1 6563 154 TRANSIENT AND STABLE VECTOR TRANSFECTION: PITFALLS, OFF-TARGET EFFECTS, ARTIFACTS. TRANSIENT AND STABLE VECTOR TRANSFECTIONS HAVE PLAYED IMPORTANT ROLES IN ILLUSTRATING THE FUNCTION OF SPECIFIC GENES/PROTEINS. THE GENERAL ASSUMPTION IS THAT SUCH A PLATFORM COULD EFFECTIVELY LINK A GIVEN GENE/PROTEIN TO GAINED PHENOTYPES, REVEALING THE MECHANISM OF HOW A GENE WORKS. HOWEVER, IN REALITY, INCREASED STUDIES HAVE SURPRISINGLY NOTICED SOME UNEXPECTED RESULTS. IN THIS REVIEW, WE DEMONSTRATE THAT AN ASSUMPTION THAT EMPTY VECTOR-TRANSFECTED CELLS PRESERVE THE CYTOGENETIC AND PHENOTYPIC CHARACTERISTICS, AND REPRESENT THE ADEQUATE CONTROL IN TRANSFECTION EXPERIMENTS IS NOT UNIVERSALLY VALID. A DNA VECTOR, A TRANSFECTION REAGENT, EXPRESSION OF AN ANTIBIOTIC RESISTANCE (TRANS)GENE, EXPRESSION OF A REPORTER (TRANS)GENE, AND SELECTION BY ACUTE/CHRONIC ANTIBIOTIC TREATMENT MAY EVOKE CELLULAR RESPONSES THAT AFFECT THE BIOCHEMICAL PROCESSES UNDER INVESTIGATION. WE EXEMPLIFY A NUMBER OF STUDIES, WHICH REPORTED OBVIOUS GENOMIC, TRANSCRIPTOMIC AND PHENOTYPIC CHANGES OF TUMOR CELLS AFTER TRANSIENT/STABLE TRANSFECTION OF AN EMPTY VECTOR. TO FURTHER ADDRESS THE COMMON MECHANISMS OF THESE UNEXPECTED FINDINGS, WE WILL APPLY THE GENOME THEORY OF SOMATIC EVOLUTION TO EXPLAIN STRESS-MEDIATED SYSTEM DYNAMICS AND THE LIMITATIONS OF PREDICTING THE SYSTEM BEHAVIOR SOLELY BASED ON TARGETED GENES. WE CONCEPTUALIZE THAT THE DIVERSE EXPERIMENTAL MANIPULATIONS (E.G., TRANSGENE OVEREXPRESSION, GENE KNOCK OUT/DOWN, CHEMICAL TREATMENTS, ACUTE CHANGES IN CULTURE CONDITIONS, ETC.) MAY ACT AS A SYSTEM STRESS, PROMOTING INTENSIVE GENOME-LEVEL ALTERATIONS (CHROMOSOMAL INSTABILITY, CIN), EPIGENETIC AND PHENOTYPIC ALTERATIONS, WHICH ARE BEYOND THE FUNCTION OF MANIPULATED GENES. SUCH ANALYSIS CALLS FOR MORE ATTENTION ON THE REDUCED SPECIFICITIES OF GENE-FOCUSED METHODOLOGIES. 2017 2 6449 43 THERAPEUTIC TARGETING OF TELOMERASE. TELOMERE LENGTH AND CELL FUNCTION CAN BE PRESERVED BY THE HUMAN REVERSE TRANSCRIPTASE TELOMERASE (HTERT), WHICH SYNTHESIZES THE NEW TELOMERIC DNA FROM A RNA TEMPLATE, BUT IS NORMALLY RESTRICTED TO CELLS NEEDING A HIGH PROLIFERATIVE CAPACITY, SUCH AS STEM CELLS. CONSEQUENTLY, TELOMERASE-BASED THERAPIES TO ELONGATE SHORT TELOMERES ARE DEVELOPED, SOME OF WHICH HAVE SUCCESSFULLY REACHED THE STAGE I IN CLINICAL TRIALS. TELOMERASE IS ALSO PERMISSIVE FOR TUMORIGENESIS AND 90% OF ALL MALIGNANT TUMORS USE TELOMERASE TO OBTAIN IMMORTALITY. THUS, REVERSAL OF TELOMERASE UPREGULATION IN TUMOR CELLS IS A POTENTIAL STRATEGY TO TREAT CANCER. NATURAL AND SMALL-MOLECULE TELOMERASE INHIBITORS, IMMUNOTHERAPEUTIC APPROACHES, OLIGONUCLEOTIDE INHIBITORS, AND TELOMERASE-DIRECTED GENE THERAPY ARE USEFUL TREATMENT STRATEGIES. TELOMERASE IS MORE WIDELY EXPRESSED THAN ANY OTHER TUMOR MARKER. THE LOW EXPRESSION IN NORMAL TISSUES, TOGETHER WITH THE LONGER TELOMERES IN NORMAL STEM CELLS VERSUS CANCER CELLS, PROVIDES SOME DEGREE OF SPECIFICITY WITH LOW RISK OF TOXICITY. HOWEVER, LONG TERM TELOMERASE INHIBITION MAY ELICIT NEGATIVE EFFECTS IN HIGHLY-PROLIFERATIVE CELLS WHICH NEED TELOMERASE FOR SURVIVAL, AND IT MAY INTERFERE WITH TELOMERE-INDEPENDENT PHYSIOLOGICAL FUNCTIONS. MOREOVER, ONLY A FEW HTERT MOLECULES ARE REQUIRED TO OVERCOME SENESCENCE IN CANCER CELLS, AND TELOMERASE INHIBITION REQUIRES PROLIFERATING CELLS OVER A SUFFICIENT NUMBER OF POPULATION DOUBLINGS TO INDUCE TUMOR SUPPRESSIVE SENESCENCE. THESE LIMITATIONS MAY EXPLAIN THE MODERATE SUCCESS RATES IN MANY CLINICAL STUDIES. DESPITE EXTENSIVE STUDIES, ONLY ONE VACCINE AND ONE TELOMERASE ANTAGONIST ARE ROUTINELY USED IN CLINICAL WORK. FOR COMPLETE ERADICATION OF ALL SUBPOPULATIONS OF CANCER CELLS A SIMULTANEOUS TARGETING OF SEVERAL MECHANISMS WILL LIKELY BE NEEDED. POSSIBLE TECHNICAL IMPROVEMENTS HAVE BEEN PROPOSED INCLUDING THE DEVELOPMENT OF MORE SPECIFIC INHIBITORS, METHODS TO INCREASE THE EFFICACY OF VACCINATION METHODS, AND PERSONALIZED APPROACHES. TELOMERASE ACTIVATION AND CELL