1 188 177 ACETYL TRANSFERASE EP300 DEFICIENCY LEADS TO CHRONIC REPLICATION STRESS MEDIATED BY DEFECTIVE FORK PROTECTION AT STALLED REPLICATION FORKS. MUTATIONS IN THE EPIGENETIC REGULATOR AND GLOBAL TRANSCRIPTIONAL ACTIVATOR, E1A BINDING PROTEIN (EP300), IS BEING INCREASINGLY REPORTED IN AGGRESSIVE HEMATOLOGICAL MALIGNANCIES INCLUDING ADULT T-CELL LEUKEMIA/LYMPHOMA (ATLL). HOWEVER, THE MECHANISTIC CONTRIBUTION OF EP300 DYSREGULATION TO CANCER INITIATION AND PROGRESSION ARE CURRENTLY UNKNOWN. INDEPENDENT INHIBITION OF EP300 IN HUMAN CELLS RESULTS IN THE DIFFERENTIAL EXPRESSION OF GENES INVOLVED IN REGULATING THE CELL CYCLE, DNA REPLICATION AND DNA DAMAGE RESPONSE. NEVERTHELESS, SPECIFIC FUNCTION PLAYED BY EP300 IN DNA REPLICATION INITIATION, PROGRESSION AND REPLICATION FORK INTEGRITY HAS NOT BEEN STUDIED. HERE, USING ATLL CELLS AS A MODEL TO STUDY EP300 DEFICIENCY AND AN P300-SELECTIVE PROTAC DEGRADER, DEGRADER AS A PHARMACOLOGIC TOOL, WE REVEAL THAT EP300-MUTATED CELLS DISPLAY PROLONGED CELL CYCLE KINETICS, DUE TO PRONOUNCED DYSREGULATIONS IN DNA REPLICATION DYNAMICS LEADING TO PERSISTENT GENOMIC INSTABILITY. ABERRANT DNA REPLICATION IN EP300-MUTATED CELLS IS CHARACTERIZED BY ELEVATED REPLICATION ORIGIN FIRING DUE TO INCREASED REPLISOME PAUSING GENOME-WIDE. WE DEMONSTRATE THAT EP300 DEFICIENCY RESULTS IN NUCLEOLYTIC DEGRADATION OF NASCENTLY SYNTHESIZED DNA AT STALLED FORKS DUE TO A PROMINENT DEFECT IN FORK STABILIZATION AND PROTECTION. THIS IN TURN RESULTS IN THE ACCUMULATION OF SINGLE STRANDED DNA GAPS AT COLLAPSED REPLICATION FORKS, IN EP300-DEFICIENT CELLS. INHIBITION OF MRE11 NUCLEASE RESCUES THE SSDNA ACCUMULATION INDICATING A DYSREGULATION IN DOWNSTREAM MECHANISMS THAT RESTRAIN NUCLEASE ACTIVITY AT STALLED FORKS. IMPORTANTLY, WE FIND THAT THE ABSENCE OF EP300 RESULTS IN DECREASED EXPRESSION OF BRCA2 PROTEIN EXPRESSION AND A DEPENDENCY ON POLD3-MEDIATED ERROR-PRONE REPLICATION RESTART MECHANISMS. THE OVERALL S-PHASE ABNORMALITIES OBSERVED LEAD TO UNDER-REPLICATED DNA IN G2/M THAT INSTIGATES MITOTIC DNA SYNTHESIS. THIS IN TURN IS ASSOCIATED WITH MITOTIC SEGREGATION DEFECTS CHARACTERIZED BY ELEVATED MICRONUCLEI FORMATION, ACCUMULATION OF CYTOSOLIC DNA AND TRANSMISSION OF UNREPAIRED INHERITED DNA LESIONS IN THE SUBSEQUENT G1-PHASE IN EP300-DEFICIENT CELLS. WE DEMONSTRATE THAT THE DNA REPLICATION DYNAMICS OF EP300-MUTATED CELLS ATLL CELLS RECAPITULATE FEATURES OF BRCA-DEFICIENT CANCERS. ALTOGETHER THESE RESULTS SUGGEST THAT MUTATIONS IN EP300 CAUSE CHRONIC DNA REPLICATION STRESS AND DEFECTIVE REPLICATION FORK RESTART RESULTS IN PERSISTENT GENOMIC INSTABILITY THAT UNDERLIE AGGRESSIVE CHEMO-RESISTANT TUMORIGENESIS IN HUMANS. 2023 2 5320 36 PU.1 IS REQUIRED TO RESTRAIN MYELOPOIESIS DURING CHRONIC INFLAMMATORY STRESS. CHRONIC INFLAMMATION IS A COMMON FEATURE OF AGING AND NUMEROUS DISEASES SUCH AS DIABETES, OBESITY, AND AUTOIMMUNE SYNDROMES AND HAS BEEN LINKED TO THE DEVELOPMENT OF HEMATOLOGICAL MALIGNANCY. BLOOD-FORMING HEMATOPOIETIC STEM CELLS (HSC) CAN CONTRIBUTE TO THESE DISEASES VIA THE PRODUCTION OF TISSUE-DAMAGING MYELOID CELLS AND/OR THE ACQUISITION OF MUTATIONS IN EPIGENETIC AND TRANSCRIPTIONAL REGULATORS THAT INITIATE EVOLUTION TOWARD LEUKEMOGENESIS. WE PREVIOUSLY SHOWED THAT THE MYELOID "MASTER REGULATOR" TRANSCRIPTION FACTOR PU.1 IS ROBUSTLY INDUCED IN HSC BY PRO-INFLAMMATORY CYTOKINES SUCH AS INTERLEUKIN (IL)-1BETA AND LIMITS THEIR PROLIFERATIVE ACTIVITY. HERE, WE USED A PU.1-DEFICIENT MOUSE MODEL TO INVESTIGATE THE BROADER ROLE OF PU.1 IN REGULATING HEMATOPOIETIC ACTIVITY IN RESPONSE TO CHRONIC INFLAMMATORY CHALLENGES. WE FOUND THAT PU.1 IS CRITICAL IN RESTRAINING INFLAMMATORY MYELOPOIESIS VIA SUPPRESSION OF CELL CYCLE AND SELF-RENEWAL GENE PROGRAMS IN MYELOID-BIASED MULTIPOTENT PROGENITOR (MPP) CELLS. OUR DATA SHOW THAT WHILE PU.1 FUNCTIONS AS A KEY DRIVER OF MYELOID DIFFERENTIATION, IT PLAYS AN EQUALLY CRITICAL ROLE IN TAILORING HEMATOPOIETIC RESPONSES TO INFLAMMATORY STIMULI WHILE LIMITING EXPANSION AND SELF-RENEWAL GENE EXPRESSION IN MPPS. THESE DATA IDENTIFY PU.1 AS A KEY REGULATOR OF "EMERGENCY" MYELOPOIESIS RELEVANT TO INFLAMMATORY DISEASE AND LEUKEMOGENESIS. 