1 2073 103 EPIGENETIC CROSSTALK IN CHRONIC INFECTION WITH HIV-1. HUMAN IMMUNODEFICIENCY VIRUS 1 (HIV-1) REPLICATES THROUGH THE INTEGRATION OF ITS VIRAL DNA INTO THE GENOME OF HUMAN IMMUNE TARGET CELLS. CHRONICALLY INFECTED INDIVIDUALS THUS CARRY A GENOMIC BURDEN OF VIRUS-DERIVED SEQUENCES THAT PERSISTS THROUGH ANTIRETROVIRAL THERAPY. THIS BURDEN CONSISTS OF A SMALL FRACTION OF INTACT, BUT TRANSCRIPTIONALLY SILENCED, I.E. LATENT, VIRAL GENOMES AND A DOMINANT FRACTION OF DEFECTIVE SEQUENCES. REMARKABLY, ALL VIRAL-DERIVED SEQUENCES ARE SUBJECT TO INTERACTION WITH HOST CELLULAR PHYSIOLOGY AT VARIOUS LEVELS. IN THIS REVIEW, WE FOCUS ON EPIGENETIC ASPECTS OF THIS INTERACTION. WE PROVIDE A COMPREHENSIVE OVERVIEW OF HOW EPIGENETIC MECHANISMS CONTRIBUTE TO ESTABLISHMENT AND MAINTENANCE OF HIV-1 GENE REPRESSION DURING LATENCY. WE FURTHERMORE SUMMARIZE FINDINGS INDICATING THAT HIV-1 INFECTION LEADS TO CHANGES IN THE EPIGENOME OF TARGET AND BYSTANDER IMMUNE CELLS. FINALLY, WE DISCUSS HOW AN IMPROVED UNDERSTANDING OF EPIGENETIC FEATURES AND MECHANISMS INVOLVED IN HIV-1 INFECTION COULD BE EXPLOITED FOR CLINICAL USE. 2020 2 3379 34 HIV LATENCY AND THE NONCODING RNA THERAPEUTIC LANDSCAPE. THE HUMAN IMMUNODEFICIENCY VIRUS (HIV) BELONGS TO THE SUBFAMILY OF LENTIVIRUSES THAT ARE CHARACTERIZED BY LONG INCUBATION PERIODS AND CHRONIC, PERSISTENT INFECTION. THE VIRUS INTEGRATES INTO THE GENOME OF INFECTED CD4+ CELLS AND, IN A SUBPOPULATION OF CELLS, ADOPTS A TRANSCRIPTIONALLY SILENT STATE, A PROCESS REFERRED TO A VIRAL LATENCY. THIS PROPERTY MAKES IT EXCEEDINGLY DIFFICULT TO THERAPEUTICALLY TARGET THE VIRUS AND ERADICATE INFECTION. IF LEFT UNTREATED, THE INEXORABLE DEMISE OF THE INFECTED INDIVIDUAL'S IMMUNE SYSTEM ENSUES, A CAUSAL RESULT OF ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS). LATENTLY INFECTED CELLS PROVIDE A RESERVOIR THAT MAINTAINS VIRAL INFECTION INDEFINITELY. IN THIS CHAPTER WE EXPLORE THE ROLE OF NONCODING RNAS IN HIV INFECTION AND IN THE ESTABLISHMENT AND MAINTENANCE OF VIRAL LATENCY. BOTH SHORT AND LONG NONCODING RNAS ARE ENDOGENOUS MODULATORS OF EPIGENETIC REGULATION IN HUMAN CELLS AND PLAY AN ACTIVE ROLE IN GENE EXPRESSION. LASTLY, WE EXPLORE THERAPEUTIC MODALITIES BASED ON EXPRESSED RNAS THAT ARE CAPABLE OF COUNTERING INFECTION, TRANSCRIPTIONALLY REGULATING THE VIRUS, AND SUPPRESSING OR ACTIVATING THE LATENT STATE. 