REJUVENATION IS SUCCESSFULLY USED IN REGENERATIVE MEDICINE FOR TISSUE ENGINEERING AND RECONSTRUCTIVE SURGERY. HOWEVER, THERE ARE ALSO A NUMBER OF PITFALLS IN THE TREATMENT WITH TELOMERASE ACTIVATING PROCEDURES FOR THE WHOLE ORGANISM AND FOR LONGER PERIODS OF TIME. EXTENDED CELL LIFESPAN MAY ACCUMULATE RARE GENETIC AND EPIGENETIC ABERRATIONS THAT CAN CONTRIBUTE TO MALIGNANT TRANSFORMATION. THEREFORE, NOVEL VECTOR SYSTEMS HAVE BEEN DEVELOPED FOR A 'MILD' INTEGRATION OF TELOMERASE INTO THE HOST GENOME AND LOSS OF THE VECTOR IN RAPIDLY-PROLIFERATING CELLS. IT IS CURRENTLY UNCLEAR IF THIS TECHNIQUE CAN ALSO BE USED IN HUMAN BEINGS TO TREAT CHRONIC DISEASES, SUCH AS ATHEROSCLEROSIS. 2016 3 6771 36 [ACQUIRED DISORDERS AND EPIGENETICS]. EPIGENETIC MODIFICATIONS, INVOLVING DNA METHYLATION AND HISTONE MODIFICATIONS, ARE MAINTAINED UPON SOMATIC CELL REPLICATION, AND ARE FUNDAMENTAL MECHANISMS FOR CELLULAR MEMORY. DNA METHYLATION OF PROMOTER CPG ISLANDS OF TUMOR-SUPPRESSOR GENES CAN SILENCE THEIR DOWNSTREAM GENES, AND CAN BE CAUSALLY INVOLVED IN CANCER DEVELOPMENT AND PROGRESSION. SINCE THIS EFFECT IS THE SAME WITH THAT OF INACTIVATING MUTATIONS, THE NATURES OF DNA METHYLATION WERE ONCE CONSIDERED TO BE SIMILAR TO MUTATIONS. HOWEVER, RECENTLY, IT WAS REVEALED THAT A LARGE NUMBER OF EPIGENETIC ALTERATIONS ARE PRESENT IN A SINGLE CANCER CELL, THAT A LARGE NUMBER OF CELLS HAVE AN EPIGENETIC ALTERATION OF A SPECIFIC GENE IN NON-CANCEROUS, THUS POLYCLONAL, TISSUES, THAT GENE SPECIFICITY IN METHYLATION INDUCTION IS PRESENT ACCORDING TO TISSUE TYPES AND INDUCERS, AND THAT CHRONIC INFLAMMATION IS DEEPLY INVOLVED IN METHYLATION INDUCTION. THESE FACTS SUGGEST THAT EPIGENETIC ALTERATIONS OF KEY GENES INVOLVED IN ACQUIRED CHRONIC DISORDERS CAN BE PRESENT IN A SIGNIFICANT FRACTION OF CELLS IN A TISSUE, AND THUS CAN IMPAIR THE FUNCTION OF THE TISSUE. ASSOCIATIONS BETWEEN EPIGENETIC ALTERATIONS AND BEHAVIOR, MEMORY, MENTAL DISORDERS, NEUROLOGICAL DISORDERS, METABOLIC DISORDERS, ALLERGY, AUTOIMMUNE DISORDERS, AND OTHER DISORDERS HAVE BEEN REPORTED. FURTHER RESEARCH IN THE FIELD IS NECESSARY TO CLARIFY THE CAUSAL ROLES OF THESE EPIGENETIC ALTERATIONS IN DISEASE DEVELOPMENT, AND TO APPLY THE FINDINGS TO NEW STRATEGIES OF DISEASE PREVENTION, DIAGNOSIS, AND TREATMENT. 2010 4 2523 34 EPIGENETICS AND THE TRANSITION FROM ACUTE TO CHRONIC PAIN. OBJECTIVE: THE OBJECTIVE OF THIS STUDY WAS TO REVIEW THE EPIGENETIC MODIFICATIONS INVOLVED IN THE TRANSITION FROM ACUTE TO CHRONIC PAIN AND TO IDENTIFY POTENTIAL TARGETS FOR THE DEVELOPMENT OF NOVEL, INDIVIDUALIZED PAIN THERAPEUTICS. BACKGROUND: EPIGENETICS IS THE STUDY OF HERITABLE MODIFICATIONS IN GENE EXPRESSION AND PHENOTYPE THAT DO NOT REQUIRE A CHANGE IN GENETIC SEQUENCE TO MANIFEST THEIR EFFECTS. ENVIRONMENTAL TOXINS, MEDICATIONS, DIET, AND PSYCHOLOGICAL STRESSES CAN ALTER EPIGENETIC PROCESSES SUCH AS DNA METHYLATION, HISTONE ACETYLATION, AND RNA INTERFERENCE. AS EPIGENETIC MODIFICATIONS POTENTIALLY PLAY AN IMPORTANT ROLE IN INFLAMMATORY CYTOKINE METABOLISM, STEROID RESPONSIVENESS, AND OPIOID SENSITIVITY, THEY ARE LIKELY KEY FACTORS IN THE DEVELOPMENT OF CHRONIC PAIN. ALTHOUGH OUR KNOWLEDGE OF THE HUMAN GENETIC CODE AND DISEASE-ASSOCIATED POLYMORPHISMS HAS GROWN SIGNIFICANTLY IN THE PAST DECADE, WE HAVE NOT YET BEEN ABLE TO ELUCIDATE THE MECHANISMS THAT LEAD TO THE DEVELOPMENT OF PERSISTENT PAIN AFTER NERVE INJURY OR SURGERY. DESIGN: THIS IS A FOCUSED LITERATURE REVIEW OF EPIGENETIC SCIENCE AND ITS RELATIONSHIP TO CHRONIC PAIN. RESULTS: SIGNIFICANT LABORATORY AND CLINICAL DATA SUPPORT THE NOTION THAT EPIGENETIC MODIFICATIONS ARE AFFECTED BY THE ENVIRONMENT AND LEAD TO DIFFERENTIAL GENE EXPRESSION. SIMILAR TO MECHANISMS INVOLVED IN THE DEVELOPMENT OF CANCER, NEURODEGENERATIVE DISEASE, AND INFLAMMATORY DISORDERS, THE LITERATURE ENDORSES AN IMPORTANT POTENTIAL ROLE FOR EPIGENETICS IN CHRONIC PAIN. CONCLUSIONS: EPIGENETIC ANALYSIS MAY IDENTIFY MECHANISMS CRITICAL TO THE DEVELOPMENT OF CHRONIC PAIN AFTER INJURY, AND MAY PROVIDE NEW PATHWAYS AND TARGET MECHANISMS FOR FUTURE DRUG DEVELOPMENT AND INDIVIDUALIZED MEDICINE. 