1 5915 124 TARGETING A PHOSPHO-STAT3-MIRNAS PATHWAY IMPROVES VESICULAR HEPATIC STEATOSIS IN AN IN VITRO AND IN VIVO MODEL. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS A LEADING CAUSE OF CHRONIC LIVER DISEASE. ALTHOUGH GENETIC PREDISPOSITION AND EPIGENETIC FACTORS CONTRIBUTE TO THE DEVELOPMENT OF NAFLD, OUR UNDERSTANDING OF THE MOLECULAR MECHANISM INVOLVED IN THE PATHOGENESIS OF THE DISEASE IS STILL EMERGING. HERE WE INVESTIGATED A POSSIBLE ROLE OF A MICRORNAS-STAT3 PATHWAY IN THE INDUCTION OF HEPATIC STEATOSIS. DIFFERENTIATED HEPARG CELLS TREATED WITH THE FATTY ACID SODIUM OLEATE (FATTY DHEPARG) RECAPITULATED FEATURES OF LIVER VESICULAR STEATOSIS AND ACTIVATED A CELL-AUTONOMOUS INFLAMMATORY RESPONSE, INDUCING STAT3-TYROSINE-PHOSPHORYLATION. WITH A GENOME-WIDE APPROACH (CHROMATIN IMMUNOPRECIPITATION SEQUENCING), MANY PHOSPHO-STAT3 BINDING SITES WERE IDENTIFIED IN FATTY DHEPARG CELLS AND SEVERAL STAT3 AND/OR NAFLD-REGULATED MICRORNAS SHOWED INCREASED EXPRESSION LEVELS, INCLUDING MIR-21. INNOVATIVE CARS (COHERENT ANTI-STOKES RAMAN SCATTERING) MICROSCOPY REVEALED THAT CHEMICAL INHIBITION OF STAT3 ACTIVITY DECREASED LIPID ACCUMULATION AND DEREGULATED STAT3-RESPONSIVE MICRORNAS, INCLUDING MIR-21, IN LIPID OVERLOADED DHEPARG CELLS. WE WERE ABLE TO SHOW IN VIVO THAT REDUCING PHOSPHO-STAT3-MIR-21 LEVELS IN C57/BL6 MICE LIVER, BY LONG-TERM TREATMENT WITH METFORMIN, PROTECTED MICE FROM AGING-DEPENDENT HEPATIC VESICULAR STEATOSIS. OUR RESULTS IDENTIFIED A MICRORNAS-PHOSPHOSTAT3 PATHWAY INVOLVED IN THE DEVELOPMENT OF HEPATIC STEATOSIS, WHICH MAY REPRESENT A MOLECULAR MARKER FOR BOTH DIAGNOSIS AND THERAPEUTIC TARGETING. 2018 2 1666 52 DOWNREGULATION OF MICRORNA-145A-5P PROMOTES STEATOSIS-TO-NASH PROGRESSION THROUGH UPREGULATION OF NR4A2. BACKGROUND & AIMS: THE MOLECULAR MECHANISMS UNDERLYING THE PROGRESSION OF SIMPLE STEATOSIS TO NON-ALCOHOLIC STEATOHEPATITIS (NASH) REMAIN INCOMPLETELY UNDERSTOOD, THOUGH THE POTENTIAL ROLE OF EPIGENETIC REGULATION BY MICRORNA (MIRNAS) IS AN AREA OF INCREASING INTEREST. IN THE PRESENT STUDY, WE AIMED TO INVESTIGATE THE ROLE AND MECHANISM OF MIRNAS DURING STEATOSIS-TO-NASH PROGRESSION. METHODS: MIR-145A-5P WAS IDENTIFIED AS AN IMPORTANT CHECKPOINT IN STEATOSIS-TO-NASH PROGRESSION. IN VIVO LOSS-OF-FUNCTION AND GAIN-OF-FUNCTION STUDIES WERE PERFORMED TO EXPLORE THE ROLE OF MIR-145A-5P AND NR4A2 IN NASH PROGRESSION. RNA-SEQUENCING AND BIOINFORMATIC ANALYSIS WERE USED TO INVESTIGATE THE TARGETS OF MIR-145A-5P. RESULTS: SUPPRESSION OF MIR-145A-5P IN THE LIVER AGGRAVATED LIPID ACCUMULATION AND ACTIVATED HEPATIC INFLAMMATION, LIVER INJURY AND FIBROSIS IN STEATOTIC MICE, WHEREAS ITS RESTORATION MARKEDLY ATTENUATED DIET-INDUCED NASH PATHOGENESIS. MECHANISTICALLY, MIR-145A-5P WAS ABLE TO DOWNREGULATE THE NUCLEAR RECEPTOR NR4A2 AND THUS INHIBIT THE EXPRESSION OF NASH-ASSOCIATED GENES. SIMILARLY, NR4A2 OVEREXPRESSION PROMOTED STEATOSIS-TO-NASH PROGRESSION WHILE LIVER-SPECIFIC NR4A2 KNOCKOUT MICE WERE PROTECTED FROM DIET-INDUCED NASH. THIS ROLE OF THE MIR-145A-5P/NR4A2 REGULATORY AXIS WAS ALSO CONFIRMED IN PRIMARY HUMAN HEPATOCYTES. FURTHERMORE, THE EXPRESSION OF