2015 3 6706 34 VIRAL GENE PRODUCTS ACTIVELY PROMOTE LATENT INFECTION BY EPIGENETIC SILENCING MECHANISMS. MANY VIRUSES UNDERGO AN ACUTE INFECTION IN THE HOST ORGANISM AND THEN ARE CLEARED BY THE ENSUING HOST IMMUNE RESPONSE, BUT OTHER VIRUSES ESTABLISH A PERSISTENT INFECTION INVOLVING A LATENT INFECTION OR A CHRONIC INFECTION. LATENT INFECTION BY THE HERPESVIRUSES OR HUMAN IMMUNODEFICIENCY VIRUS INVOLVES EPIGENETIC SILENCING OF THE DNA GENOME OR PROVIRAL GENOME, RESPECTIVELY. LATENT INFECTION WAS PREVIOUSLY THOUGHT TO BE A DEFAULT PATHWAY RESULTING FROM INFECTION OF A NONPERMISSIVE CELL, BUT RECENT STUDIES HAVE SHOWN THAT VIRAL GENE PRODUCTS CAN PROMOTE EPIGENETIC SILENCING AND LATENT INFECTION. THIS REVIEW WILL SUMMARIZE THE VIRAL GENE PRODUCTS THAT HAVE BEEN SHOWN TO PROMOTE EPIGENETIC SILENCING OF THE GENOMES AND THEIR POTENTIAL FOR THERAPEUTICS TO TARGET THESE VIRAL GENE PRODUCTS AND DISRUPT OR LOCK IN LATENT INFECTION. 2017 4 6044 35 THE COMPLEX BIOLOGY OF HUMAN CYTOMEGALOVIRUS LATENCY. WHILE MANY VIRAL INFECTIONS ARE LIMITED AND EVENTUALLY RESOLVED BY THE HOST IMMUNE RESPONSE OR BY DEATH OF THE HOST, OTHER VIRUSES ESTABLISH LONG-TERM RELATIONSHIPS WITH THE HOST BY WAY OF A PERSISTENT INFECTION, THAT RANGE FROM CHRONIC VIRUSES THAT MAY BE EVENTUALLY CLEARED TO THOSE THAT ESTABLISH LIFE-LONG PERSISTENT OR LATENT INFECTION. VIRUSES INFECTING HOSTS FROM BACTERIA TO HUMANS ESTABLISH QUIESCENT INFECTIONS THAT MUST BE REACTIVATED TO PRODUCE PROGENY. FOR MAMMALIAN VIRUSES, MOST NOTABLY HERPESVIRUSES, THIS QUIESCENT MAINTENANCE OF VIRAL GENOMES IN THE ABSENCE OF VIRUS REPLICATION IS REFERRED TO AS LATENCY. THE LATENT STRATEGY ALLOWS THE VIRUS TO PERSIST QUIESCENTLY WITHIN A SINGLE HOST UNTIL CONDITIONS INDICATE A NEED TO REACTIVATE TO REACH A NEW HOST OR, TO RE-SEED A RESERVOIR WITHIN THE HOST. HERE, I REVIEW COMMON THEMES IN VIRAL STRATEGIES TO REGULATE THE LATENT CYCLE AND REACTIVATE FROM IT RANGING FROM BACTERIOPHAGE TO HERPESVIRUSES WITH A FOCUS ON HUMAN CYTOMEGALOVIRUS (HCMV). THEMES CENTRAL TO HERPESVIRUS LATENCY INCLUDE, EPIGENETIC REPRESSION OF VIRAL GENE EXPRESSION AND MECHANISMS TO REGULATE HOST SIGNALING AND SURVIVAL. CRITICAL TO THE SUCCESS OF A LATENT PROGRAM ARE MECHANISMS BY WHICH THE VIRUS CAN "SENSE" FLUCTUATIONS IN HOST BIOLOGY (WITHIN THE HOST) OR ENVIRONMENT (OUTSIDE THE HOST) AND MAKE APPROPRIATE "DECISIONS" TO MAINTAIN LATENCY OR RE-INITIATE THE REPLICATIVE PROGRAM. THE SIGNALS OR ENVIRONMENTS THAT INDICATE THE ESTABLISHMENT OF A LATENT STATE, THE VERY NATURE OF THE LATENT STATE, AS WELL AS THE SIGNALS DRIVING REACTIVATION HAVE BEEN TOPICS OF INTENSE STUDY FROM BACTERIOPHAGE TO HUMAN VIRUSES, AS THESE QUESTIONS ENCOMPASS THE HEIGHT OF COMPLEXITY IN VIRUS-HOST INTERACTIONS-WHERE THE HOST AND THE VIRUS COEXIST. 