2012 5 2412 42 EPIGENETIC SIDE-EFFECTS OF COMMON PHARMACEUTICALS: A POTENTIAL NEW FIELD IN MEDICINE AND PHARMACOLOGY. THE TERM "EPIGENETICS" REFERS TO DNA AND CHROMATIN MODIFICATIONS THAT PERSIST FROM ONE CELL DIVISION TO THE NEXT, DESPITE A LACK OF CHANGE IN THE UNDERLYING DNA SEQUENCE. THE "EPIGENOME" REFERS TO THE OVERALL EPIGENETIC STATE OF A CELL, AND SERVES AS AN INTERFACE BETWEEN THE ENVIRONMENT AND THE GENOME. THE EPIGENOME IS DYNAMIC AND RESPONSIVE TO ENVIRONMENTAL SIGNALS NOT ONLY DURING DEVELOPMENT, BUT ALSO THROUGHOUT LIFE; AND IT IS BECOMING INCREASINGLY APPARENT THAT CHEMICALS CAN CAUSE CHANGES IN GENE EXPRESSION THAT PERSIST LONG AFTER EXPOSURE HAS CEASED. HERE WE PRESENT THE HYPOTHESIS THAT COMMONLY-USED PHARMACEUTICAL DRUGS CAN CAUSE SUCH PERSISTENT EPIGENETIC CHANGES. DRUGS MAY ALTER EPIGENETIC HOMEOSTASIS BY DIRECT OR INDIRECT MECHANISMS. DIRECT EFFECTS MAY BE CAUSED BY DRUGS WHICH AFFECT CHROMATIN ARCHITECTURE OR DNA METHYLATION. FOR EXAMPLE THE ANTIHYPERTENSIVE HYDRALAZINE INHIBITS DNA METHYLATION. AN EXAMPLE OF AN INDIRECTLY ACTING DRUG IS ISOTRETINOIN, WHICH HAS TRANSCRIPTION FACTOR ACTIVITY. A TWO-TIER MECHANISM IS POSTULATED FOR INDIRECT EFFECTS IN WHICH ACUTE EXPOSURE TO A DRUG INFLUENCES SIGNALING PATHWAYS THAT MAY LEAD TO AN ALTERATION OF TRANSCRIPTION FACTOR ACTIVITY AT GENE PROMOTERS. THIS STIMULATION RESULTS IN THE ALTERED EXPRESSION OF RECEPTORS, SIGNALING MOLECULES, AND OTHER PROTEINS NECESSARY TO ALTER GENETIC REGULATORY CIRCUITS. WITH MORE CHRONIC EXPOSURE, CELLS ADAPT BY AN UNKNOWN HYPOTHETICAL PROCESS THAT RESULTS IN MORE PERMANENT MODIFICATIONS TO DNA METHYLATION AND CHROMATIN STRUCTURE, LEADING TO ENDURING ALTERATION OF A GIVEN EPIGENETIC NETWORK. THEREFORE, ANY EPIGENETIC SIDE-EFFECT CAUSED BY A DRUG MAY PERSIST AFTER THE DRUG IS DISCONTINUED. IT IS FURTHER PROPOSED THAT SOME IATROGENIC DISEASES SUCH AS TARDIVE DYSKINESIA AND DRUG-INDUCED SLE ARE EPIGENETIC IN NATURE. IF THIS HYPOTHESIS IS CORRECT THE CONSEQUENCES FOR MODERN MEDICINE ARE PROFOUND, SINCE IT WOULD IMPLY THAT OUR CURRENT UNDERSTANDING OF PHARMACOLOGY IS AN OVERSIMPLIFICATION. WE PROPOSE THAT EPIGENETIC SIDE-EFFECTS OF PHARMACEUTICALS MAY BE INVOLVED IN THE ETIOLOGY OF HEART DISEASE, CANCER, NEUROLOGICAL AND COGNITIVE DISORDERS, OBESITY, DIABETES, INFERTILITY, AND SEXUAL DYSFUNCTION. IT IS SUGGESTED THAT A SYSTEMS BIOLOGY APPROACH EMPLOYING MICROARRAY ANALYSES OF GENE EXPRESSION AND METHYLATION PATTERNS CAN LEAD TO A BETTER UNDERSTANDING OF LONG-TERM SIDE-EFFECTS OF DRUGS, AND THAT IN THE FUTURE, EPIGENETIC ASSAYS SHOULD BE INCORPORATED INTO THE SAFETY ASSESSMENT OF ALL PHARMACEUTICAL DRUGS. THIS NEW APPROACH TO PHARMACOLOGY HAS BEEN TERMED "PHAMACOEPIGENOMICS", THE IMPACT OF WHICH MAY BE EQUAL TO OR GREATER THAN THAT OF PHARMACOGENETICS. WE PROVIDE HERE AN OVERVIEW OF THIS POTENTIALLY MAJOR NEW FIELD IN PHARMACOLOGY AND MEDICINE. 2009 6 6031 25 THE CANCER EPIGENOME: ITS ORIGINS, CONTRIBUTIONS TO TUMORIGENESIS, AND TRANSLATIONAL IMPLICATIONS. EPIGENETIC ABNORMALITIES IN LUNG AND OTHER CANCERS CONTINUE TO BE DEFINED AT A RAPID PACE. WE ARE COMING TO APPRECIATE THAT CANCERS HAVE AN "EPIGENETIC LANDSCAPE" WHEREIN GENES VULNERABLE TO ABNORMALITIES, SUCH AS PROMOTER DNA HYPERMETHYLATION AND ASSOCIATED GENE SILENCING, TEND TO RESIDE IN DEFINED NUCLEAR POSITIONS AND CHROMOSOME DOMAINS AND RELATIONSHIPS TO CHROMATIN REGULATION, WHICH FACILITATES STATES OF STEM CELL RENEWAL. THESE SAME GENES AND DOMAINS ARE ALSO VULNERABLE TO EPIGENETIC ABNORMALITIES INDUCED BY FACTORS TO WHICH CELLS ARE EXPOSED DURING CANCER RISK STATES, SUCH AS CHRONIC INFLAMMATION. WE CAN USE ALL OF THIS BASIC INFORMATION FOR TRANSLATIONAL PURPOSES IN TERMS OF DERIVING BIOMARKERS FOR CANCER RISK STATES AND DETECTION AND THERAPEUTIC STRATEGIES. 