2023 3 3365 28 HISTONE METHYLATION IN PRE-CANCEROUS LIVER DISEASES AND HEPATOCELLULAR CARCINOMA: RECENT OVERVIEW. HEPATOCELLULAR CARCINOMA (HCC) IS THE PREVALENT FORM OF LIVER CANCER IN ADULTS AND THE FOURTH MOST COMMON CAUSE OF CANCER-RELATED DEATH WORLDWIDE. HCC PREDOMINANTLY ARISES IN THE CONTEXT OF CIRRHOSIS AS A RESULT OF CHRONIC LIVER DISEASE, INJURY AND INFLAMMATION. FULL-BLOWN HCC HAS POOR PROGNOSIS BECAUSE IT IS HIGHLY AGGRESSIVE AND RESISTANT TO THERAPY. CONSEQUENTLY, INTERVENTIONS THAT CAN PREVENT OR RESTRAIN HCC EMERGENCE FROM PRE-CANCEROUS DISEASED LIVER ARE A DESIRABLE STRATEGY. HISTONE METHYLATION IS A DYNAMIC, REVERSIBLE EPIGENETIC MODIFICATION INVOLVING THE ADDITION OR REMOVAL OF METHYL GROUPS FROM LYSINE, ARGININE OR GLUTAMINE RESIDUES. ABERRANT ACTIVITY OF HISTONE METHYLATION WRITERS, ERASES AND READERS HAS BEEN IMPLICATED IN SEVERAL CANCER TYPES, INCLUDING HCC. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF RESEARCH ON THE ROLE OF HISTONE METHYLATION IN PRE-CANCEROUS AND CANCEROUS HCC PUBLISHED OVER THE LAST 5 YEARS. IN PARTICULAR, WE PRESENT THE EVIDENCE LINKING ENVIRONMENTAL FACTORS SUCH AS DIET, VIRAL INFECTIONS AND CARCINOGENIC AGENTS WITH DYSREGULATION OF HISTONE METHYLATION DURING LIVER CANCER PROGRESSION WITH THE AIM TO HIGHLIGHT FUTURE THERAPEUTIC POSSIBILITIES. 2023 4 6123 29 THE EPIGENETIC MACHINERY IN VASCULAR DYSFUNCTION AND HYPERTENSION. HYPERTENSION (HT) IS AMONG THE MAJOR COMPONENTS OF THE METABOLIC SYNDROME, I.E., OBESITY, DYSLIPIDEMIA, AND HYPERGLYCEMIA/INSULIN RESISTANCE. IT REPRESENTS A SIGNIFICANT HEALTH PROBLEM WITH FOREMOST RISKS FOR CHRONIC CARDIOVASCULAR DISEASE AND A SIGNIFICANT CAUSE OF MORBIDITY AND MORTALITY WORLDWIDE. THEREFORE, IT IS NOT SURPRISING THAT THIS DISORDER CONSTITUTES A SERIOUS PUBLIC HEALTH CONCERN. ALTHOUGH MULTIPLE STUDIES HAVE STRESSED THE MULTIFACTORIAL NATURE OF HT, THE PATHOGENESIS REMAINS LARGELY UNKNOWN. HOWEVER, IF WE WANT TO REDUCE THE GLOBAL PREVALENCE OF HT, RESTRAIN THE NUMBER OF DEATHS (CURRENTLY 9.4 MILLION/YEAR IN THE WORLD), AND ALLEVIATE THE SOCIO-ECONOMIC BURDEN, A DEEPER INSIGHT INTO THE MECHANISMS IS URGENTLY NEEDED IN ORDER TO DEFINE NEW MEANINGFUL THERAPEUTIC TARGETS. RECENTLY, THE ROLE OF EPIGENETICS IN THE DEVELOPMENT OF VARIOUS COMPLEX DISEASES HAS ATTRACTED MUCH ATTENTION. IN THE PRESENT REVIEW, WE PROVIDE A CRITICAL UPDATE ON THE AVAILABLE LITERATURE AND ONGOING RESEARCH REGARDING THE EPIGENETIC MODIFICATIONS OF GENES INVOLVED IN SEVERAL PATHWAYS OF ELEVATED BLOOD PRESSURE, ESPECIALLY THOSE LINKED TO THE VASCULAR EPITHELIUM. THIS REVIEW ALSO FOCUSES ON THE ROLE OF MICRORNA (MIRNA) IN THE REGULATION OF GENE EXPRESSION ASSOCIATED WITH HT AND OF FETAL PROGRAMMING MEDIATING SUSCEPTIBILITY TO HT IN ADULTHOOD. 2017 5 374 35 AN ENDOSIRNA-BASED REPRESSION MECHANISM COUNTERACTS TRANSPOSON ACTIVATION DURING GLOBAL DNA DEMETHYLATION IN EMBRYONIC STEM CELLS. ERASURE OF DNA METHYLATION AND REPRESSIVE CHROMATIN MARKS IN THE MAMMALIAN GERMLINE LEADS TO RISK OF TRANSCRIPTIONAL ACTIVATION OF TRANSPOSABLE ELEMENTS (TES). HERE, WE USED MOUSE EMBRYONIC STEM CELLS (ESCS) TO IDENTIFY AN ENDOSIRNA-BASED MECHANISM INVOLVED IN SUPPRESSION OF TE TRANSCRIPTION. IN ESCS WITH DNA DEMETHYLATION INDUCED BY ACUTE DELETION OF DNMT1, WE SAW AN INCREASE IN SENSE TRANSCRIPTION AT TES, RESULTING IN AN ABUNDANCE OF SENSE/ANTISENSE TRANSCRIPTS LEADING TO HIGH LEVELS OF ARGONAUTE2 (AGO2)-BOUND SMALL RNAS. INHIBITION OF DICER OR AGO2 EXPRESSION REVEALED THAT SMALL RNAS ARE INVOLVED IN AN IMMEDIATE RESPONSE TO DEMETHYLATION-INDUCED TRANSPOSON ACTIVATION, WHILE THE DEPOSITION OF REPRESSIVE HISTONE MARKS FOLLOWS AS A CHRONIC RESPONSE. IN VIVO, WE ALSO FOUND TE-SPECIFIC ENDOSIRNAS PRESENT DURING PRIMORDIAL GERM CELL DEVELOPMENT. OUR RESULTS SUGGEST THAT ANTISENSE TE TRANSCRIPTION IS A "TRAP" THAT ELICITS AN ENDOSIRNA RESPONSE TO RESTRAIN ACUTE TRANSPOSON ACTIVITY DURING EPIGENETIC REPROGRAMMING IN THE MAMMALIAN GERMLINE. 