2022 5 2399 29 EPIGENETIC REPROGRAMMING OF HOST GENES IN VIRAL AND MICROBIAL PATHOGENESIS. ONE OF THE KEY QUESTIONS IN THE STUDY OF MAMMALIAN GENE REGULATION IS HOW EPIGENETIC METHYLATION PATTERNS ON HISTONES AND DNA ARE INITIATED AND ESTABLISHED. THESE STABLE, HERITABLE, COVALENT MODIFICATIONS ARE LARGELY ASSOCIATED WITH THE REPRESSION OR SILENCING OF GENE TRANSCRIPTION, AND WHEN DEREGULATED CAN BE INVOLVED IN THE DEVELOPMENT OF HUMAN DISEASES SUCH AS CANCER. THIS ARTICLE REVIEWS EXAMPLES OF VIRUSES AND BACTERIA KNOWN OR THOUGHT TO INDUCE EPIGENETIC CHANGES IN HOST CELLS, AND HOW THIS MIGHT CONTRIBUTE TO DISEASE. THE HERITABLE NATURE OF THESE PROCESSES IN GENE REGULATION SUGGESTS THAT THEY COULD PLAY IMPORTANT ROLES IN CHRONIC DISEASES ASSOCIATED WITH MICROBIAL PERSISTENCE; THEY MIGHT ALSO EXPLAIN SO-CALLED 'HIT-AND-RUN' PHENOMENA IN INFECTIOUS DISEASE PATHOGENESIS. 2010 6 2600 30 EPIGENETICS REGULATION DURING VIRUS-HOST INTERACTION AND THEIR EFFECTS ON THE VIRUS AND HOST CELL. EPIGENETICS, A FIELD OF STUDY FOCUSED ON CELLULAR GENE REGULATION INDEPENDENT OF DNA SEQUENCE ALTERATIONS, ENCOMPASSES DNA METHYLATION, HISTONE MODIFICATION AND MICRORNA MODIFICATION. EPIGENETICS PROCESSES PLAY A PIVOTAL ROLE IN GOVERNING THE LIFE CYCLES OF VIRUSES, ENABLING THEIR TRANSMISSION, PERSISTENCE, AND MAINTENANCE WITH IN HOST ORGANISMS. THIS REVIEW EXAMINES THE EPIGENETICS REGULATION OF DIVERSE VIRUS INCLUDING ORTHOMOXYVIRUSES, CORONAVIRUS, RETROVIRIDAE, MONONEGAVIRALES, AND POXVIRUSES AMONG OTHERS. THE INVESTIGATION ENCOMPASSES TEN REPRESENTATIVE VIRUSES FROM THESE FAMILIES. DETAILED EXPLORATION OF THE EPIGENETIC MECHANISMS UNDERLYING EACH VIRUS TYPE, INVOLVING MIRNA MODIFICATION, HISTONE MODIFICATION AND DNA METHYLATION, SHEDS LIGHT ON THE INTRICATE AND MULTIFACETED EPIGENETIC INTERPLAY BETWEEN VIRUSES AND THEIR HOSTS. FURTHERMORE, THIS REVIEW INVESTIGATES THE INFLUENCE OF THESE EPIGENETIC PROCESSES ON INFECTION CYCLES, EMPHASIZING THE UTILIZATION OF EPIGENETICS BY VIRUSES SUCH AS EPSTEIN-BARR VIRUS AND HUMAN IMMUNODEFICIENCY VIRUS (HIV) TO REGULATE GENE EXPRESSION DURING CHRONIC OR LATENT INFECTIONS, CONTROL LATENCY, AND TRANSITION TO LYTIC INFECTION. FINALLY, THE PAPER EXPLORES THE NOVEL TREATMENTS POSSIBILITIES STEMMING FROM THIS EPIGENETIC UNDERSTANDING. 2023 7 6710 27 VIRAL-INDUCED HUMAN CARCINOGENESIS: AN OXIDATIVE STRESS PERSPECTIVE. ONCOGENIC TRANSFORMATION OCCURS VIA MANY DIFFERENT MECHANISMS. ALTERATIONS IN THE EXPRESSION OF CERTAIN KEY GENES (ONCOGENES AND/OR TUMOR SUPPRESSOR GENES) CONTRIBUTE TO THE DEVELOPMENT OF THE TUMORIGENIC STATE OF UNCONTROLLED CELL PROLIFERATION. TUMOR VIRUSES' STUDIES HAVE CONTRIBUTED OVER THE LAST 2 DECADES SIGNIFICANTLY IN CANCER ETIOLOGY, FIRST BY PROVIDING VALUABLE INFORMATION ON THE MECHANISMS AND DISSECTION OF CELL SIGNALING AND GROWTH CONTROL PATHWAYS AND SECOND BY BEING