2012 7 6809 27 [EPIGENETICS IN INFLAMMATORY SYSTEMIC DISEASES]. IN ADDITION TO ANALYSIS OF THE GENETIC CODE, IN RECENT YEARS MORE AND MORE STUDIES HAVE CONCENTRATED ON CHANGES IN THE EPIGENETIC CODE. EPIGENETIC MECHANISMS DETERMINE WHICH GENES IN A CELL ARE TRANSCRIBED AND THUS FORM THE PHENOTYPE OF A CELL. THE EPIGENETIC CODE CAN BE CHANGED BY ENVIRONMENTAL INFLUENCES, WHICH ALLOWS CELLS TO ADAPT TO LONGSTANDING CHANGES IN THE ENVIRONMENT. THEREFORE, IT IS FEASIBLE TO ASSUME THAT EPIGENETIC CHANGES ARE THE MOLECULAR BASIS FOR LONG-TERM EFFECTS OF THE ENVIRONMENT ON DISEASE DEVELOPMENT. IN PARTICULAR IN TUMORS AND CHRONIC INFLAMMATORY DISEASES EPIGENETIC CHANGES WERE FOUND TO CORRELATE WITH DISEASE SEVERITY AND PROGRESSION. KNOWLEDGE ABOUT THESE EPIGENETIC CHANGES MIGHT HELP THAT EPIGENETIC MODIFICATIONS CAN BE USED IN THE FUTURE AS BIOMARKERS, PROGNOSTIC FACTORS AND THERAPEUTIC TARGETS. 2014 8 6257 29 THE MOLECULAR BASIS OF TOLERANCE. TOLERANCE IS DEFINED AS THE DIMINISHED RESPONSE TO ALCOHOL OR OTHER DRUGS OVER THE COURSE OF REPEATED OR PROLONGED EXPOSURE. THIS MECHANISM ALLOWS PHYSIOLOGICAL PROCESSES TO ACHIEVE STABILITY IN A CONSTANTLY CHANGING ENVIRONMENT. THE ONSET OF TOLERANCE MAY OCCUR WITHIN MINUTES, DURING A SINGLE EXPOSURE TO ALCOHOL (I.E., ACUTE TOLERANCE), OR OVER LONGER TIMEFRAMES AND WITH PROLONGED EXPOSURE TO ALCOHOL (I.E., RAPID OR CHRONIC TOLERANCE). CHANGES IN TOLERANCE INDUCED BY ALCOHOL MAY AFFECT SEVERAL PROCESSES AT THE MOLECULAR, CELLULAR, OR BEHAVIORAL LEVEL. THESE EFFECTS OFTEN ARE INTERRELATED AND MAY BE DIFFICULT TO SEPARATE. THIS ARTICLE DESCRIBES CHANGES AT THE MOLECULAR LEVEL THAT ARE RELATED TO THE ONSET OF ACUTE, RAPID, OR CHRONIC TOLERANCE. IT FOCUSES ON NEURONAL MEMBRANE-BOUND CHANNELS AND THE FACTORS THAT AFFECT THEIR FUNCTION AND PRODUCTION, SUCH AS MODIFICATION OF PROTEIN SYNTHESIS AND ACTIVITY, INTERACTION WITH THE MEMBRANE LIPID MICROENVIRONMENT, EPIGENETIC EFFECTS ON CYTOPLASMIC REGULATION, AND GENE TRANSCRIPTION. ALSO CONSIDERED IS THE GENETICS OF TOLERANCE. 2008 9 6715 32 VITAMIN A AND THE EPIGENOME. THE EPIGENETIC PHENOMENA REFER TO HERITABLE CHANGES IN GENE EXPRESSION OTHER THAN THOSE IN THE DNA SEQUENCE, SUCH AS DNA METHYLATION AND HISTONE MODIFICATIONS. MAJOR RESEARCH PROGRESS IN THE LAST FEW YEARS HAS PROVIDED FURTHER PROOF THAT ENVIRONMENTAL FACTORS, INCLUDING DIET AND NUTRITION, CAN INFLUENCE PHYSIOLOGIC AND PATHOLOGIC PROCESSES THROUGH EPIGENETIC ALTERATIONS, WHICH IN TURN INFLUENCE GENE EXPRESSION. THIS INFLUENCE IS TERMED NUTRITIONAL EPIGENETICS, AND ONE PROMINENT EXAMPLE IS THE REGULATION OF GENE TRANSCRIPTION BY VITAMIN A THROUGH INTERACTION TO ITS NUCLEAR RECEPTOR. VITAMIN A IS CRITICAL THROUGHOUT LIFE. TOGETHER WITH ITS DERIVATIVES, IT REGULATES DIVERSE PROCESSES INCLUDING REPRODUCTION, EMBRYOGENESIS, VISION, GROWTH, CELLULAR DIFFERENTIATION AND PROLIFERATION, MAINTENANCE OF EPITHELIAL CELLULAR INTEGRITY AND IMMUNE FUNCTION. HERE WE REVIEW THE EPIGENETIC ROLE OF VITAMIN A IN CANCER, STEM CELLS DIFFERENTIATION, PROLIFERATION, AND IMMUNITY. THE DATA PRESENTED HERE SHOW THAT RETINOIC ACID IS A POTENT AGENT CAPABLE OF INDUCING ALTERATIONS IN EPIGENETIC MODIFICATIONS THAT PRODUCE VARIOUS EFFECTS ON THE PHENOTYPE. MEDICAL BENEFITS OF VITAMIN A AS AN EPIGENETIC MODULATOR, ESPECIALLY WITH RESPECT TO ITS CHRONIC USE AS NUTRITIONAL SUPPLEMENT, SHOULD RELY ON OUR FURTHER UNDERSTANDING OF ITS EPIGENETIC EFFECTS DURING HEALTH AND DISEASE, AS WELL AS THROUGH DIFFERENT GENERATIONS. 