2017 6 6397 32 THE ROLE OF TRANSPOSABLE ELEMENTS IN AGING AND CANCER. TRANSPOSABLE ELEMENTS (TES) CONSTITUTE A LARGE PORTION OF THE HUMAN GENOME. VARIOUS MECHANISMS AT THE TRANSCRIPTION AND POST-TRANSCRIPTION LEVELS DEVELOPED TO SUPPRESS TE ACTIVITY IN HEALTHY CONDITIONS. HOWEVER, A GROWING BODY OF EVIDENCE SUGGESTS THAT TE DYSREGULATION IS INVOLVED IN VARIOUS HUMAN DISEASES, INCLUDING AGE-RELATED DISEASES AND CANCER. IN THIS REVIEW, WE EXPLAINED HOW SENSING TES BY THE IMMUNE SYSTEM COULD INDUCE INNATE IMMUNE RESPONSES, CHRONIC INFLAMMATION, AND FOLLOWING AGE-RELATED DISEASES. WE ALSO NOTED THAT INFLAMMAGEING AND EXOGENOUS CARCINOGENS COULD TRIGGER THE UPREGULATION OF TES IN PRECANCEROUS CELLS. INCREASED INFLAMMATION COULD ENHANCE EPIGENETIC PLASTICITY AND UPREGULATION OF EARLY DEVELOPMENTAL TES, WHICH REWIRES THE TRANSCRIPTIONAL NETWORKS AND GIFT THE SURVIVAL ADVANTAGE TO THE PRECANCEROUS CELLS. IN ADDITION, UPREGULATED TES COULD INDUCE GENOME INSTABILITY, ACTIVATION OF ONCOGENES, OR INHIBITION OF TUMOR SUPPRESSORS AND CONSEQUENT CANCER INITIATION AND PROGRESSION. SO, WE SUGGEST THAT TES COULD BE CONSIDERED THERAPEUTIC TARGETS IN AGING AND CANCER. 2023 7 436 28 ANTIFRAGILITY AND ANTIINFLAMMAGING: CAN THEY PLAY A ROLE FOR A HEALTHY LONGEVITY? ONE OF THE MOST EXCITING CHALLENGES OF THE RESEARCH ON AGING IS TO EXPLAIN HOW THE ENVIRONMENTAL FACTORS INTERACT WITH THE GENETIC BACKGROUND TO MODULATE THE CHANCES TO REACH THE EXTREME LIMIT OF HUMAN LIFE IN HEALTHY CONDITIONS. THE COMPLEX EPIGENETIC MECHANISMS CAN EXPLAIN BOTH THE INTERACTION BETWEEN DNA AND ENVIRONMENTAL FACTORS, AND THE LONG-DISTANCE PERSISTENCE OF LIFESTYLE EFFECTS, DUE TO THE SO CALLED "EPIGENETIC MEMORY". ONE OF THE MOST EXTENSIVELY INVESTIGATED THEORIES ON AGING FOCUSES ON THE INFLAMMATORY RESPONSES, SUGGESTING THAT THE AGE-RELATED PROGRESSION OF LOW-GRADE AND THEREFORE FOR LONG TIME SUBCLINICAL, CHRONIC, SYSTEMIC, INFLAMMATORY PROCESS, NAMED "INFLAMMAGING", COULD BE THE MOST RELEVANT RISK FACTOR FOR THE DEVELOPMENT AND PROGRESSION OF THE MOST COMMON AGE-RELATED DISEASES AND ULTIMATELY OF DEATH. THE RESULTS OF MANY STUDIES ON LONG-LIVED PEOPLE, ESPECIALLY ON CENTENARIANS, SUGGESTED THAT HEALTHY OLD PEOPLE CAN COPE WITH INFLAMMAGING UPREGULATING THE ANTIINFLAMMAGING RESPONSES. OVERALL, A GENETIC MAKE-UP CODING FOR A STRONG ANTIINFLAMMAGING RESPONSE AND AN AGE-RELATED ABILITY TO REMODEL KEY METABOLIC PATHWAYS TO COPE WITH A PLETHORA OF ANTIGENS AND STRESSORS SEEM TO BE THE BEST WAYS FOR REACH THE EXTREME LIMIT OF HUMAN LIFESPAN IN HEALTH STATUS. IN THIS SCENARIO, WE WONDERED IF THE ANTIFRAGILITY CONCEPT, RECENTLY DEVELOPED IN THE FRAMEWORK OF BUSINESS AND RISK ANALYSIS, COULD ADD SOME INFORMATION TO DISENTANGLE THE HETEROGENEOUS NATURE OF THE AGING PROCESS IN HUMAN. THE ANTIFRAGILITY IS THE PROPERTY OF THE COMPLEX SYSTEMS TO INCREASE THEIR PERFORMANCES BECAUSE OF HIGH STRESS. BASED ON THIS THEORY WE WERE WONDERING IF SOME SUBJECTS COULD BE ABLE TO MODULATE FASTER THAN OTHERS THEIR EPIGENOME TO COPE WITH A PLETHORA OF STRESSORS DURING LIFE, PROBABLY MODULATING THE INFLAMMATORY AND ANTI-INFLAMMATORY RESPONSES. IN THIS FRAMEWORK, ANTIFRAGILITY COULD SHARE SOME COMMON MECHANISMS WITH ANTI-INFLAMMAGING, MODULATING THE ABILITY TO RESTRAIN THE INFLAMMATORY RESPONSES, SO THAT ANTIFRAGILITY AND ANTIINFLAMMAGING COULD BE VIEWED AS DIFFERENT PIECES OF THE SAME PUZZLE, BOTH IMPINGING UPON THE CHANCES TO TRAVEL ALONG THE HEALTHY AGING TRAJECTORY. 2023 8 2342 26 EPIGENETIC REGULATION OF MACROPHAGE POLARIZATION AND FUNCTION. MACROPHAGE POLARIZATION REFERS TO DEVELOPMENT OF A SPECIFIC PHENOTYPE IMPORTANT FOR TISSUE HOMEOSTASIS OR HOST DEFENSE IN RESPONSE TO ENVIRONMENTAL CUES. ENVIRONMENTAL FACTORS THAT INDUCE MACROPHAGE POLARIZATION INCLUDE CYTOKINES AND MICROBIAL FACTORS PRODUCED BY PATHOGENS OR COMMENSAL MICROBIOTA. SIGNALING PATHWAYS UTILIZED BY THESE POLARIZING FACTORS HAVE BEEN WELL CHARACTERIZED, BUT IT IS LESS CLEAR HOW SIGNALS ARE CONVERTED INTO COMPLEX AND SUSTAINED PATTERNS OF GENE EXPRESSION, AND HOW MACROPHAGES ARE REPROGRAMMED DURING POLARIZATION TO ALTER THEIR RESPONSES TO SUBSEQUENT ENVIRONMENTAL CHALLENGES. EMERGING EVIDENCE, REVIEWED HERE, SUGGESTS AN IMPORTANT ROLE FOR EPIGENETIC MECHANISMS IN MODULATING AND TRANSMITTING SIGNALS DURING MACROPHAGE POLARIZATION AND REPROGRAMMING. DEEPER UNDERSTANDING OF EPIGENETIC REGULATION OF MACROPHAGE PHENOTYPE WILL ENABLE DEVELOPMENT OF GENE-SPECIFIC THERAPEUTIC APPROACHES TO ENHANCE HOST DEFENSE WHILE PRESERVING TISSUE INTEGRITY AND PREVENTING CHRONIC INFLAMMATORY DISEASES. 