CAUSATIVE AGENTS OF HUMAN NEOPLASIA. VIRUSES CONTRIBUTE TO THE DEVELOPMENT OF THE NEOPLASTIC STATE THROUGH MANY MECHANISMS: INACTIVATION OF TUMOR SUPPRESSOR GENES, HYPERSTIMULATION OF CELLULAR PROTO-ONCOGENE TRANSCRIPTION, OR BY VIRAL PROTEIN INTERFERENCE WITH THE CELLULAR TRANSCRIPTION, SIGNAL TRANSDUCTION, DNA REPAIR AND APOPTOSIS PATHWAYS AND INDUCTION OF CHRONIC OXIDATIVE STRESS. ON THE OTHER HAND, ONLY RECENTLY RESEARCH HAS PROVIDED EVIDENCE OF THE EPIGENETIC PATHWAY INVOLVEMENT AND ESPECIALLY THE DNA METHYLATION MACHINERY. TO THIS END, BOTH HYPOMETHYLATION-INDUCED ONCOGENIC ACTIVATION AND/OR HYPERMETHYLATION-INDUCED TUMOR SUPPRESSOR GENE SILENCING ARE LINKED WITH VIRAL-INDUCED CARCINOGENESIS. IN THIS REVIEW, WE DISCUSS THE CURRENT STATUS OF KNOWLEDGE ON VIRAL-ASSOCIATED CARCINOGENESIS WITH EMPHASIS ON THE MECHANISMS OF OXIDATIVE STRESS AND DNA DAMAGE INDUCTION IN HUMANS BY VIRUSES AS WELL AS IMPLICATIONS IN CANCER TREATMENT. 2010 8 4434 25 MOLECULAR DISSECTION OF CD8(+) T-CELL DYSFUNCTION. CHRONIC VIRAL INFECTIONS AND CANCER OFTEN LEAD TO THE EMERGENCE OF DYSFUNCTIONAL OR 'EXHAUSTED' CD8(+) T CELLS, AND THE RESTORATION OF THEIR FUNCTIONS IS CURRENTLY THE FOCUS OF THERAPEUTIC INTERVENTIONS. IN THIS REVIEW, WE DETAIL RECENT ADVANCES IN THE ANNOTATION OF THE GENE MODULES AND THE EPIGENETIC LANDSCAPE ASSOCIATED WITH T-CELL DYSFUNCTION. TOGETHER WITH ANALYSIS OF SINGLE-CELL TRANSCRIPTOMES, THESE FINDINGS HAVE ENABLED A DEEPER AND MORE PRECISE UNDERSTANDING OF THE TRANSCRIPTIONAL MECHANISMS THAT INDUCE AND MAINTAIN THE DYSFUNCTIONAL STATE AND HIGHLIGHT THE HETEROGENEITY OF CD8(+) T-CELL PHENOTYPES PRESENT IN CHRONICALLY INFLAMED TISSUE. WE DISCUSS THE RELEVANCE OF THESE FINDINGS FOR UNDERSTANDING THE TRANSCRIPTIONAL AND SPATIAL REGULATION OF DYSFUNCTIONAL T CELLS AND FOR THE DESIGN OF THERAPEUTICS. 2017 9 3703 23 INFLAMMATORY SIGNALLING AS MEDIATOR OF EPIGENETIC MODULATION IN TISSUE-SPECIFIC CHRONIC INFLAMMATION. RECENT SUCCESSES OF THERAPEUTIC INTERVENTION IN CHRONIC INFLAMMATORY DISEASES USING EPIGENETIC MODIFIERS SUCH AS HISTONE DEACETYLASE INHIBITORS AND INHIBITORS OF DNA METHYLATION SUGGEST THAT EPIGENETIC REPROGRAMMING PLAYS A ROLE IN THE AETIOLOGY OF THESE DISEASES. THE EPIGENETIC SIGNATURE OF A GIVEN IMMUNE CELL IS REFLECTED IN THE HISTORY OF MODIFICATIONS FROM DIFFERENT SIGNALS THE CELL HAS BEEN SUBJECTED TO DURING DIFFERENTIATION. LIKE OTHER CELLS, DIFFERENTIATING IMMUNE CELLS ARE DEPENDENT ON A COMPLEX COMBINATION OF INTER- AND INTRACELL SIGNALLING AS WELL AS TRANSCRIPTION MACHINERIES TO MODULATE THEIR EPIGENOMES IN ORDER TO MEDIATE DIFFERENTIATION. DESPITE EXTENSIVE RESEARCH INTO THESE PROCESSES, THE LINK BETWEEN CELLULAR SIGNALLING AND EPIGENETIC MODULATION REMAINS POORLY UNDERSTOOD. HERE, WE REVIEW RECENT PROGRESS AND DISCUSS KEY FACTORS DRIVING EPIGENETIC MODULATION IN CHRONIC INFLAMMATION. 