2017 10 733 30 CANCER EPIGENETICS: LINKING BASIC BIOLOGY TO CLINICAL MEDICINE. CANCER EVOLUTION AT ALL STAGES IS DRIVEN BY BOTH EPIGENETIC ABNORMALITIES AS WELL AS GENETIC ALTERATIONS. DYSREGULATION OF EPIGENETIC CONTROL EVENTS MAY LEAD TO ABNORMAL PATTERNS OF DNA METHYLATION AND CHROMATIN CONFIGURATIONS, BOTH OF WHICH ARE CRITICAL CONTRIBUTORS TO THE PATHOGENESIS OF CANCER. THESE EPIGENETIC ABNORMALITIES ARE SET AND MAINTAINED BY MULTIPLE PROTEIN COMPLEXES AND THE INTERPLAY BETWEEN THEIR INDIVIDUAL COMPONENTS INCLUDING DNA METHYLATION MACHINERY, HISTONE MODIFIERS, PARTICULARLY, POLYCOMB (PCG) PROTEINS, AND CHROMATIN REMODELING PROTEINS. RECENT ADVANCES IN GENOME-WIDE TECHNOLOGY HAVE REVEALED THAT THE INVOLVEMENT OF THESE DYSREGULATED EPIGENETIC COMPONENTS APPEARS TO BE EXTENSIVE. MOREOVER, THERE IS A GROWING CONNECTION BETWEEN EPIGENETIC ABNORMALITIES IN CANCER AND CONCEPTS CONCERNING STEM-LIKE CELL SUBPOPULATIONS AS A DRIVING FORCE FOR CANCER. EMERGING DATA SUGGEST THAT ASPECTS OF THE EPIGENETIC LANDSCAPE INHERENT TO NORMAL EMBRYONIC AND ADULT STEM/PROGENITOR CELLS MAY HELP FOSTER, UNDER THE STRESS OF CHRONIC INFLAMMATION OR ACCUMULATING REACTIVE OXYGEN SPECIES, EVOLUTION OF MALIGNANT SUBPOPULATIONS. FINALLY, UNDERSTANDING MOLECULAR MECHANISMS INVOLVED IN INITIATION AND MAINTENANCE OF EPIGENETIC ABNORMALITIES IN ALL TYPES OF CANCER HAS GREAT POTENTIAL FOR TRANSLATIONAL PURPOSES. THIS IS ALREADY EVIDENT FOR EPIGENETIC BIOMARKER DEVELOPMENT, AND FOR PHARMACOLOGICAL TARGETING AIMED AT REVERSING CANCER-SPECIFIC EPIGENETIC ALTERATIONS. 2011 11 6199 31 THE IMPORTANCE OF EPIGENETICS IN THE DEVELOPMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE. IT IS GENERALLY ACCEPTED THAT GENETIC PREDISPOSITION PLAYS A ROLE IN COPD DEVELOPMENT IN SUSCEPTIBLE INDIVIDUALS. THEREFORE, MANY CANDIDATE GENES THAT COULD BE LINKED TO THE DEVELOPMENT OF DISEASE HAVE BEEN EXAMINED IN COPD. HOWEVER, INCONSISTENT RESULTS IN DIFFERENT STUDY POPULATIONS OFTEN LIMIT THIS APPROACH, SUGGESTING THAT NOT ONLY GENETICS, BUT ALSO OTHER FACTORS, MAY BE CONTRIBUTED TO THE SUSCEPTIBILITY TO COPD. EPIGENETIC MECHANISMS CAN AFFECT THE TRANSCRIPTIONAL ACTIVITY OF SPECIFIC GENES, AT DIFFERENT POINTS IN TIME, AND IN DIFFERENT ORGANS. MOREOVER, THESE MECHANISMS CAN HAVE AN EFFECT ON PEOPLE'S HEALTH. RECENTLY, THERE IS EMERGING EVIDENCE SUPPORTING A ROLE OF EPIGENETICS FOR THE REGULATION OF INFLAMMATORY GENES IN DISEASES SUCH AS ASTHMA AND COPD. MOREOVER, RECENT STUDIES SUGGEST THAT THE CURRENTLY USED TREATMENTS INCLUDING CORTICOSTEROIDS MAY WORK THROUGH EPIGENETIC MECHANISMS. EPIGENETIC REGULATION CAN BE REPROGRAMMED, POTENTIALLY AFFECTING THE RISK, AETIOLOGY AND TREATMENT OF VARIOUS DISEASE STATES. THE EPIGENETICALLY INFLUENCED PHENOTYPE COULD BE REVERSED WITH DEMETHYLATING OR DEACETYLATING AGENTS, CONSISTENT WITH EPIGENETIC PLASTICITY. THE POSTNATAL REVERSIBILITY OF THESE METHYLATION OR ACETYLATION EVENTS MAY THEREFORE PROVIDE GOOD OPPORTUNITIES FOR INTERVENTION. THE RECOGNITION OF THE ROLE OF GENETIC AND EPIGENETIC MECHANISMS IN THE DEVELOPMENT OF COPD MAY IDENTIFY NOVEL TARGETS THAT HATCH NEW THERAPIES FOR PATIENTS WITH COPD. 2011 12 6533 35 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 13 5928 26 TARGETING EPIGENETIC MECHANISMS FOR PAIN RELIEF. EPIGENETIC CHANGES ARE CHEMICAL MODIFICATIONS TO CHROMATIN THAT MODULATE GENE ACTIVITY WITHOUT ALTERING THE DNA SEQUENCE. WHILE RESEARCH ON EPIGENETICS HAS GROWN EXPONENTIALLY OVER THE PAST FEW YEARS, VERY FEW STUDIES HAVE INVESTIGATED EPIGENETIC MECHANISMS IN RELATION TO PAIN STATES. HOWEVER, EPIGENETIC MECHANISMS ARE CRUCIAL TO MEMORY FORMATION THAT REQUIRES SIMILAR SYNAPTIC PLASTICITY TO PAIN PROCESSING, INDICATING THAT THEY MAY PLAY A KEY ROLE IN THE CONTROL OF PAIN STATES. THIS ARTICLE REVIEWS THE EARLY EVIDENCE SUGGESTING THAT EPIGENETIC MECHANISMS ARE ENGAGED AFTER INJURY AND IN CHRONIC PAIN STATES, AND THAT DRUGS USED CLINICALLY TO TARGET THE EPIGENETIC MACHINERY FOR THE TREATMENT OF CANCER MIGHT BE USEFUL FOR THE MANAGEMENT OF CHRONIC PAIN. 2012 14 1796 36 EFFECT OF GERM-FREE STATUS ON TRANSCRIPTIONAL PROFILES IN THE NUCLEUS ACCUMBENS AND TRANSCRIPTOMIC RESPONSE TO CHRONIC MORPHINE. OPIOID USE DISORDER IS A PUBLIC HEALTH CRISIS THAT CAUSES TREMENDOUS SUFFERING FOR PATIENTS AS WELL AS SUBSTANTIAL SOCIAL AND ECONOMIC COSTS FOR SOCIETY. THERE ARE CURRENTLY AVAILABLE TREATMENTS FOR PATIENTS WITH OPIOID USE DISORDER, BUT THEY REMAIN INTOLERABLE OR INEFFECTIVE FOR MANY. THUS THE NEED TO DEVELOP NEW AVENUES FOR THERAPEUTICS