2013 9 6053 20 THE CRUCIAL ROLE OF NLRP3 INFLAMMASOME IN VIRAL INFECTION-ASSOCIATED FIBROSING INTERSTITIAL LUNG DISEASES. IDIOPATHIC PULMONARY FIBROSIS (IPF), ONE OF THE MOST COMMON FIBROSING INTERSTITIAL LUNG DISEASES (ILD), IS A CHRONIC-AGE-RELATED RESPIRATORY DISEASE THAT RISES FROM REPEATED MICRO-INJURY OF THE ALVEOLAR EPITHELIUM. ENVIRONMENTAL INFLUENCES, INTRINSIC FACTORS, GENETIC AND EPIGENETIC RISK FACTORS THAT LEAD TO CHRONIC INFLAMMATION MIGHT BE IMPLICATED IN THE DEVELOPMENT OF IPF. THE EXACT TRIGGERS THAT INITIATE THE FIBROTIC RESPONSE IN IPF REMAIN ENIGMATIC, BUT THERE IS NOW INCREASING EVIDENCE SUPPORTING THE ROLE OF CHRONIC EXPOSURE OF VIRAL INFECTION. DURING VIRAL INFECTION, ACTIVATION OF THE NLRP3 INFLAMMASOME BY INTEGRATING MULTIPLE CELLULAR AND MOLECULAR SIGNALING IMPLICATES ROBUST INFLAMMATION, FIBROBLAST PROLIFERATION, ACTIVATION OF MYOFIBROBLAST, MATRIX DEPOSITION, AND ABERRANT EPITHELIAL-MESENCHYMAL FUNCTION. OVERALL, THE CROSSTALK OF THE NLRP3 INFLAMMASOME AND VIRUSES CAN ACTIVATE IMMUNE RESPONSES AND INFLAMMASOME-ASSOCIATED MOLECULES IN THE DEVELOPMENT, PROGRESSION, AND EXACERBATION OF IPF. 2021 10 3688 41 INFLAMMATION: GEARING THE JOURNEY TO CANCER. CHRONIC INFLAMMATION PLAYS A MULTIFACETED ROLE IN CARCINOGENESIS. MOUNTING EVIDENCE FROM PRECLINICAL AND CLINICAL STUDIES SUGGESTS THAT PERSISTENT INFLAMMATION FUNCTIONS AS A DRIVING FORCE IN THE JOURNEY TO CANCER. THE POSSIBLE MECHANISMS BY WHICH INFLAMMATION CAN CONTRIBUTE TO CARCINOGENESIS INCLUDE INDUCTION OF GENOMIC INSTABILITY, ALTERATIONS IN EPIGENETIC EVENTS AND SUBSEQUENT INAPPROPRIATE GENE EXPRESSION, ENHANCED PROLIFERATION OF INITIATED CELLS, RESISTANCE TO APOPTOSIS, AGGRESSIVE TUMOR NEOVASCULARIZATION, INVASION THROUGH TUMOR-ASSOCIATED BASEMENT MEMBRANE AND METASTASIS, ETC. INFLAMMATION-INDUCED REACTIVE OXYGEN AND NITROGEN SPECIES CAUSE DAMAGE TO IMPORTANT CELLULAR COMPONENTS (E.G., DNA, PROTEINS AND LIPIDS), WHICH CAN DIRECTLY OR INDIRECTLY CONTRIBUTE TO MALIGNANT CELL TRANSFORMATION. OVEREXPRESSION, ELEVATED SECRETION, OR ABNORMAL ACTIVATION OF PROINFLAMMATORY MEDIATORS, SUCH AS CYTOKINES, CHEMOKINES, CYCLOOXYGENASE-2, PROSTAGLANDINS, INDUCIBLE NITRIC OXIDE SYNTHASE, AND NITRIC OXIDE, AND A DISTINCT NETWORK OF INTRACELLULAR SIGNALING MOLECULES INCLUDING UPSTREAM KINASES AND TRANSCRIPTION FACTORS FACILITATE TUMOR PROMOTION AND PROGRESSION. WHILE INFLAMMATION PROMOTES DEVELOPMENT OF CANCER, COMPONENTS OF THE TUMOR MICROENVIRONMENT, SUCH AS TUMOR CELLS, STROMAL CELLS IN SURROUNDING TISSUE AND INFILTRATED INFLAMMATORY/IMMUNE CELLS GENERATE AN INTRATUMORAL INFLAMMATORY STATE BY ABERRANT EXPRESSION OR ACTIVATION OF SOME PROINFLAMMATORY MOLECULES. MANY OF PROINFLAMMATORY MEDIATORS, ESPECIALLY CYTOKINES, CHEMOKINES AND PROSTAGLANDINS, TURN ON THE ANGIOGENIC SWITCHES MAINLY CONTROLLED BY VASCULAR ENDOTHELIAL GROWTH FACTOR, THEREBY INDUCING INFLAMMATORY ANGIOGENESIS AND TUMOR CELL-STROMA COMMUNICATION. THIS WILL END UP WITH TUMOR ANGIOGENESIS, METASTASIS AND INVASION. MOREOVER, CELLULAR MICRORNAS ARE EMERGING AS A POTENTIAL LINK BETWEEN INFLAMMATION AND CANCER. THE PRESENT ARTICLE HIGHLIGHTS THE ROLE OF VARIOUS PROINFLAMMATORY MEDIATORS IN CARCINOGENESIS AND THEIR PROMISE AS POTENTIAL TARGETS FOR CHEMOPREVENTION OF INFLAMMATION-ASSOCIATED CARCINOGENESIS. 