MIR-145A-5P WAS REDUCED AND THE EXPRESSION OF NR4A2 WAS INCREASED IN THE LIVERS OF PATIENTS WITH NASH, WHILE THEIR EXPRESSION LEVELS SIGNIFICANTLY NEGATIVELY AND POSITIVELY CORRELATED WITH FEATURES OF LIVER PATHOLOGY, RESPECTIVELY. CONCLUSIONS: OUR FINDINGS HIGHLIGHT THE ROLE OF THE MIR-145A-5P/NR4A2 REGULATORY AXIS IN STEATOSIS-TO-NASH PROGRESSION, SUGGESTING THAT EITHER SUPPLEMENTATION OF MIR-145A-5P OR PHARMACOLOGICAL INHIBITION OF NR4A2 IN HEPATOCYTES MAY PROVIDE A PROMISING THERAPEUTIC APPROACH FOR THE TREATMENT OF NASH. IMPACT AND IMPLICATIONS: NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS A DYNAMIC SPECTRUM OF CHRONIC LIVER DISEASES RANGING FROM SIMPLE STEATOSIS TO NON-ALCOHOLIC STEATOHEPATITIS (NASH). UNFORTUNATELY, THERE ARE CURRENTLY NO APPROVED DRUGS FOR NASH. OUR CURRENT STUDY IDENTIFIED MIR-145A-5P AS A NOVEL REGULATOR THAT INHIBITS STEATOSIS-TO-NASH PROGRESSION. WE FOUND THAT MIR-145A-5P WAS ABLE TO DOWNREGULATE THE NUCLEAR RECEPTOR NR4A2 TO SUPPRESS THE EXPRESSION OF NASH-ASSOCIATED GENES. THE DIFFERENTIAL EXPRESSION OF MIR-145A-5P AND NR4A2 WAS FURTHER CONFIRMED IN PATIENTS WITH NASH, RAISING THE POSSIBILITY THAT SUPPLEMENTATION OF MIR-145A-5P OR SUPPRESSION OF NR4A2 IN HEPATOCYTES MIGHT PROVIDE NOVEL STRATEGIES FOR TREATING NASH. 2023 3 2780 42 EZH2 DOWN-REGULATION EXACERBATES LIPID ACCUMULATION AND INFLAMMATION IN IN VITRO AND IN VIVO NAFLD. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS ONE OF THE MOST PREVALENT, CHRONIC LIVER DISEASES, WORLDWIDE. IT IS A MULTIFACTORIAL DISEASE CAUSED BY COMPLEX INTERACTIONS BETWEEN GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS. RECENTLY, SEVERAL MICRORNAS, SOME OF WHICH EPIGENETICALLY REGULATED, HAVE BEEN FOUND TO BE UP- AND/OR DOWN-REGULATED DURING NAFLD DEVELOPMENT. HOWEVER, IN NAFLD, THE ESSENTIAL ROLE OF THE POLYCOMB GROUP PROTEIN ENHANCER OF ZESTE HOMOLOG 2 (EZH2), WHICH CONTROLS THE EPIGENETIC SILENCING OF SPECIFIC GENES AND/OR MICRORNAS BY TRIMETHYLATING LYS27 ON HISTONE H3, STILL REMAINS UNKNOWN. IN THIS STUDY, WE DEMONSTRATE THAT THE NUCLEAR EXPRESSION/ACTIVITY OF THE EZH2 PROTEIN IS DOWN-REGULATED BOTH IN LIVERS FROM NAFLD RATS AND IN THE FREE FATTY ACID-TREATED HEPG2. THE DROP IN EZH2 IS INVERSELY CORRELATED WITH: (I) LIPID ACCUMULATION; (II) THE EXPRESSION OF PRO-INFLAMMATORY MARKERS INCLUDING TNF-ALPHA AND TGF-BETA; AND (III) THE EXPRESSION OF MIR-200B AND MIR-155. CONSISTENTLY, THE PHARMACOLOGICAL INHIBITION OF EZH2 BY 3-DEAZANEPLANOCIN A (DZNEP) SIGNIFICANTLY REDUCES EZH2 EXPRESSION/ACTIVITY, WHILE IT INCREASES LIPID ACCUMULATION, INFLAMMATORY MOLECULES AND MICRORNAS. IN CONCLUSION, THE RESULTS OF THIS STUDY SUGGEST THAT THE DEFECTIVE ACTIVITY OF EZH2 CAN ENHANCE THE NAFLD DEVELOPMENT BY FAVOURING STEATOSIS AND THE DE-REPRESSION OF THE INFLAMMATORY GENES AND THAT OF SPECIFIC MICRORNAS. 2013 4 5438 34 REMOVAL OF EPIGENETIC REPRESSIVE MARK ON INFLAMMATORY GENES IN FAT LIVER. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS THE MOST COMMON CHRONIC LIVER DISEASE WORLDWIDE. THE DETAILED EPIGENOMIC CHANGES DURING FAT ACCUMULATION IN LIVER ARE NOT CLEAR YET. HERE, WE PERFORMED CHIP-SEQ ANALYSIS IN THE LIVER TISSUES OF HIGH-FAT DIET AND REGULAR CHOW DIET MICE AND INVESTIGATED THE DYNAMIC LANDSCAPES OF H3K27AC AND H3K9ME3 MARKS ON CHROMATIN. WE FIND THAT THE ACTIVATED TYPICAL ENHANCERS MARKED WITH H3K27AC ARE ENRICHED ON LIPID METABOLIC PATHWAYS IN FAT LIVER; HOWEVER, SUPER ENHANCERS DO NOT CHANGE MUCH. THE REGIONS COVERED WITH H3K9ME3 REPRESSIVE MARK SEEM TO UNDERGO GREAT CHANGES, AND ITS PEAK NUMBER AND INTENSITY BOTH DECREASE IN FAT LIVER. THE ENHANCERS LOCATED IN LOST H3K9ME3 REGIONS ARE ENRICHED IN LIPID METABOLISM AND INFLAMMATORY PATHWAYS; AND MOTIF ANALYSIS SHOWS THAT THEY ARE POTENTIAL TARGETS FOR TRANSCRIPTION FACTORS INVOLVED IN METABOLIC AND INFLAMMATORY PROCESSES. OUR STUDY HAS REVEALED THAT H3K9ME3 MAY PLAY AN IMPORTANT ROLE DURING THE PATHOGENESIS OF NAFLD THROUGH REGULATING THE ACCESSIBILITY OF ENHANCERS. 2023 5 6106 36 THE EMERGING ROLE OF MICRORNAS IN NAFLD: HIGHLIGHT OF MICRORNA-29A IN MODULATING OXIDATIVE STRESS, INFLAMMATION, AND BEYOND. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS A COMMON CAUSE OF CHRONIC LIVER DISEASE AND RANGES FROM STEATOSIS TO STEATOHEPATITIS AND TO LIVER FIBROSIS. LIPOTOXICITY IN HEPATOCYTES, ELEVATED OXIDATIVE STRESS AND THE ACTIVATION OF PROINFLAMMATORY MEDIATORS OF KUPFFER CELLS, AND FIBROGENIC PATHWAYS OF ACTIVATED HEPATIC STELLATE CELLS CAN CONTRIBUTE TO THE DEVELOPMENT OF NAFLD. MICRORNAS (MIRS) PLAY A CRUCIAL ROLE IN THE DYSREGULATED METABOLISM AND INFLAMMATORY SIGNALING CONNECTED WITH NAFLD AND ITS PROGRESSION TOWARDS MORE SEVERE STAGES. OF NOTE, THE PROTECTIVE EFFECT OF NON-CODING MIR-29A ON LIVER DAMAGE AND ITS VERSATILE ACTION ON EPIGENETIC ACTIVITY, MITOCHONDRIAL HOMEOSTASIS AND IMMUNOMODULATION MAY IMPROVE OUR PERCEPTION OF THE PATHOGENESIS OF NAFLD. HEREIN, WE REVIEW THE BIOLOGICAL FUNCTIONS OF CRITICAL MIRS IN NAFLD, AS WELL AS HIGHLIGHT THE EMERGING ROLE OF MIR-29A IN THERAPEUTIC APPLICATION AND THE RECENT ADVANCES IN MOLECULAR MECHANISMS UNDERLYING ITS LIVER PROTECTIVE EFFECT. 2020 6 4286 42 MICRORNA EXPRESSION ANALYSIS IN HIGH FAT DIET-INDUCED NAFLD-NASH-HCC PROGRESSION: STUDY ON C57BL/6J MICE. BACKGROUND: HEPATOCELLULAR CARCINOMA (HCC) IS THE MOST COMMON MALIGNANT TUMOR OF THE LIVER. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS A FREQUENT CHRONIC LIVER DISORDER IN DEVELOPED COUNTRIES. NAFLD CAN PROGRESS THROUGH THE MORE SEVERE NON ALCOHOLIC STEATOHEPATITIS (NASH), CIRRHOSIS AND, LASTLY, HCC. GENETIC AND EPIGENETIC ALTERATIONS OF CODING GENES AS WELL AS DEREGULATION OF MICRORNAS (MIRNAS) ACTIVITY PLAY A ROLE IN HCC DEVELOPMENT. IN THIS STUDY, THE C57BL/6J MOUSE MODEL WAS LONG TERM HIGH-FAT (HF) OR LOW-FAT (LF) DIET FED, IN ORDER TO ANALYZE MOLECULAR MECHANISMS RESPONSIBLE FOR THE HEPATIC DAMAGE PROGRESSION. METHODS: MICE WERE HF OR LF DIET FED FOR DIFFERENT TIME POINTS, THEN PLASMA AND HEPATIC TISSUES WERE COLLECTED. HISTOLOGICAL AND CLINICAL CHEMISTRY ASSAYS WERE PERFORMED TO ASSESS THE PROGRESSION OF LIVER DISEASE. MICRORNAS' DIFFERENTIAL EXPRESSION WAS EVALUATED ON POOLED RNAS FROM TISSUES, AND SOME MIRNAS SHOWING DYSREGULATION WERE FURTHER ANALYZED AT THE INDIVIDUAL LEVEL. RESULTS: CHOLESTEROL, LOW AND HIGH DENSITY LIPOPROTEINS, TRIGLYCERIDES AND ALANINE AMINOTRANSFERASE INCREASE WAS DETECTED IN HF MICE. GROSS ANATOMICAL EXAMINATION REVEALED HEPATOMEGALY IN HF LIVERS, AND HISTOLOGICAL ANALYSIS HIGHLIGHTED DIFFERENT DEGREES AND LEVELS OF STEATOSIS, INFLAMMATORY INFILTRATE AND FIBROSIS IN HF AND LF ANIMALS, DEMONSTRATING THE PROGRESSION FROM NAFLD THROUGH NASH. MACROSCOPIC NODULES, SHOWING TYPICAL NEOPLASTIC FEATURES, WERE OBSERVED IN 20% OF HF DIET FED MICE. FIFTEEN MIRNAS DIFFERENTIALLY EXPRESSED IN HF WITH RESPECT TO LF HEPATIC TISSUES DURING THE PROGRESSION OF LIVER DAMAGE, AND IN TUMORS WITH RESPECT TO HF NON TUMOR LIVER SPECIMENS WERE IDENTIFIED. AMONG THEM, MIR-340-5P, MIR-484, MIR-574-3P, MIR-720, WHOSE EXPRESSION WAS NEVER DESCRIBED IN NAFLD, NASH AND HCC TISSUES, AND MIR-125A-5P AND MIR-182, WHICH SHOWED EARLY AND SIGNIFICANT DYSREGULATION IN THE SEQUENTIAL HEPATIC DAMAGE PROCESS. CONCLUSIONS: IN THIS STUDY, FIFTEEN MICRORNAS WHICH WERE MODULATED IN HEPATIC TISSUES AND IN TUMORS DURING THE TRANSITION NAFLD-NASH-HCC ARE REPORTED. BESIDES SOME ALREADY DESCRIBED, NEW AND EARLY DYSREGULATED MIRNAS WERE IDENTIFIED. FUNCTIONAL ANALYSES ARE NEEDED TO VALIDATE THE RESULTS HERE OBTAINED, AND TO BETTER DEFINE THE ROLE OF THESE MOLECULES IN THE PROGRESSION OF THE HEPATIC DISEASE. 2016 7 5921 37 TARGETING CLINICAL EPIGENETIC REPROGRAMMING FOR CHEMOPREVENTION OF METABOLIC AND VIRAL HEPATOCELLULAR CARCINOMA. OBJECTIVE: HEPATOCELLULAR CARCINOMA (HCC) IS THE FASTEST-GROWING CAUSE OF CANCER-RELATED MORTALITY WITH CHRONIC VIRAL HEPATITIS AND NON-ALCOHOLIC STEATOHEPATITIS (NASH) AS MAJOR AETIOLOGIES. TREATMENT OPTIONS FOR HCC ARE UNSATISFACTORY AND CHEMOPREVENTIVE APPROACHES ARE ABSENT. CHRONIC HEPATITIS C (CHC) RESULTS IN EPIGENETIC ALTERATIONS DRIVING HCC RISK AND PERSISTING FOLLOWING CURE. HERE, WE AIMED TO INVESTIGATE EPIGENETIC MODIFICATIONS AS TARGETS FOR LIVER CANCER CHEMOPREVENTION. DESIGN: LIVER TISSUES FROM PATIENTS WITH NASH AND CHC WERE ANALYSED BY CHIP-SEQ (H3K27AC) AND RNA-SEQ. THE LIVER DISEASE-SPECIFIC EPIGENETIC AND TRANSCRIPTIONAL REPROGRAMMING IN PATIENTS WAS MODELLED IN A LIVER CELL CULTURE SYSTEM. PERTURBATION STUDIES COMBINED WITH A TARGETED SMALL MOLECULE SCREEN FOLLOWED BY IN VIVO AND EX VIVO VALIDATION WERE USED TO IDENTIFY CHROMATIN MODIFIERS AND READERS FOR HCC CHEMOPREVENTION. RESULTS: IN PATIENTS, CHC AND NASH SHARE SIMILAR EPIGENETIC AND TRANSCRIPTOMIC MODIFICATIONS DRIVING CANCER RISK. USING A CELL-BASED SYSTEM MODELLING EPIGENETIC MODIFICATIONS IN PATIENTS, WE IDENTIFIED CHROMATIN READERS AS TARGETS TO REVERT LIVER GENE TRANSCRIPTION DRIVING CLINICAL HCC RISK. PROOF-OF-CONCEPT STUDIES IN A NASH-HCC MOUSE MODEL SHOWED THAT THE PHARMACOLOGICAL INHIBITION OF CHROMATIN READER BROMODOMAIN 4 INHIBITED LIVER DISEASE PROGRESSION AND HEPATOCARCINOGENESIS BY RESTORING TRANSCRIPTIONAL REPROGRAMMING OF THE GENES THAT WERE EPIGENETICALLY ALTERED IN PATIENTS. CONCLUSION: OUR RESULTS UNRAVEL THE FUNCTIONAL RELEVANCE OF METABOLIC AND VIRUS-INDUCED EPIGENETIC ALTERATIONS FOR PATHOGENESIS OF HCC DEVELOPMENT AND IDENTIFY CHROMATIN READERS AS TARGETS FOR CHEMOPREVENTION IN PATIENTS WITH CHRONIC LIVER DISEASES. 