANGES AID IN DNA DAMAGE ACCESSIBILITY AND SIGNALING. SEVERAL PROTEINS AND COMPLEXES INVOLVED IN EPIGENETIC SILENCING DURING BOTH DEVELOPMENT AND CANCER HAVE BEEN FOUND TO BE LOCALIZED TO SITES OF DNA DAMAGE. THE CHROMATIN-BASED RESPONSE TO DNA DAMAGE IS CONSIDERED A TRANSIENT EVENT, WITH CHROMATIN BEING RESTORED TO NORMAL AS DNA DAMAGE REPAIR IS COMPLETED. HOWEVER, IN INDIVIDUALS CHRONICALLY EXPOSED TO ENVIRONMENTAL TOXICANTS OR WITH CHRONIC INFLAMMATORY DISEASE, REPEATED DNA DAMAGE-INDUCED CHROMATIN REARRANGEMENT MAY ULTIMATELY LEAD TO PERMANENT EPIGENETIC ALTERATIONS. UNDERSTANDING THE MECHANISM BEHIND EXPOSURE-INDUCED EPIGENETIC CHANGES WILL ALLOW US TO DEVELOP STRATEGIES TO PREVENT OR REVERSE THESE CHANGES. THIS REVIEW FOCUSES ON EPIGENETIC CHANGES AND DNA DAMAGE INDUCED BY ENVIRONMENTAL EXPOSURES, THE CHROMATIN CHANGES THAT OCCUR AROUND SITES OF DNA DAMAGE, AND HOW THESE TRANSIENT CHROMATIN CHANGES MAY LEAD TO HERITABLE EPIGENETIC ALTERATIONS AT SITES OF CHRONIC EXPOSURE. 2014 20 2280 35 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