2009 10 2663 28 EPSTEIN-BARR VIRUS PROMOTES B CELL LYMPHOMAS BY MANIPULATING THE HOST EPIGENETIC MACHINERY. DURING THE PAST DECADE, THE RAPID DEVELOPMENT OF HIGH-THROUGHPUT NEXT-GENERATION SEQUENCING TECHNOLOGIES HAS SIGNIFICANTLY REINFORCED OUR UNDERSTANDING OF THE ROLE OF EPIGENETICS IN HEALTH AND DISEASE. ALTERED FUNCTIONS OF EPIGENETIC MODIFIERS LEAD TO THE DISRUPTION OF THE HOST EPIGENOME, ULTIMATELY INDUCING CARCINOGENESIS AND DISEASE PROGRESSION. EPSTEIN-BARR VIRUS (EBV) IS AN ENDEMIC HERPESVIRUS THAT IS ASSOCIATED WITH SEVERAL MALIGNANT TUMOURS, INCLUDING B-CELL RELATED LYMPHOMAS. IN EBV-INFECTED CELLS, THE EPIGENOMIC LANDSCAPE IS EXTENSIVELY RESHAPED BY VIRAL ONCOPROTEINS, WHICH DIRECTLY INTERACT WITH EPIGENETIC MODIFIERS AND MODULATE THEIR FUNCTION. THIS PROCESS IS FUNDAMENTAL FOR THE EBV LIFE CYCLE, PARTICULARLY FOR THE ESTABLISHMENT AND MAINTENANCE OF LATENCY IN B CELLS; HOWEVER, THE ALTERATION OF THE HOST EPIGENETIC MACHINERY ALSO CONTRIBUTES TO THE DYSREGULATED EXPRESSION OF SEVERAL CELLULAR GENES, INCLUDING TUMOUR SUPPRESSOR GENES, WHICH CAN DRIVE LYMPHOMA DEVELOPMENT. THIS REVIEW OUTLINES THE MOLECULAR MECHANISMS UNDERLYING THE EPIGENETIC MANIPULATION INDUCED BY EBV THAT LEAD TO TRANSFORMED B CELLS, AS WELL AS NOVEL THERAPEUTIC INTERVENTIONS TO TARGET EBV-ASSOCIATED B-CELL LYMPHOMAS. 2020 11 3799 25 INTERPLAY BETWEEN INFLAMMATION AND EPIGENETIC CHANGES IN CANCER. IMMUNE RESPONSES CAN SUPPRESS TUMORIGENESIS, BUT ALSO CONTRIBUTE TO CANCER INITIATION AND PROGRESSION SUGGESTING A COMPLEX INTERACTION BETWEEN THE IMMUNE SYSTEM AND CANCER. EPIGENETIC ALTERATIONS, WHICH ARE HERITABLE CHANGES IN GENE EXPRESSION WITHOUT CHANGES TO THE DNA SEQUENCE, ALSO PLAY A ROLE IN CARCINOGENESIS THROUGH SILENCING EXPRESSION OF TUMOR SUPPRESSOR GENES AND ACTIVATING ONCOGENIC SIGNALING. INTERESTINGLY, EPITHELIAL CELLS AT SITES OF CHRONIC INFLAMMATION UNDERGO DNA METHYLATION ALTERATIONS THAT ARE SIMILAR TO THOSE PRESENT IN CANCER CELLS, SUGGESTING THAT INFLAMMATION MAY INITIATE CANCER-SPECIFIC EPIGENETIC CHANGES IN EPITHELIAL CELLS. FURTHERMORE, EPIGENETIC CHANGES OCCUR DURING IMMUNE CELL DIFFERENTIATION AND PARTICIPATE IN REGULATING THE IMMUNE RESPONSE, INCLUDING THE REGULATION OF INFLAMMATORY CYTOKINES. CANCER CELLS UTILIZE EPIGENETIC SILENCING OF IMMUNE-RELATED GENES TO EVADE THE IMMUNE RESPONSE. THIS CHAPTER WILL DETAIL THE INTERACTIONS BETWEEN INFLAMMATION AND EPIGENETICS IN TUMOR INITIATION, PROMOTION, AND IMMUNE EVASION AND HOW THESE CONNECTIONS ARE BEING LEVERAGED IN CANCER PREVENTION AND TREATMENT. 