2008 11 4563 31 MYELOID DNA METHYLTRANSFERASE3B DEFICIENCY AGGRAVATES PULMONARY FIBROSIS BY ENHANCING PROFIBROTIC MACROPHAGE ACTIVATION. BACKGROUND: IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC, PROGRESSIVE AND SEVERE DISEASE CHARACTERIZED BY EXCESSIVE MATRIX DEPOSITION IN THE LUNGS. MACROPHAGES PLAY CRUCIAL ROLES IN MAINTAINING LUNG HOMEOSTASIS BUT ARE ALSO CENTRAL IN THE PATHOGENESIS OF LUNG DISEASES LIKE PULMONARY FIBROSIS. ESPECIALLY, MACROPHAGE POLARIZATION/ACTIVATION SEEMS TO PLAY A CRUCIAL ROLE IN PATHOLOGY AND EPIGENETIC REPROGRAMING IS WELL-KNOWN TO REGULATE MACROPHAGE POLARIZATION. DNA METHYLATION ALTERATIONS IN IPF LUNGS HAVE BEEN WELL DOCUMENTED, BUT THE ROLE OF DNA METHYLATION IN SPECIFIC CELL TYPES, ESPECIALLY MACROPHAGES, IS POORLY DEFINED. METHODS: IN ORDER TO DETERMINE THE ROLE OF DNA METHYLATION IN MACROPHAGES DURING PULMONARY FIBROSIS, WE SUBJECTED MACROPHAGE SPECIFIC DNA METHYLTRANSFERASE (DNMT)3B, WHICH MEDIATES THE DE NOVO DNA METHYLATION, DEFICIENT MICE TO THE BLEOMYCIN-INDUCED PULMONARY FIBROSIS MODEL. MACROPHAGE POLARIZATION AND FIBROTIC PARAMETERS WERE EVALUATED AT 21 DAYS AFTER BLEOMYCIN ADMINISTRATION. DNMT3B KNOCKOUT AND WILD TYPE BONE MARROW-DERIVED MACROPHAGES WERE STIMULATED WITH EITHER INTERLEUKIN (IL)4 OR TRANSFORMING GROWTH FACTOR BETA 1 (TGFB1) IN VITRO, AFTER WHICH PROFIBROTIC GENE EXPRESSION AND DNA METHYLATION AT THE ARG1 PROMOTOR WERE DETERMINED. RESULTS: WE SHOW THAT DNMT3B DEFICIENCY PROMOTES ALTERNATIVE MACROPHAGE POLARIZATION INDUCED BY IL4 AND TGFB1 IN VITRO AND ALSO ENHANCES PROFIBROTIC MACROPHAGE POLARIZATION IN THE ALVEOLAR SPACE DURING PULMONARY FIBROSIS IN VIVO. MOREOVER, MYELOID SPECIFIC DELETION OF DNMT3B PROMOTED THE DEVELOPMENT OF EXPERIMENTAL PULMONARY FIBROSIS. CONCLUSIONS: IN SUMMARY, THESE DATA SUGGEST THAT MYELOID DNMT3B REPRESSES FIBROTIC MACROPHAGE POLARIZATION AND PROTECTS AGAINST BLEOMYCIN INDUCED PULMONARY FIBROSIS. 2022 12 4116 35 MECHANISMS OF AIRWAY EPITHELIAL INJURY AND ABNORMAL REPAIR IN ASTHMA AND COPD. THE AIRWAY EPITHELIUM COMPRISES OF DIFFERENT CELL TYPES AND ACTS AS A PHYSICAL BARRIER PREVENTING PATHOGENS, INCLUDING INHALED PARTICLES AND MICROBES, FROM ENTERING THE LUNGS. GOBLET CELLS AND SUBMUCOSAL GLANDS PRODUCE MUCUS THAT TRAPS PATHOGENS, WHICH ARE EXPELLED FROM THE RESPIRATORY TRACT BY CILIATED CELLS. BASAL CELLS ACT AS PROGENITOR CELLS, DIFFERENTIATING INTO DIFFERENT EPITHELIAL CELL TYPES, TO MAINTAIN HOMEOSTASIS FOLLOWING INJURY. ADHERENS AND TIGHT JUNCTIONS BETWEEN CELLS MAINTAIN THE EPITHELIAL BARRIER FUNCTION AND REGULATE THE MOVEMENT OF MOLECULES ACROSS IT. IN THIS REVIEW WE DISCUSS HOW ABNORMAL EPITHELIAL STRUCTURE AND FUNCTION, CAUSED BY CHRONIC INJURY AND ABNORMAL REPAIR, DRIVES AIRWAY DISEASE AND SPECIFICALLY ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). IN BOTH DISEASES, INHALED ALLERGENS, POLLUTANTS AND MICROBES DISRUPT JUNCTIONAL COMPLEXES AND PROMOTE CELL DEATH, IMPAIRING THE BARRIER FUNCTION AND LEADING TO INCREASED PENETRATION OF PATHOGENS AND A CONSTANT AIRWAY IMMUNE RESPONSE. IN ASTHMA, THE INFLAMMATORY RESPONSE PRECIPITATES THE EPITHELIAL INJURY AND DRIVES ABNORMAL BASAL CELL DIFFERENTIATION. THIS LEADS TO REDUCED CILIATED CELLS, GOBLET CELL HYPERPLASIA AND INCREASED EPITHELIAL MESENCHYMAL TRANSITION, WHICH CONTRIBUTE TO IMPAIRED MUCOCILIARY CLEARANCE AND AIRWAY REMODELLING. IN COPD, CHRONIC OXIDATIVE STRESS AND INFLAMMATION TRIGGER PREMATURE EPITHELIAL CELL SENESCENCE, WHICH CONTRIBUTES TO LOSS OF EPITHELIAL INTEGRITY AND AIRWAY INFLAMMATION AND REMODELLING. INCREASED NUMBERS OF BASAL CELLS SHOWING DEREGULATED DIFFERENTIATION, CONTRIBUTES TO CILIARY DYSFUNCTION AND MUCOUS HYPERPRODUCTION IN COPD AIRWAYS. DEFECTIVE ANTIOXIDANT, ANTIVIRAL AND DAMAGE REPAIR MECHANISMS, POSSIBLY DUE TO GENETIC OR EPIGENETIC FACTORS, MAY CONFER SUSCEPTIBILITY TO AIRWAY EPITHELIAL DYSFUNCTION IN THESE DISEASES. THE CURRENT EVIDENCE SUGGESTS THAT A CONSTANT CYCLE OF INJURY AND ABNORMAL REPAIR OF THE EPITHELIUM DRIVES CHRONIC AIRWAY INFLAMMATION AND REMODELLING IN ASTHMA AND COPD. MECHANISTIC UNDERSTANDING OF INJURY SUSCEPTIBILITY AND DAMAGE RESPONSE MAY LEAD TO IMPROVED THERAPIES FOR THESE DISEASES. 