2021 8 5533 30 ROLE AND MECHANISM OF DNA METHYLATION AND ITS INHIBITORS IN HEPATIC FIBROSIS. LIVER FIBROSIS IS A REPAIR RESPONSE TO INJURY CAUSED BY VARIOUS CHRONIC STIMULI THAT CONTINUALLY ACT ON THE LIVER. AMONG THEM, THE ACTIVATION OF HEPATIC STELLATE CELLS (HSCS) AND THEIR TRANSFORMATION INTO A MYOFIBROBLAST PHENOTYPE IS A KEY EVENT LEADING TO LIVER FIBROSIS, HOWEVER THE MECHANISM HAS NOT YET BEEN ELUCIDATED. THE MOLECULAR BASIS OF HSC ACTIVATION INVOLVES CHANGES IN THE REGULATION OF GENE EXPRESSION WITHOUT CHANGES IN THE GENOME SEQUENCE, NAMELY, VIA EPIGENETIC REGULATION. DNA METHYLATION IS A KEY FOCUS OF EPIGENETIC RESEARCH, AS IT AFFECTS THE EXPRESSION OF FIBROSIS-RELATED, METABOLISM-RELATED, AND TUMOR SUPPRESSOR GENES. INCREASING STUDIES HAVE SHOWN THAT DNA METHYLATION IS CLOSELY RELATED TO SEVERAL PHYSIOLOGICAL AND PATHOLOGICAL PROCESSES INCLUDING HSC ACTIVATION AND LIVER FIBROSIS. THIS REVIEW AIMED TO DISCUSS THE MECHANISM OF DNA METHYLATION IN THE PATHOGENESIS OF LIVER FIBROSIS, EXPLORE DNA METHYLATION INHIBITORS AS POTENTIAL THERAPIES FOR LIVER FIBROSIS, AND PROVIDE NEW INSIGHTS ON THE PREVENTION AND CLINICAL TREATMENT OF LIVER FIBROSIS. 2023 9 5012 34 PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA AS A TARGET AND REGULATOR OF EPIGENETIC MECHANISMS IN NONALCOHOLIC FATTY LIVER DISEASE. PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA (PPARGAMMA) BELONGS TO THE SUPERFAMILY OF NUCLEAR RECEPTORS THAT CONTROL THE TRANSCRIPTION OF MULTIPLE GENES. ALTHOUGH IT IS FOUND IN MANY CELLS AND TISSUES, PPARGAMMA IS MOSTLY EXPRESSED IN THE LIVER AND ADIPOSE TISSUE. PRECLINICAL AND CLINICAL STUDIES SHOW THAT PPARGAMMA TARGETS SEVERAL GENES IMPLICATED IN VARIOUS FORMS OF CHRONIC LIVER DISEASE, INCLUDING NONALCOHOLIC FATTY LIVER DISEASE (NAFLD). CLINICAL TRIALS ARE CURRENTLY UNDERWAY TO INVESTIGATE THE BENEFICIAL EFFECTS OF PPARGAMMA AGONISTS ON NAFLD/NONALCOHOLIC STEATOHEPATITIS. UNDERSTANDING PPARGAMMA REGULATORS MAY THEREFORE AID IN UNRAVELING THE MECHANISMS GOVERNING THE DEVELOPMENT AND PROGRESSION OF NAFLD. RECENT ADVANCES IN HIGH-THROUGHPUT BIOLOGY AND GENOME SEQUENCING HAVE GREATLY FACILITATED THE IDENTIFICATION OF EPIGENETIC MODIFIERS, INCLUDING DNA METHYLATION, HISTONE MODIFIERS, AND NON-CODING RNAS AS KEY FACTORS THAT REGULATE PPARGAMMA IN NAFLD. IN CONTRAST, LITTLE IS STILL KNOWN ABOUT THE PARTICULAR MOLECULAR MECHANISMS UNDERLYING THE INTRICATE RELATIONSHIPS BETWEEN THESE EVENTS. THE PAPER THAT FOLLOWS OUTLINES OUR CURRENT UNDERSTANDING OF THE CROSSTALK BETWEEN PPARGAMMA AND EPIGENETIC REGULATORS IN NAFLD. ADVANCES IN THIS FIELD ARE LIKELY TO AID IN THE DEVELOPMENT OF EARLY NONINVASIVE DIAGNOSTICS AND FUTURE NAFLD TREATMENT STRATEGIES BASED ON PPARGAMMA EPIGENETIC CIRCUIT MODIFICATION. 