2016 12 1057 28 CLINICAL MANIFESTATIONS AND EPIGENETIC REGULATION OF ORAL HERPESVIRUS INFECTIONS. THE ORAL CAVITY IS OFTEN THE FIRST SITE WHERE VIRUSES INTERACT WITH THE HUMAN BODY. THE ORAL EPITHELIUM IS A MAJOR SITE OF VIRAL ENTRY, REPLICATION AND SPREAD TO OTHER CELL TYPES, WHERE CHRONIC INFECTION CAN BE ESTABLISHED. IN ADDITION, SALIVA HAS BEEN SHOWN AS A PRIMARY ROUTE OF PERSON-TO-PERSON TRANSMISSION FOR MANY VIRUSES. FROM A CLINICAL PERSPECTIVE, VIRAL INFECTION CAN LEAD TO SEVERAL ORAL MANIFESTATIONS, RANGING FROM COMMON INTRAORAL LESIONS TO TUMORS. DESPITE THE CLINICAL AND BIOLOGICAL RELEVANCE OF INITIAL ORAL INFECTION, LITTLE IS KNOWN ABOUT THE MECHANISM OF REGULATION OF THE VIRAL LIFE CYCLE IN THE ORAL CAVITY. SEVERAL VIRUSES UTILIZE HOST EPIGENETIC MACHINERY TO PROMOTE THEIR OWN LIFE CYCLE. IMPORTANTLY, VIRAL HIJACKING OF HOST CHROMATIN-MODIFYING ENZYMES CAN ALSO LEAD TO THE DYSREGULATION OF HOST FACTORS AND IN THE CASE OF ONCOGENIC VIRUSES MAY ULTIMATELY PLAY A ROLE IN PROMOTING TUMORIGENESIS. GIVEN THE KNOWN ROLES OF EPIGENETIC REGULATION OF VIRAL INFECTION, EPIGENETIC-TARGETED ANTIVIRAL THERAPY HAS BEEN RECENTLY EXPLORED AS A THERAPEUTIC OPTION FOR CHRONIC VIRAL INFECTION. IN THIS REVIEW, WE HIGHLIGHT THREE HERPESVIRUSES WITH KNOWN ROLES IN ORAL INFECTION, INCLUDING HERPES SIMPLEX VIRUS TYPE 1, EPSTEIN-BARR VIRUS AND KAPOSI'S SARCOMA-ASSOCIATED HERPESVIRUS. WE FOCUS ON THE RESPECTIVE ORAL CLINICAL MANIFESTATIONS OF THESE VIRUSES AND THEIR EPIGENETIC REGULATION, WITH A SPECIFIC EMPHASIS ON THE VIRAL LIFE CYCLE IN THE ORAL EPITHELIUM. 2021 13 6771 25 [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 14 2854 25 FROM HEPATITIS TO HEPATOCELLULAR CARCINOMA: A PROPOSED MODEL FOR CROSS-TALK BETWEEN INFLAMMATION AND EPIGENETIC MECHANISMS. INFLAMMATION REPRESENTS THE BODY'S NATURAL RESPONSE TO TISSUE DAMAGE; HOWEVER, CHRONIC INFLAMMATION MAY ACTIVATE CELL PROLIFERATION AND INDUCE DEREGULATION OF CELL DEATH IN AFFECTED TISSUES. CHRONIC INFLAMMATION IS AN IMPORTANT FACTOR IN THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC), ALTHOUGH THE PRECISE UNDERLYING MECHANISM REMAINS UNKNOWN. EPIGENETIC EVENTS, WHICH ARE CONSIDERED KEY MECHANISMS IN THE REGULATION OF GENE ACTIVITY STATES, ARE ALSO COMMONLY DEREGULATED IN HCC. HERE, WE REVIEW THE EVIDENCE THAT CHRONIC INFLAMMATION MIGHT DEREGULATE EPIGENETIC PROCESSES, THUS PROMOTING ONCOGENIC TRANSFORMATION, AND WE PROPOSE A WORKING HYPOTHESIS THAT EPIGENETIC DEREGULATION IS AN UNDERLYING MECHANISM BY WHICH INFLAMMATION MIGHT PROMOTE HCC DEVELOPMENT. IN THIS SCENARIO, DIFFERENT COMPONENTS OF THE