DEVELOPMENT IN THIS SPACE IS GREAT. SUBSTANTIAL WORK IN MODELS OF SUBSTANCE USE DISORDERS, INCLUDING OPIOID USE DISORDER, DEMONSTRATES THAT PROLONGED EXPOSURE TO DRUGS OF ABUSE LEADS TO MARKED TRANSCRIPTIONAL AND EPIGENETIC DYSREGULATION IN LIMBIC SUBSTRUCTURES. IT IS WIDELY BELIEVED THAT THESE CHANGES IN GENE REGULATION IN RESPONSE TO DRUGS ARE A KEY DRIVING FACTOR IN THE PERPETUATION OF DRUG TAKING AND SEEKING BEHAVIORS. THUS, DEVELOPMENT OF INTERVENTIONS THAT COULD SHAPE TRANSCRIPTIONAL REGULATION IN RESPONSE TO DRUGS OF ABUSE WOULD BE OF HIGH VALUE. OVER THE PAST DECADE THERE HAS BEEN A SURGE IN RESEARCH DEMONSTRATING THAT THE RESIDENT BACTERIA OF THE GASTROINTESTINAL TRACT, COLLECTIVELY THE GUT MICROBIOME, CAN HAVE TREMENDOUS INFLUENCE ON NEUROBIOLOGICAL AND BEHAVIORAL PLASTICITY. PREVIOUS WORK FROM OUR GROUP AND OTHERS HAS DEMONSTRATED THAT ALTERATIONS IN THE GUT MICROBIOME CAN ALTER BEHAVIORAL RESPONSES TO OPIOIDS IN MULTIPLE PARADIGMS. ADDITIONALLY, WE HAVE PREVIOUSLY REPORTED THAT DEPLETION OF THE GUT MICROBIOME WITH ANTIBIOTICS MARKEDLY SHIFTS THE TRANSCRIPTOME OF THE NUCLEUS ACCUMBENS FOLLOWING PROLONGED MORPHINE EXPOSURE. IN THIS MANUSCRIPT WE PRESENT A COMPREHENSIVE ANALYSIS OF THE EFFECTS OF THE GUT MICROBIOME ON TRANSCRIPTIONAL REGULATION OF THE NUCLEUS ACCUMBENS FOLLOWING MORPHINE BY UTILIZING GERM-FREE, ANTIBIOTIC TREATED, AND CONTROL MICE. THIS ALLOWS FOR DETAILED UNDERSTANDING OF THE ROLE OF THE MICROBIOME IN REGULATING BASELINE TRANSCRIPTOMIC CONTROL, AS WELL AS RESPONSE TO MORPHINE. WE FIND THAT GERM-FREE STATUS LEADS TO A MARKED GENE DYSREGULATION IN A MANNER DISTINCT TO ADULT MICE TREATED WITH ANTIBIOTICS, AND THAT ALTERED GENE PATHWAYS ARE HIGHLY RELATED TO CELLULAR METABOLIC PROCESSES. THESE DATA PROVIDE ADDITIONAL INSIGHT INTO THE ROLE OF THE GUT MICROBIOME IN MODULATING BRAIN FUNCTION AND LAY A FOUNDATION FOR FURTHER STUDY IN THIS AREA. 2023 15 3404 34 HOW EPIGENETICS IMPACTS ON HUMAN DISEASES. EPIGENETICS IS A RAPIDLY GROWING FIELD OF BIOLOGY THAT STUDIES THE CHANGES IN GENE EXPRESSION THAT ARE NOT DUE TO ALTERATIONS IN THE DNA SEQUENCE BUT RATHER THE CHEMICAL MODIFICATIONS OF DNA AND ITS ASSOCIATED PROTEINS. EPIGENETIC MECHANISMS CAN PROFOUNDLY INFLUENCE GENE EXPRESSION, CELL DIFFERENTIATION, TISSUE DEVELOPMENT, AND DISEASE SUSCEPTIBILITY. UNDERSTANDING EPIGENETIC CHANGES IS ESSENTIAL TO ELUCIDATE THE MECHANISMS UNDERLYING THE INCREASINGLY RECOGNIZED ROLE OF ENVIRONMENTAL AND LIFESTYLE FACTORS IN HEALTH AND DISEASE AND THE INTERGENERATIONAL TRANSMISSION OF PHENOTYPES. RECENT STUDIES SUGGEST EPIGENETICS MAY BE CRITICAL IN VARIOUS DISEASES, FROM CARDIOVASCULAR DISEASE AND CANCER TO NEURODEVELOPMENTAL AND NEURODEGENERATIVE DISORDERS. EPIGENETIC MODIFICATIONS ARE POTENTIALLY REVERSIBLE AND COULD PROVIDE NEW THERAPEUTIC AVENUES FOR TREATING THESE DISEASES USING EPIGENETIC MODULATORS. MOREOVER, EPIGENETICS PROVIDE INSIGHT INTO DISEASE PATHOGENESIS AND BIOMARKERS FOR DISEASE DIAGNOSIS AND RISK STRATIFICATION. NEVERTHELESS, EPIGENETIC INTERVENTIONS HAVE THE POTENTIAL FOR UNINTENDED CONSEQUENCES AND MAY POTENTIALLY LEAD TO INCREASED RISKS OF UNEXPECTED OUTCOMES, SUCH AS ADVERSE DRUG REACTIONS, DEVELOPMENTAL ABNORMALITIES, AND CANCER. THEREFORE, RIGOROUS STUDIES ARE ESSENTIAL TO MINIMIZE THE RISKS ASSOCIATED WITH EPIGENETIC THERAPIES AND TO DEVELOP SAFE AND EFFECTIVE INTERVENTIONS FOR IMPROVING HUMAN HEALTH. THIS ARTICLE PROVIDES A SYNTHETIC AND HISTORICAL VIEW OF THE ORIGIN OF EPIGENETICS AND SOME OF THE MOST RELEVANT ACHIEVEMENTS. 