2023 13 4674 26 NEW INSIGHTS INTO THE ROLE AND MECHANISM OF PARTIAL EPITHELIAL-MESENCHYMAL TRANSITION IN KIDNEY FIBROSIS. EPITHELIAL-MESENCHYMAL TRANSITION (EMT) IS DESCRIBED AS THE PROCESS IN WHICH INJURED RENAL TUBULAR EPITHELIAL CELLS UNDERGO A PHENOTYPE CHANGE, ACQUIRING MESENCHYMAL CHARACTERISTICS AND MORPHING INTO FIBROBLASTS. INITIALLY, IT WAS WIDELY THOUGHT OF AS A CRITICAL MECHANISM OF FIBROGENESIS UNDERLYING CHRONIC KIDNEY DISEASE. HOWEVER, EVIDENCE THAT RENAL TUBULAR EPITHELIAL CELLS CAN CROSS THE BASEMENT MEMBRANE AND BECOME FIBROBLASTS IN THE RENAL INTERSTITIUM IS RARE, LEADING TO DEBATE ABOUT THE EXISTENCE OF EMT. RECENT RESEARCH HAS DEMONSTRATED THAT AFTER INJURY, RENAL TUBULAR EPITHELIAL CELLS ACQUIRE MESENCHYMAL CHARACTERISTICS AND THE ABILITY TO PRODUCE A VARIETY OF PROFIBROTIC FACTORS AND CYTOKINES, BUT REMAIN ATTACHED TO THE BASEMENT MEMBRANE. ON THIS BASIS, A NEW CONCEPT OF "PARTIAL EPITHELIAL-MESENCHYMAL TRANSITION (PEMT)" WAS PROPOSED TO EXPLAIN THE CONTRIBUTION OF RENAL EPITHELIAL CELLS TO RENAL FIBROGENESIS. IN THIS REVIEW, WE DISCUSS THE CONCEPT OF PEMT AND THE MOST RECENT FINDINGS RELATED TO THIS PROCESS, INCLUDING CELL CYCLE ARREST, METABOLIC ALTERNATION OF EPITHELIAL CELLS, INFILTRATION OF IMMUNE CELLS, EPIGENETIC REGULATION AS WELL AS THE NOVEL SIGNALING PATHWAYS THAT MEDIATE THIS DISTURBED EPITHELIAL-MESENCHYMAL COMMUNICATION. A DEEPER UNDERSTANDING OF THE ROLE AND THE MECHANISM OF PEMT MAY HELP IN DEVELOPING NOVEL THERAPIES TO PREVENT AND HALT FIBROSIS IN KIDNEY DISEASE. 2020 14 1764 38 EARLY-IMMEDIATE GENE EGR1 IS ASSOCIATED WITH TGFBETA1 REGULATION OF EPIGENETIC READER BROMODOMAIN-CONTAINING PROTEIN 4 VIA THE CANONICAL SMAD3 SIGNALING IN HEPATIC STELLATE CELLS IN VITRO AND IN VIVO. UPON CHRONIC DAMAGE TO THE LIVER, MULTIPLE CYTOKINES STIMULATE HEPATIC STELLATE CELLS (HSCS), CAUSING THE ALTERATIONS OF GENE EXPRESSION PROFILES AND THUS LEADING TO HSC ACTIVATION, A KEY STEP IN LIVER FIBROGENESIS. ACTIVATED HSCS ARE THE DOMINANT CONTRIBUTORS TO LIVER FIBROSIS. BROMODOMAIN CONTAINING PROTEIN 4 (BRD4), AN IMPORTANT EPIGENETIC READER, WAS DEMONSTRATED TO CONCENTRATE ON HUNDREDS OF ENHANCERS ASSOCIATED WITH GENES INVOLVED IN MULTIPLE PROFIBROTIC PATHWAYS, THEREBY DIRECTING HSC ACTIVATION AND THE FIBROTIC RESPONSES. THE PRESENT STUDIES WERE DESIGNED TO EXAMINE THE EFFECT OF TRANSFORMING GROWTH FACTOR BETA-1 (TGFBETA1), THE MOST POTENT PRO-FIBROTIC CYTOKINE, ON BRD4 EXPRESSION IN HSCS AND, IF SO, ELUCIDATED THE UNDERLYING MECHANISMS IN VITRO AND IN VIVO. THE EXPERIMENTS EMPLOYED THE HETEROGENEOUS TGFBETA1 KNOCKOUT (TGFBETA1(+/-) ) MICE, GENE KNOCKDOWN IN VIVO, AND A MODEL OF THIOACETAMIDE (TAA)-INDUCED LIVER INJURY. THE RESULTS REVEALED THAT TGFBETA1 ENHANCED BRD4 EXPRESSION IN HSCS, WHICH WAS MEDIATED, AT LEAST, BY SMAD3 SIGNALING AND EARLY-IMMEDIATE GENE EGR1 (EARLY GROWTH RESPONSE-1). TGFBETA1-INDUCED SMAD3 SIGNALING INCREASED EGR1 EXPRESSION AND PROMOTED EGR1 BINDING TO BRD4 PROMOTER AT A SITE AROUND -111 BP, PROMOTING BRD4 EXPRESSION. EGR1 KNOCKDOWN REDUCED BRD4 EXPRESSION IN HSCS IN A MOUSE MODEL OF TAA-INDUCED LIVER INJURY AND LESSENED LIVER FIBROSIS. DOUBLE FLUORESCENCE STAINING DEMONSTRATED A STRONG INCREASE IN BRD4 EXPRESSION IN ACTIVATED HSCS IN FIBROTIC AREAS OF THE HUMAN LIVERS, PARALLELING THE UPREGULATION OF P-SMAD3 AND EGR1. THIS RESEARCH SUGGESTED NOVEL MOLECULAR EVENTS UNDERLYING THE ROLES OF THE MASTER PRO-FIBROTIC CYTOKINE TGFBETA1 IN HSC ACTIVATION AND LIVER FIBROGENESIS. 2022 15 4774 32 NUCLEIC ACID APTAMERS TARGETING EPIGENETIC REGULATORS: AN INNOVATIVE THERAPEUTIC OPTION. EPIGENETIC MECHANISMS INCLUDE DNA METHYLATION, POSTTRANSLATIONAL MODIFICATIONS OF HISTONES, CHROMATIN REMODELING FACTORS, AND POST TRANSCRIPTIONAL GENE REGULATION BY NONCODING RNAS. ALL TOGETHER, THESE PROCESSES REGULATE GENE EXPRESSION BY CHANGING CHROMATIN ORGANIZATION AND DNA ACCESSIBILITY. TARGETING ENZYMATIC REGULATORS RESPONSIBLE FOR DNA AND CHROMATIN MODIFICATIONS HOLD PROMISE FOR MODULATING THE TRANSCRIPTIONAL REGULATION OF GENES THAT ARE INVOLVED IN CANCER, AS WELL AS IN CHRONIC NONCOMMUNICABLE METABOLIC DISEASES LIKE OBESITY, DIABETES, AND CARDIOVASCULAR DISEASES. INCREASINGLY STUDIES ARE EMERGING, LEADING TO THE IDENTIFICATION OF SPECIFIC AND EFFECTIVE MOLECULES TARGETING EPIGENETIC PATHWAYS INVOLVED IN DISEASE