INFLAMMATORY RESPONSE MIGHT DIRECTLY AND INDIRECTLY INDUCE CHANGES IN EPIGENETIC MACHINERIES ('EPIGENETIC SWITCH'), INCLUDING THOSE INVOLVED IN SETTING AND PROPAGATING NORMAL PATTERNS OF DNA METHYLATION, HISTONE MODIFICATIONS AND NON-CODING RNAS IN HEPATOCYTES. WE DISCUSS THE POSSIBILITY THAT SELF-REINFORCING CROSS-TALK BETWEEN INFLAMMATION AND EPIGENETIC MECHANISMS MIGHT AMPLIFY INFLAMMATORY SIGNALS AND MAINTAIN A CHRONIC STATE OF INFLAMMATION CULMINATING IN CANCER DEVELOPMENT. THE POTENTIAL ROLE OF INFLAMMATION-EPIGENOME INTERACTIONS IN THE EMERGENCE AND MAINTENANCE OF CANCER STEM CELLS IS ALSO DISCUSSED. 2012 15 5325 23 PULMONARY PATHOGEN-INDUCED EPIGENETIC MODIFICATIONS. EPIGENETICS GENERALLY INVOLVES GENETIC CONTROL BY FACTORS OTHER THAN OUR OWN DNA SEQUENCE. RECENT RESEARCH HAS FOCUSED ON DELINEATING THE MECHANISMS OF TWO MAJOR EPIGENETIC PHENOMENA: DNA METHYLATION AND HISTONE MODIFICATION. AS EPIGENETICS INVOLVES MANY CELLULAR PROCESSES, IT IS NO SURPRISE THAT IT CAN ALSO INFLUENCE DISEASE-ASSOCIATED GENE EXPRESSION. A DIRECT LINK BETWEEN RESPIRATORY INFECTIONS, HOST CELL EPIGENETIC REGULATIONS, AND CHRONIC LUNG DISEASES IS STILL UNKNOWN. RECENT STUDIES HAVE REVEALED BACTERIUM- OR VIRUS-INDUCED EPIGENETIC CHANGES IN THE HOST CELLS. IN THIS REVIEW, WE FOCUSED ON RESPIRATORY PATHOGENS (VIRUSES, BACTERIA, AND FUNGI) INDUCED EPIGENETIC MODULATIONS (DNA METHYLATION AND HISTONE MODIFICATION) THAT MAY CONTRIBUTE TO LUNG DISEASE PATHOPHYSIOLOGY BY PROMOTING HOST DEFENSE OR ALLOWING PATHOGEN PERSISTENCE. 2023 16 4849 32 OPIOID-MEDIATED HIV-1 IMMUNOPATHOGENESIS. DESPITE THE ABILITY OF COMBINATION ANTIRETROVIRAL THERAPY TO DRAMATICALLY SUPPRESS VIREMIA, THE BRAIN CONTINUES TO BE A RESERVOIR OF HIV-1 LOW-LEVEL REPLICATION. ADDING FURTHER COMPLEXITY TO THIS IS THE COMORBIDITY OF DRUG ABUSE WITH HIV-1 ASSOCIATED NEUROCOGNITIVE DISORDERS AND NEUROHIV. AMONG SEVERAL ABUSED DRUGS, THE USE OF OPIATES IS HIGHLY PREVALENT IN HIV-1 INFECTED INDIVIDUALS, BOTH AS AN ABUSED DRUG AS WELL AS FOR PAIN MANAGEMENT. OPIOIDS AND THEIR RECEPTORS HAVE ATTAINED NOTABLE ATTENTION OWING TO THEIR ABILITY TO MODULATE IMMUNE FUNCTIONS, IN TURN, IMPACTING DISEASE PROGRESSION. VARIOUS CELL CULTURE, ANIMAL AND HUMAN STUDIES HAVE IMPLICATED THE ROLE OF OPIOIDS AND THEIR RECEPTORS IN MODULATING VIRAL REPLICATION AND VIRUS-MEDIATED PATHOLOGY BOTH POSITIVELY AND NEGATIVELY. FURTHER, THE COMBINATORIAL EFFECTS OF HIV-1/HIV-1 PROTEINS AND MORPHINE HAVE DEMONSTRATED ACTIVATION OF INFLAMMATORY SIGNALING IN THE HOST SYSTEM. HEREIN, WE SUMMARIZED THE CURRENT KNOWLEDGE ON THE ROLE OF OPIOIDS ON PERIPHERAL IMMUNOPATHOGENESIS, VIRAL IMMUNOPATHOGENESIS, EPIGENETIC PROFILES OF THE HOST AND VIRAL GENOME, NEUROPATHOGENESIS OF SIV/SHIV-INFECTED NON-HUMAN PRIMATES, BLOOD-BRAIN-BARRIER, HIV-1 VIRAL LATENCY, AND VIRAL REBOUND. OVERALL, THIS REVIEW PROVIDES RECENT INSIGHTS INTO THE ROLE OF OPIOIDS IN HIV-1 IMMUNOPATHOGENESIS. GRAPHICAL ABSTRACT. 