2023 16 2541 27 EPIGENETICS IN KIDNEY DEVELOPMENT AND RENAL DISEASE. THE STUDY OF EPIGENETICS IS INTIMATELY LINKED AND INSEPARABLE FROM DEVELOPMENTAL BIOLOGY. MANY OF THE GENES THAT IMPRINT EPIGENETIC INFORMATION ON CHROMATIN FUNCTION DURING THE SPECIFICATION OF CELL LINEAGES IN THE DEVELOPING EMBRYO. THESE INCLUDE THE HISTONE METHYLTRANSFERASES AND THEIR COFACTORS OF THE POLYCOMB AND TRITHORAX GENE FAMILIES. HOW HISTONE METHYLATION IS ESTABLISHED AND WHAT REGULATES THE TISSUE AND LOCUS SPECIFICITY OF HISTONE METHYLATION IS AN EMERGING AREA OF RESEARCH. THE EMBRYONIC KIDNEY IS USED AS A MODEL TO UNDERSTAND HOW DNA-BINDING PROTEINS CAN SPECIFY CELL LINEAGES AND HOW SUCH PROTEINS INTERACT DIRECTLY WITH THE HISTONE METHYLATION MACHINERY TO GENERATE A UNIQUE EPIGENOME FOR PARTICULAR TISSUES AND CELL TYPES. IN ADULT TISSUES, HISTONE METHYLATION MARKS MUST BE MAINTAINED FOR NORMAL GENE EXPRESSION PATTERNS. IN CHRONIC AND ACUTE RENAL DISEASE, EPIGENETIC MARKS ARE BEING CHARACTERIZED AND CORRELATED WITH THE ESTABLISHMENT OF METABOLIC MEMORY, IN PART TO EXPLAIN THE PERSISTENCE OF PATHOLOGIES EVEN WHEN OPTIMAL TREATMENT MODALITIES ARE USED. THUS, THE STATE OF THE EPIGENOME IN ADULT CELLS MUST BE CONSIDERED WHEN ATTEMPTING TO ALLEVIATE OR ALTER GENE EXPRESSION PATTERNS IN DISEASE. 2015 17 5926 33 TARGETING EPIGENETIC MECHANISMS FOR CHRONIC PAIN: A VALID APPROACH FOR THE DEVELOPMENT OF NOVEL THERAPEUTICS. CHRONIC PAIN IS A MULTIFACETED AND COMPLEX CONDITION. BROADLY CLASSIFIED INTO SOMATIC, VISCERAL, OR NEUROPATHIC PAIN, IT IS POORLY MANAGED DESPITE ITS PREVALENCE. CURRENT DRUGS USED FOR THE TREATMENT OF CHRONIC PAIN ARE LIMITED BY TOLERANCE WITH LONG-TERM USE, ABUSE POTENTIAL, AND MULTIPLE ADVERSE SIDE EFFECTS. THE PERSISTENT NATURE OF PAIN SUGGESTS THAT EPIGENETIC MACHINERY MAY BE A CRITICAL FACTOR DRIVING CHRONIC PAIN. IN THIS REVIEW, WE DISCUSS THE LATEST INSIGHTS INTO EPIGENETIC PROCESSES, INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS, AND MICRORNAS, AND WE DESCRIBE THEIR INVOLVEMENT IN THE PATHOPHYSIOLOGY OF CHRONIC PAIN AND WHETHER EPIGENETIC MODIFICATIONS COULD BE APPLIED AS FUTURE THERAPEUTIC TARGETS FOR CHRONIC PAIN. WE PROVIDE EVIDENCE FROM EXPERIMENTAL MODELS AND TRANSLATIONAL RESEARCH IN HUMAN TISSUE THAT HAVE ENHANCED OUR UNDERSTANDING OF EPIGENETIC PROCESSES MEDIATING NOCICEPTION, AND WE THEN SPECULATE ON THE POTENTIAL FUTURE USE OF MORE SPECIFIC AND SELECTIVE AGENTS THAT TARGET EPIGENETIC MECHANISMS TO ATTENUATE PAIN. 2016 18 2914 41 GENE REGULATORY NETWORK UNDERLYING THE IMMORTALIZATION OF EPITHELIAL CELLS. BACKGROUND: TUMORIGENIC TRANSFORMATION OF HUMAN EPITHELIAL CELLS IN VITRO HAS BEEN DESCRIBED EXPERIMENTALLY AS THE POTENTIAL RESULT OF SPONTANEOUS IMMORTALIZATION. THIS PROCESS IS CHARACTERIZED BY A SERIES OF CELL-STATE TRANSITIONS, IN WHICH NORMAL EPITHELIAL CELLS ACQUIRE FIRST A SENESCENT STATE WHICH IS LATER SURPASSED TO ATTAIN A MESENCHYMAL STEM-LIKE PHENOTYPE WITH A POTENTIALLY TUMORIGENIC BEHAVIOR. IN THIS PAPER WE AIM TO PROVIDE A SYSTEM-LEVEL MECHANISTIC EXPLANATION TO THE EMERGENCE OF THESE CELL TYPES, AND TO THE TIME-ORDERED TRANSITION PATTERNS THAT ARE COMMON TO NEOPLASIAS OF EPITHELIAL ORIGIN. TO THIS END, WE FIRST INTEGRATE PUBLISHED FUNCTIONAL AND WELL-CURATED MOLECULAR DATA OF THE COMPONENTS AND INTERACTIONS THAT HAVE BEEN FOUND TO BE INVOLVED IN SUCH CELL STATES AND TRANSITIONS INTO A NETWORK OF 41 MOLECULAR COMPONENTS. WE THEN REDUCE THIS INITIAL NETWORK BY REMOVING SIMPLE MEDIATORS (I.E., LINEAR PATHWAYS), AND FORMALIZE THE RESULTING REGULATORY CORE INTO LOGICAL RULES THAT GOVERN THE DYNAMICS OF EACH OF THE NETWORK COMPONENTS AS A FUNCTION OF THE STATES OF ITS REGULATORS. RESULTS: COMPUTATIONAL DYNAMIC ANALYSIS SHOWS THAT OUR PROPOSED GENE REGULATORY NETWORK MODEL RECOVERS EXACTLY THREE ATTRACTORS, EACH OF THEM DEFINED BY A SPECIFIC GENE EXPRESSION PROFILE THAT CORRESPONDS TO THE EPITHELIAL, SENESCENT, AND MESENCHYMAL STEM-LIKE CELLULAR PHENOTYPES, RESPECTIVELY. WE SHOW THAT ALTHOUGH A MESENCHYMAL STEM-LIKE STATE CAN BE ATTAINED EVEN UNDER UNPERTURBED PHYSIOLOGICAL CONDITIONS, THE LIKELIHOOD OF CONVERGING TO THIS STATE IS INCREASED WHEN PRO-INFLAMMATORY CONDITIONS ARE SIMULATED, PROVIDING A SYSTEMS-LEVEL MECHANISTIC EXPLANATION FOR THE CARCINOGENIC ROLE OF CHRONIC INFLAMMATORY CONDITIONS OBSERVED IN THE CLINIC. WE ALSO FOUND THAT THE REGULATORY CORE YIELDS AN EPIGENETIC LANDSCAPE THAT RESTRICTS TEMPORAL PATTERNS OF PROGRESSION BETWEEN THE STEADY STATES, SUCH THAT RECOVERED PATTERNS RESEMBLE THE TIME-ORDERED TRANSITIONS OBSERVED DURING THE SPONTANEOUS IMMORTALIZATION OF EPITHELIAL CELLS, BOTH IN VIVO AND IN VITRO. CONCLUSION: OUR STUDY STRONGLY SUGGESTS THAT THE IN VITRO TUMORIGENIC TRANSFORMATION OF EPITHELIAL CELLS, WHICH STRONGLY CORRELATES WITH THE PATTERNS OBSERVED DURING THE PATHOLOGICAL PROGRESSION OF EPITHELIAL CARCINOGENESIS IN VIVO, EMERGES FROM UNDERLYING REGULATORY NETWORKS INVOLVED IN EPITHELIAL TRANS-DIFFERENTIATION DURING DEVELOPMENT. 