ONSET. IN THIS REGARD, RNA INTERFERENCE, WHICH USES SMALL RNAS TO REDUCE GENE EXPRESSION AND NUCLEIC ACID APTAMERS ARE ARISING AS VERY PROMISING CANDIDATES IN THERAPEUTIC APPROACH. COMMON TO ALL THESE STRATEGIES IS THE IMPERATIVE CHALLENGE OF SPECIFICITY. IN THIS REGARD, NUCLEIC ACID APTAMERS HAVE EMERGED AS AN ATTRACTIVE CLASS OF CARRIER MOLECULES DUE TO THEIR ABILITY TO BIND WITH HIGH AFFINITY TO SPECIFIC LIGANDS, THEIR HIGH CHEMICAL FLEXIBILITY AS WELL AS TISSUE PENETRATION CAPABILITY. IN THIS REVIEW, WE WILL FOCUS ON THE RECENT PROGRESS IN THE FIELD OF APTAMERS USED AS TARGETING MOIETIES ABLE TO RECOGNIZE AND REVERT EPIGENETICS MARKS INVOLVED IN DISEASES ONSET. 2018 16 4512 22 MUC1-C IN CHRONIC INFLAMMATION AND CARCINOGENESIS; EMERGENCE AS A TARGET FOR CANCER TREATMENT. CHRONIC INFLAMMATION IS A HIGHLY PREVALENT CONSEQUENCE OF CHANGES IN ENVIRONMENTAL AND LIFESTYLE FACTORS THAT CONTRIBUTE TO THE DEVELOPMENT OF CANCER. THE BASIS FOR THIS CRITICAL ASSOCIATION HAS LARGELY REMAINED UNCLEAR. THE MUC1 GENE EVOLVED IN MAMMALS TO PROTECT EPITHELIA FROM THE EXTERNAL ENVIRONMENT. THE MUC1-C SUBUNIT PROMOTES RESPONSES FOUND IN WOUND HEALING AND CANCER. MUC1-C INDUCES EMT, EPIGENETIC REPROGRAMMING, DEDIFFERENTIATION AND PLURIPOTENCY FACTOR EXPRESSION, WHICH WHEN PROLONGED IN CHRONIC INFLAMMATION PROMOTE CANCER PROGRESSION. AS DISCUSSED IN THIS REVIEW, MUC1-C ALSO DRIVES DRUG RESISTANCE AND IMMUNE EVASION, AND IS AN IMPORTANT TARGET FOR CANCER THERAPEUTICS NOW UNDER DEVELOPMENT. 2020 17 6182 31 THE IMPACT OF ADIPOSE TISSUE-DERIVED MIRNAS IN METABOLIC SYNDROME, OBESITY, AND CANCER. OBESITY IS A MULTIFACTORIAL AND COMPLEX CONDITION THAT IS CHARACTERIZED BY ABNORMAL AND EXCESSIVE WHITE ADIPOSE TISSUE ACCUMULATION, WHICH CAN LEAD TO THE DEVELOPMENT OF METABOLIC DISEASES, SUCH AS TYPE 2 DIABETES MELLITUS, NONALCOHOLIC FATTY LIVER DISEASE, CARDIOVASCULAR DISEASES, AND SEVERAL TYPES OF CANCER. OBESITY IS CHARACTERIZED BY EXCESSIVE ADIPOSE TISSUE ACCUMULATION AND ASSOCIATED WITH ALTERATIONS IN IMMUNITY, DISPLAYING A CHRONIC LOW-GRADE INFLAMMATION PROFILE. ADIPOSE TISSUE IS A DYNAMIC AND COMPLEX ENDOCRINE ORGAN COMPOSED NOT ONLY BY ADIPOCYTES, BUT SEVERAL IMMUNOLOGICAL CELLS, WHICH CAN SECRETE HORMONES, CYTOKINES AND MANY OTHER FACTORS CAPABLE OF REGULATING METABOLIC HOMEOSTASIS AND SEVERAL CRITICAL BIOLOGICAL PATHWAYS. REMARKABLY, ADIPOSE TISSUE IS A MAJOR SOURCE OF CIRCULATING MICRORNAS (MIRNAS), RECENTLY DESCRIBED AS A NOVEL FORM OF ADIPOKINES. SEVERAL ADIPOSE TISSUE-DERIVED MIRNAS ARE DEEPLY ASSOCIATED WITH ADIPOCYTES DIFFERENTIATION AND HAVE BEEN IDENTIFIED WITH AN ESSENTIAL ROLE IN OBESITY-ASSOCIATED INFLAMMATION, INSULIN RESISTANCE, AND TUMOR MICROENVIRONMENT. DURING OBESITY, ADIPOSE TISSUE CAN COMPLETELY CHANGE THE PROFILE OF THE SECRETED MIRNAS, INFLUENCING CIRCULATING MIRNAS AND IMPACTING THE DEVELOPMENT OF DIFFERENT PATHOLOGICAL CONDITIONS, SUCH AS OBESITY, METABOLIC SYNDROME, AND CANCER. IN THIS REVIEW, WE DISCUSS HOW MIRNAS CAN ACT AS EPIGENETIC REGULATORS AFFECTING ADIPOGENESIS, ADIPOCYTE DIFFERENTIATION, LIPID METABOLISM, BROWNING OF THE WHITE ADIPOSE TISSUE, GLUCOSE HOMEOSTASIS, AND INSULIN RESISTANCE, IMPACTING DEEPLY OBESITY AND METABOLIC DISEASES. MOREOVER, WE CHARACTERIZE HOW MIRNAS CAN OFTEN ACT AS ONCOGENIC AND TUMOR SUPPRESSOR MOLECULES, SIGNIFICANTLY MODULATING CANCER ESTABLISHMENT AND PROGRESSION. FURTHERMORE, WE HIGHLIGHT IN THIS MANUSCRIPT HOW ADIPOSE TISSUE-DERIVED MIRNAS CAN FUNCTION AS IMPORTANT NEW THERAPEUTIC TARGETS. 