2020 17 2036 23 EPIGENETIC CHANGES OF THE IMMUNE SYSTEM WITH ROLE IN TUMOR DEVELOPMENT. TUMOR DEVELOPMENT IS CLOSELY RELATED TO CHRONIC INFLAMMATION AND TO EVASION OF IMMUNE DEFENSE MECHANISMS BY NEOPLASTIC CELLS. THE MEDIATORS OF THE INFLAMMATORY PROCESS AS WELL AS PROTEINS INVOLVED IN IMMUNE RESPONSE OR IMMUNE RESPONSE EVASION CAN BE SUBJECT TO VARIOUS EPIGENETIC CHANGES SUCH AS METHYLATION, ACETYLATION, OR PHOSPHORYLATION. SOME OF THESE, SUCH AS CYTOKINE SUPPRESSORS, ARE UNDERGOING REPRESSION THROUGH EPIGENETIC CHANGES, AND OTHERS SUCH AS CYTOKINES OR CHEMOKINES ARE UNDERGOING ACTIVATION THROUGH EPIGENETIC CHANGES, BOTH MODIFICATIONS HAVING AS A RESULT TUMOR PROGRESSION. THE ACTIVATING CHANGES CAN AFFECT THE RECEPTOR MOLECULES INVOLVED IN IMMUNE RESPONSE AND THESE PROMOTE INFLAMMATION AND SUBSEQUENTLY TUMOR DEVELOPMENT WHILE THE INACTIVATING CHANGES SEEM TO BE RELATED TO THE TUMOR REGRESSION PROCESS. THE PROTEINS INVOLVED IN ANTIGEN PRESENTATION, AND, THEREFORE IN IMMUNE RESPONSE ESCAPE, SUCH AS CLASSICAL HLA PROTEINS AND RELATED APM (ANTIGEN PRESENTATION MACHINERY) WITH THEIR EPIGENETIC CHANGES CONTRIBUTE TO THE TUMOR DEVELOPMENT PROCESS, EITHER TO TUMOR PROGRESSION OR REGRESSION, DEPENDING ON THE IMMUNE EFFECTOR CELLS THAT ARE IN PLAY. 2018 18 1283 23 DECIPHERING THE EPIGENETIC CODE OF T LYMPHOCYTES. THE MULTIPLE LINEAGES AND DIFFERENTIATION STATES THAT CONSTITUTE THE T-CELL COMPARTMENT ALL DERIVE FROM A COMMON THYMIC PRECURSOR. THESE DISTINCT TRANSCRIPTIONAL STATES ARE MAINTAINED BOTH IN TIME AND AFTER MULTIPLE ROUNDS OF CELL DIVISION BY THE CONCERTED ACTIONS OF A SMALL SET OF LINEAGE-DEFINING TRANSCRIPTION FACTORS THAT ACT IN CONJUNCTION WITH A SUITE OF CHROMATIN-MODIFYING ENZYMES TO ACTIVATE, REPRESS, AND FINE-TUNE GENE EXPRESSION. THESE CHROMATIN MODIFICATIONS COLLECTIVELY PROVIDE AN EPIGENETIC CODE THAT ALLOWS THE STABLE AND HERITABLE MAINTENANCE OF THE T-CELL PHENOTYPE. RECENTLY, IT HAS BECOME APPARENT THAT THE EPIGENETIC CODE REPRESENTS A THERAPEUTIC TARGET FOR A VARIETY OF IMMUNE CELL DISORDERS, INCLUDING LYMPHOMA AND ACUTE AND CHRONIC INFLAMMATORY DISEASES. HERE, WE REVIEW THE RECENT ADVANCES IN EPIGENETIC REGULATION OF GENE EXPRESSION, PARTICULARLY AS IT RELATES TO THE T-CELL DIFFERENTIATION AND FUNCTION. 2014 19 733 27 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 20 6533 29 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