2023 10 2323 24 EPIGENETIC REGULATION OF HEPATIC STELLATE CELL ACTIVATION AND MACROPHAGE IN CHRONIC LIVER INFLAMMATION. CHRONIC LIVER INFLAMMATION IS A COMPLEX PATHOLOGICAL PROCESS UNDER DIFFERENT STRESS CONDITIONS, AND THE ROLES OF STELLATE CELLS AND MACROPHAGES IN CHRONIC LIVER INFLAMMATION HAVE BEEN WIDELY REPORTED. MODERATE LIVER INFLAMMATION CAN PROTECT THE LIVER FROM DAMAGE AND FACILITATE THE RECOVERY OF LIVER INJURY. HOWEVER, AN INFLAMMATORY RESPONSE THAT IS TOO INTENSE CAN RESULT IN MASSIVE DEATH OF HEPATOCYTES, WHICH LEADS TO IRREVERSIBLE DAMAGE TO THE LIVER PARENCHYMA. EPIGENETIC REGULATION PLAYS A KEY PART IN LIVER INFLAMMATION. THIS STUDY REVIEWS THE REGULATION OF EPIGENETICS ON STELLATE CELLS AND MACROPHAGES TO EXPLORE THE NEW MECHANISMS OF EPIGENETICS ON LIVER INFLAMMATION AND PROVIDE NEW IDEAS FOR THE TREATMENT OF LIVER DISEASE. 2021 11 413 37 ANALYSIS OF MIRNAS PROFILES IN SERUM OF PATIENTS WITH STEATOSIS AND STEATOHEPATITIS. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS EMERGING AS ONE OF THE MOST COMMON CHRONIC LIVER DISEASES WORLDWIDE, AFFECTING 25% OF THE WORLD POPULATION. IN RECENT YEARS, THERE HAS BEEN INCREASING EVIDENCE FOR THE INVOLVEMENT OF MICRORNAS IN THE EPIGENETIC REGULATION OF GENES TAKING PART IN THE DEVELOPMENT OF STEATOSIS AND STEATOHEPATITIS-TWO MAIN STAGES OF NAFLD PATHOGENESIS. IN THE PRESENT STUDY, MIRNA PROFILES WERE STUDIED IN GROUPS OF PATIENTS WITH STEATOSIS AND STEATOHEPATITIS TO COMPARE THE CHARACTERISTICS OF RNA-DEPENDENT EPIGENETIC REGULATION OF THE STAGES OF NAFLD DEVELOPMENT. ACCORDING TO THE RESULTS OF MIRNA SCREENING, 23 MIRNAS WERE DIFFERENTIALLY EXPRESSED SERUM IN A GROUP OF PATIENTS WITH STEATOHEPATITIS AND 2 IN A GROUP OF PATIENTS WITH STEATOSIS. MIR-195-5P AND MIR-16-5P ARE COMMON DIFFERENTIALLY EXPRESSED MIRNAS FOR BOTH STEATOSIS AND STEATOHEPATITIS. WE ANALYZED THE OBTAINED RESULTS: THE SEARCH FOR TARGET GENES FOR THE DIFFERENTIALLY EXPRESSED MIRNAS IN OUR STUDY AND THE SUBSEQUENT GENE SET ENRICHMENT ANALYSIS PERFORMED ON KEGG AND REACTOME DATABASES REVEALED WHICH METABOLIC PATHWAYS UNDERGO CHANGES IN RNA-DEPENDENT EPIGENETIC REGULATION IN STEATOSIS AND STEATOHEPATITIS. NEW FINDINGS WITHIN THE FRAMEWORK OF THIS STUDY ARE THE DYSREGULATION OF NEUROHUMORAL PATHWAYS IN THE PATHOGENESIS OF NAFLD AS AN OBJECT OF CHANGES IN RNA-DEPENDENT EPIGENETIC REGULATION. THE MIRNAS DIFFERENTIALLY EXPRESSED IN OUR STUDY WERE FOUND TO TARGET 7% OF GENES IN THE CLASSIC PATHOGENESIS OF NAFLD IN THE GROUP OF PATIENTS WITH STEATOSIS AND 50% IN THE GROUP OF PATIENTS WITH STEATOHEPATITIS. THE EFFECTS OF THESE MICRORNAS ON GENES FOR THE PATHOGENESIS OF NAFLD WERE ANALYZED IN DETAIL. MIR-374A-5P, MIR-1-3P AND MIR-23A-3P DO NOT TARGET GENES DIRECTLY INVOLVED IN THE PATHOGENESIS OF NAFLD. THE DIFFERENTIALLY EXPRESSED MIRNAS FOUND IN THIS STUDY TARGET GENES LARGELY RESPONSIBLE FOR MITOCHONDRIAL FUNCTION. THE ROLE OF MIR-423-5P, MIR-143-5P AND MIR-200C-3 IN REGULATING APOPTOTIC PROCESSES IN THE LIVER AND HEPATOCARCINOGENESIS IS OF INTEREST FOR FUTURE EXPERIMENTAL STUDIES. THESE MIR-374A, MIR-143, MIR-1, MIR-23A, AND MIR-423 HAVE POTENTIAL FOR STEATOHEPATITIS DIAGNOSIS AND ARE POORLY STUDIED IN THE CONTEXT OF NAFLD. THUS, THIS WORK OPENS UP PROSPECTS FOR FURTHER STUDIES OF MICRORNAS AS DIAGNOSTIC AND THERAPEUTIC BIOMARKERS FOR NAFLD. 2021 12 1128 29 COMPREHENSIVE ANALYSIS OF EPIGENETIC AND EPITRANSCRIPTOMIC GENES' EXPRESSION IN HUMAN NAFLD. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS A MULTIFACTORIAL CONDITION WITH A COMPLEX ETIOLOGY. ITS INCIDENCE IS INCREASING GLOBALLY IN PARALLEL WITH THE OBESITY EPIDEMIC, AND IT IS NOW CONSIDERED THE MOST COMMON LIVER DISEASE IN WESTERN COUNTRIES. THE PRECISE MECHANISMS UNDERLYING THE DEVELOPMENT AND PROGRESSION OF NAFLD ARE COMPLEX AND STILL POORLY UNDERSTOOD. THE DYSREGULATION OF EPIGENETIC AND EPITRANSCRIPTOMIC MECHANISMS IS INCREASINGLY RECOGNIZED TO PLAY PATHOGENIC ROLES IN MULTIPLE CONDITIONS, INCLUDING CHRONIC LIVER DISEASES. HERE, WE HAVE PERFORMED A COMPREHENSIVE ANALYSIS OF THE EXPRESSION OF EPIGENETIC AND EPITRANSCRIPTOMIC GENES IN A TOTAL OF 903 LIVER TISSUE SAMPLES CORRESPONDING TO PATIENTS WITH NORMAL LIVER, OBESE PATIENTS, AND PATIENTS WITH NON-ALCOHOLIC FATTY LIVER (NAFL) AND NON-ALCOHOLIC STEATOHEPATITIS (NASH), ADVANCING STAGES IN NAFLD PROGRESSION. WE INTEGRATED TEN TRANSCRIPTOMIC DATASETS IN AN UNBIASED MANNER, ENABLING THEIR ROBUST ANALYSIS AND COMPARISON. WE DESCRIBE THE COMPLETE LANDSCAPE OF EPIGENETIC AND EPITRANSCRIPTOMIC GENES' EXPRESSION ALONG THE COURSE OF THE DISEASE. WE IDENTIFY SIGNATURES OF GENES SIGNIFICANTLY DYSREGULATED IN ASSOCIATION WITH DISEASE PROGRESSION, PARTICULARLY WITH LIVER FIBROSIS DEVELOPMENT. MOST OF THESE EPIGENETIC AND EPITRANSCRIPTOMIC EFFECTORS HAVE NOT BEEN PREVIOUSLY DESCRIBED IN HUMAN NAFLD, AND THEIR ALTERED EXPRESSION MAY HAVE PATHOGENIC IMPLICATIONS. WE ALSO PERFORMED A COMPREHENSIVE ANALYSIS OF THE EXPRESSION OF ENZYMES INVOLVED IN THE METABOLISM OF THE SUBSTRATES AND COFACTORS OF EPIGENETIC AND EPITRANSCRIPTOMIC EFFECTORS. THIS STUDY PROVIDES NOVEL INFORMATION ON NAFLD PATHOGENESIS AND MAY ALSO GUIDE THE IDENTIFICATION OF DRUG TARGETS TO TREAT THIS CONDITION AND ITS PROGRESSION TOWARDS HEPATOCELLULAR CARCINOMA. 2023 13 4659 38 NEW APPROACHES FOR STUDYING ALCOHOLIC LIVER DISEASE. ALCOHOLIC LIVER DISEASE (ALD) IS MAJOR CAUSE OF CHRONIC LIVER INJURY WHICH RESULTS IN LIVER FIBROSIS AND CIRRHOSIS. ACCORDING TO THE SURVEILLANCE REPORT PUBLISHED BY THE NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM, LIVER CIRRHOSIS IS THE 12TH LEADING CAUSE OF DEATH IN THE UNITED STATES WITH 48 % OF THESE DEATHS BEING ATTRIBUTED TO EXCESSIVE ALCOHOL CONSUMPTION. ALD INCLUDES A SPECTRUM OF DISORDERS FROM SIMPLE STEATOSIS TO STEATOHEPATITIS, FIBROSIS, AND HEPATOCELLULAR CARCINOMA. SEVERAL MECHANISMS PLAY A CRITICAL ROLE IN THE PATHOGENESIS OF ALD. THESE INCLUDE ETHANOL-INDUCED OXIDATIVE STRESS AND DEPLETION OF GLUTATHIONE, PATHOLOGICAL METHIONINE METABOLISM, INCREASED GUT PERMEABILITY AND RELEASE OF ENDOTOXINS INTO THE PORTAL BLOOD, RECRUITMENT AND ACTIVATION OF INFLAMMATORY CELLS INCLUDING BONE MARROW-DERIVED AND LIVER RESIDENT MACROPHAGES (KUPFFER CELLS). CHRONIC ALCOHOL CONSUMPTION RESULTS IN LIVER DAMAGE AND ACTIVATION OF HEPATIC STELLATE CELLS (HSCS) AND MYOFIBROBLASTS, LEADING TO LIVER FIBROSIS. HERE WE DISCUSS THE CURRENT VIEW ON FACTORS THAT ARE SPECIFIC FOR DIFFERENT STAGES OF ALD AND THOSE THAT REGULATE ITS PROGRESSION, INCLUDING CYTOKINES AND CHEMOKINES, ALCOHOL-RESPONSIVE INTRACELLULAR SIGNALING PATHWAYS, AND TRANSCRIPTIONAL FACTORS. WE ALSO REVIEW RECENT STUDIES DEMONSTRATING THAT ALCOHOL-MEDIATED CHANGES CAN BE REGULATED ON AN EPIGENETIC LEVEL, INCLUDING MICRORNAS. FINALLY, WE DISCUSS THE REVERSIBILITY OF LIVER FIBROSIS AND INACTIVATION OF HSCS AS A POTENTIAL STRATEGY FOR TREATING ALCOHOL-INDUCED LIVER DAMAGE. 