2020 18 241 35 ADIPOCYTE, IMMUNE CELLS, AND MIRNA CROSSTALK: A NOVEL REGULATOR OF METABOLIC DYSFUNCTION AND OBESITY. OBESITY IS CHARACTERIZED AS A COMPLEX AND MULTIFACTORIAL EXCESS ACCRETION OF ADIPOSE TISSUE (AT) ACCOMPANIED WITH ALTERATIONS IN THE IMMUNE RESPONSE THAT AFFECTS VIRTUALLY ALL AGE AND SOCIOECONOMIC GROUPS AROUND THE GLOBE. THE ABNORMAL ACCUMULATION OF AT LEADS TO SEVERAL METABOLIC DISEASES, INCLUDING NONALCOHOLIC FATTY LIVER DISORDER (NAFLD), LOW-GRADE INFLAMMATION, TYPE 2 DIABETES MELLITUS (T2DM), CARDIOVASCULAR DISORDERS (CVDS), AND CANCER. AT IS AN ENDOCRINE ORGAN COMPOSED OF ADIPOCYTES AND IMMUNE CELLS, INCLUDING B-CELLS, T-CELLS AND MACROPHAGES. THESE IMMUNE CELLS SECRETE VARIOUS CYTOKINES AND CHEMOKINES AND CROSSTALK WITH ADIPOKINES TO MAINTAIN METABOLIC HOMEOSTASIS AND LOW-GRADE CHRONIC INFLAMMATION. A NOVEL FORM OF ADIPOKINES, MICRORNA (MIRS), IS EXPRESSED IN MANY DEVELOPING PERIPHERAL TISSUES, INCLUDING ATS, T-CELLS, AND MACROPHAGES, AND MODULATES THE IMMUNE RESPONSE. MIRS ARE ESSENTIAL FOR INSULIN RESISTANCE, MAINTAINING THE TUMOR MICROENVIRONMENT, AND OBESITY-ASSOCIATED INFLAMMATION (OAI). THE ABNORMAL REGULATION OF AT, T-CELLS, AND MACROPHAGE MIRS MAY CHANGE THE FUNCTION OF DIFFERENT ORGANS INCLUDING THE PANCREAS, HEART, LIVER, AND SKELETAL MUSCLE. SINCE OBESITY AND INFLAMMATION ARE CLOSELY ASSOCIATED, THE DYSREGULATED EXPRESSION OF MIRS IN INFLAMMATORY ADIPOCYTES, T-CELLS, AND MACROPHAGES SUGGEST THE IMPORTANCE OF MIRS IN OAI. THEREFORE, IN THIS REVIEW ARTICLE, WE HAVE ELABORATED THE ROLE OF MIRS AS EPIGENETIC REGULATORS AFFECTING ADIPOCYTE DIFFERENTIATION, IMMUNE RESPONSE, AT BROWNING, ADIPOGENESIS, LIPID METABOLISM, INSULIN RESISTANCE (IR), GLUCOSE HOMEOSTASIS, OBESITY, AND METABOLIC DISORDERS. FURTHER, WE WILL DISCUSS A SET OF ALTERED MIRS AS NOVEL BIOMARKERS FOR METABOLIC DISEASE PROGRESSION AND THERAPEUTIC TARGETS FOR OBESITY. 2021 19 6201 30 THE INFLAMMATORY MICROENVIRONMENT AND MICROBIOME IN PROSTATE CANCER DEVELOPMENT. CHRONIC INFLAMMATION PROMOTES THE DEVELOPMENT OF SEVERAL TYPES OF SOLID CANCERS AND MIGHT CONTRIBUTE TO PROSTATE CARCINOGENESIS. THIS HYPOTHESIS PARTLY ORIGINATES IN THE FREQUENT OBSERVATION OF INFLAMMATORY CELLS IN THE PROSTATE MICROENVIRONMENT OF ADULT MEN. INFLAMMATION IS ASSOCIATED WITH PUTATIVE PROSTATE CANCER PRECURSOR LESIONS, TERMED PROLIFERATIVE INFLAMMATORY ATROPHY. INFLAMMATION MIGHT DRIVE PROSTATE CARCINOGENESIS VIA OXIDATIVE STRESS AND GENERATION OF REACTIVE OXYGEN SPECIES THAT INDUCE MUTAGENESIS. ADDITIONALLY, INFLAMMATORY STRESS MIGHT CAUSE EPIGENETIC ALTERATIONS THAT PROMOTE NEOPLASTIC TRANSFORMATION. PROLIFERATIVE INFLAMMATORY ATROPHY IS ENRICHED FOR PROLIFERATIVE LUMINAL EPITHELIAL CELLS OF INTERMEDIATE PHENOTYPE THAT MIGHT BE PRONE TO GENOMIC ALTERATIONS LEADING TO PROSTATIC INTRAEPITHELIAL NEOPLASIA AND PROSTATE CANCER. STUDIES IN ANIMALS SUGGEST THAT INFLAMMATORY CHANGES IN THE PROSTATE MICROENVIRONMENT CONTRIBUTE TO REPROGRAMMING OF PROSTATE EPITHELIAL CELLS, A POSSIBLE STEP IN TUMOUR INITIATION. PROSTATIC INFECTION, CONCURRENT WITH EPITHELIAL BARRIER DISRUPTION, MIGHT BE A KEY DRIVER OF AN INFLAMMATORY MICROENVIRONMENT; THE DISCOVERY OF A URINARY MICROBIOME INDICATES A POTENTIAL SOURCE OF FREQUENT EXPOSURE OF THE PROSTATE TO A DIVERSE NUMBER OF MICROORGANISMS. HENCE, CURRENT EVIDENCE SUGGESTS THAT INFLAMMATION AND ATROPHY ARE INVOLVED IN PROSTATE CARCINOGENESIS AND SUGGESTS A ROLE FOR THE MICROBIOME IN ESTABLISHING AN INFLAMMATORY PROSTATE MICROENVIRONMENT THAT MIGHT PROMOTE PROSTATE CANCER DEVELOPMENT AND PROGRESSION. 2018 20 1720 29 DYSREGULATED N6-METHYLADENOSINE (M(6)A) PROCESSING IN HEPATOCELLULAR CARCINOMA. N6-METHYLADENOSINE (M(6)A) IS THE MOST THOROUGHLY STUDIED TYPE OF INTERNAL RNA MODIFICATION, AS THIS EPIGENETIC MODIFICATION IS THE MOST ABUNDANT IN EUKARYOTIC RNAS TO DATE. THIS MODIFICATION OCCURS IN VARIOUS TYPES OF RNAS AND PLAYS SIGNIFICANT ROLES IN DOMINANT RNA-RELATED PROCESSES, SUCH AS TRANSLATION, SPLICING, EXPORT AND DEGRADATION. THESE PROCESSES ARE CATALYZED BY THREE TYPES OF PROMINENT ENZYMES: WRITERS, ERASERS AND READERS. INCREASING EVIDENCE HAS SHOWN THAT M(6)A MODIFICATION IS VITAL FOR THE REGULATION OF GENE EXPRESSION, CARCINOGENESIS, TUMOR PROGRESSION AND OTHER ABNORMAL CHANGES, AND RECENT STUDIES HAVE SHOWN THAT M(6)A IS IMPORTANT IN THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC). HEREIN, WE SUMMARIZE THE NATURE AND REGULATORY MECHANISMS OF M(6)A MODIFICATION, INCLUDING ITS ROLE IN THE PATHOGENESIS OF HCC AND RELATED CHRONIC LIVER DISEASES. WE ALSO HIGHLIGHT THE CLINICAL SIGNIFICANCE AND FUTURE STRATEGIES INVOLVING RNA M(6)A MODIFICATIONS IN HCC. 2021