2017 19 3123 36 GETTING AN INSIGHT INTO THE COMPLEXITY OF MAJOR CHRONIC INFLAMMATORY AND DEGENERATIVE DISEASES: A POTENTIAL NEW SYSTEMIC APPROACH TO THEIR TREATMENT. AS THE MODERN SOCIETY IS TROUBLED BY MULTI-FACTORIAL DISEASES, RESEARCH HAS BEEN CONDUCTED ON COMPLEX REALITIES INCLUDING CHRONIC INFLAMMATION, CANCER, OBESITY, HIV INFECTION, METABOLIC SYNDROME AND ITS DETRIMENTAL CARDIOVASCULAR COMPLICATIONS AS WELL AS DEPRESSION AND OTHER BRAIN DISORDERS. DETERIORATION OF CRUCIAL HOMEOSTATIC MECHANISMS IN SUCH DISEASES INVARIABLY RESULTS IN ACTIVATION OF INFLAMMATORY MEDIATORS, CHRONIC INFLAMMATION, LOSS IN IMMUNOLOGICAL FUNCTION, INCREASED SUSCEPTIBILITY TO DISEASES, ALTERATION OF METABOLISM, DECREASE OF ENERGY PRODUCTION AND NEURO-COGNITIVE DECLINE. REGULATION OF GENES EXPRESSION BY EPIGENETIC CODE IS THE DOMINANT MECHANISM FOR THE TRANSDUCTION OF ENVIRONMENTAL INPUTS, SUCH AS STRESS AND INFLAMMATION TO LASTING PHYSIOLOGICAL CHANGES. ACUTE AND CHRONIC STRESS DETERMINES DNA METHYLATION AND HISTONE MODIFICATIONS IN BRAIN REGIONS WHICH MAY CONTRIBUTE TO NEURO-DEGENERATIVE DISORDERS. NUCLEAR GLUCOCORTICOIDS RECEPTOR INTERACTS WITH THE EPIGENOMA RESULTING IN A CORTISOL RESISTANCE STATUS ASSOCIATED WITH A DETERIORATION OF THE METABOLIC AND IMMUNE FUNCTIONS. GONADAL STEROIDS RECEPTORS HAVE A SIMILAR CAPACITY TO PRODUCE EPIGENOMIC REORGANIZATION OF CHROMATINE STRUCTURE. EPIGENOMIC-INDUCED REDUCTION IN IMMUNE CELLS TELOMERES LENGTH HAS BEEN OBSERVED IN MANY DEGENERATIVE DISEASES, INCLUDING ALL TYPES OF CANCER. THE FINAL RESULT OF THESE EPIGENETIC ALTERATIONS IS A SERIOUS DAMAGE TO THE NEURO-ENDOCRINE-IMMUNE-METABOLIC ADAPTIVE SYSTEMS. IN THIS STUDY, WE PROPOSE A TREATMENT WITH STEM CELLS DIFFERENTIATION STAGE FACTORS TAKEN FROM ZEBRAFISH EMBRYOS WHICH ARE ABLE TO REGULATE THE GENES EXPRESSION OF NORMAL AND PATHOLOGICAL STEM CELLS IN A DIFFERENT SPECIFIC WAY. 2015 20 1686 35 DRUGGING THE PAIN EPIGENOME. MORE THAN 20% OF ADULTS WORLDWIDE EXPERIENCE DIFFERENT TYPES OF CHRONIC PAIN, WHICH ARE FREQUENTLY ASSOCIATED WITH SEVERAL COMORBIDITIES AND A DECREASE IN QUALITY OF LIFE. SEVERAL APPROVED PAINKILLERS ARE AVAILABLE, BUT CURRENT ANALGESICS ARE OFTEN HAMPERED BY INSUFFICIENT EFFICACY AND/OR SEVERE ADVERSE EFFECTS. CONSEQUENTLY, NOVEL STRATEGIES FOR SAFE, HIGHLY EFFICACIOUS TREATMENTS ARE HIGHLY DESIRABLE, PARTICULARLY FOR CHRONIC PAIN. EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS AND MICRORNAS (MIRNAS) STRONGLY AFFECT THE REGULATION OF GENE EXPRESSION, POTENTIALLY FOR LONG PERIODS OVER YEARS OR EVEN GENERATIONS, AND HAVE BEEN ASSOCIATED WITH PATHOPHYSIOLOGICAL PAIN. SEVERAL STUDIES, MOSTLY IN ANIMALS, REVEALED THAT INHIBITORS OF DNA METHYLATION, ACTIVATORS AND INHIBITORS OF HISTONE MODIFICATION AND MODULATORS OF MIRNAS REVERSE A NUMBER OF PATHOLOGICAL CHANGES IN THE PAIN EPIGENOME, WHICH ARE ASSOCIATED WITH ALTERED EXPRESSION OF PAIN-RELEVANT GENES. THIS EPIGENETIC MODULATION MIGHT THEN REDUCE THE NOCICEPTIVE RESPONSE AND PROVIDE NOVEL THERAPEUTIC OPTIONS FOR ANALGESIC THERAPY OF CHRONIC PAIN STATES. HOWEVER, A NUMBER OF CHALLENGES, SUCH AS NONSPECIFIC EFFECTS AND POOR DELIVERY TO TARGET CELLS AND TISSUES, HINDER THE RAPID DEVELOPMENT OF SUCH ANALGESICS. IN THIS REVIEW, WE CRITICALLY SUMMARIZE DATA ON EPIGENETICS AND PAIN, FOCUSING ON CHALLENGES IN CLINICAL DEVELOPMENT AS WELL AS POSSIBLE NEW APPROACHES TO THE DRUG MODULATION OF THE PAIN EPIGENOME. 2017