2014 14 5386 33 REDOX HOMEOSTASIS AND EPIGENETICS IN NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD). NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD), AN ACCUMULATION OF INTRA-HEPATIC TRIGLYCERIDES THAT IS OFTEN CONSIDERED THE HEPATIC MANIFESTATION OF INSULIN RESISTANCE, IS THE MOST COMMON CAUSE OF CHRONIC LIVER DISEASE IN THE WESTERN COUNTRIES WITH UP TO ONE THIRD OF THE POPULATION AFFECTED. NAFLD IS A SPECTRUM OF DISTURBANCES THAT ENCOMPASSES VARIOUS DEGREES OF LIVER DAMAGE RANGING FROM SIMPLE STEATOSIS TO NON-ALCOHOLIC STEATOHEPATITIS (NASH). NASH IS CHARACTERIZED BY HEPATOCELLULAR INJURY/INFLAMMATION WITH OR WITHOUT FIBROSIS. THE INDIVIDUALS WITH NAFLD DEVELOP NASH IN 10% OF THE CASES, AND ARE ALSO AT RISK OF DEVELOPING HEPATOCELLULAR CARCINOMA (HCC). EPIGENETIC MECHANISMS OF NUCLEAR CHROMATIN REMODELING, SUCH AS DNA METHYLATION, POST-TRANSLATIONAL MODIFICATIONS OF HISTONES, AND INCORPORATION OF HISTONE VARIANTS INTO THE CHROMATIN ARE INCREASINGLY RECOGNIZED AS CRUCIAL FACTORS IN THE PATHOPHYSIOLOGY OF NAFLD. NAFLD IS OFTEN ACCOMPANIED BY OXIDATIVE STRESS: REACTIVE OXYGEN SPECIES (ROS) ARE IMPLICATED IN ALTERED REDUCTION/OXIDATION (REDOX) REACTIONS THAT ATTACK CELLULAR MACROMOLECULES AND ARE DETECTED IN THE LIVER OF PATIENTS AND ANIMAL MODELS OF NAFLD. IN THIS REVIEW, WE SUMMARIZE RECENT KNOWLEDGE ADVANCEMENTS IN THE HEPATIC EPIGENETIC AND REDOX MECHANISMS, AND THEIR POSSIBLE LINKS, INVOLVED IN THE PATHOGENESIS AND TREATMENT OF NAFLD. 2013 15 2104 29 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 16 6092 27 THE EFFECTS OF EPIGENETIC MODIFICATION ON THE OCCURRENCE AND PROGRESSION OF LIVER DISEASES AND THE INVOLVED MECHANISM. INTRODUCTION: EPIGENETIC MODIFICATION IS A TYPE OF GENE EXPRESSION AND REGULATION THAT DOES NOT INVOLVE CHANGES IN DNA SEQUENCES. AN INCREASING NUMBER OF STUDIES HAVE PROVEN THAT EPIGENETIC MODIFICATIONS PLAY AN IMPORTANT ROLE IN THE OCCURRENCE AND PROGRESSION OF LIVER DISEASES THROUGH THE GENE REGULATION AND PROTEIN EXPRESSIONS OF HEPATOCELLULAR LIPID METABOLISM, INFLAMMATORY REACTION, CELL PROLIFERATION, AND ACTIVATION, ETC.AREAS COVERED: IN THIS STUDY, WE ELABORATED AND ANALYZED THE UNDERLYING FUNCTIONAL MECHANISM OF EPIGENETIC MODIFICATION IN ALCOHOLIC LIVER DISEASE (ALD), NONALCOHOLIC FATTY LIVER DISEASE (NAFLD), LIVER FIBROSIS (LF), VIRAL HEPATITIS, HEPATOCELLULAR CARCINOMA (HCC), AND RESEARCH PROGRESS OF RECENT YEARS.EXPERT OPINION: THE FURTHER UNDERSTANDING OF EPIGENETIC MECHANISMS THAT CAN REGULATE GENE EXPRESSION AND CELL PHENOTYPE LEADS TO NEW INSIGHTS IN EPIGENETIC CONTROL OF CHRONIC LIVER DISEASE. CURRENTLY, HEPATOLOGISTS ARE EXPLORING THE ROLE OF DNA METHYLATION, HISTONE/CHROMATIN MODIFICATION, AND NON-CODING RNA IN SPECIFIC LIVER PATHOLOGY. THESE FINDINGS HAVE LED TO ADVANCES IN DIRECT EPIGENETIC BIOMARKER TESTING OF PATIENT TISSUE OR BODY FLUID SPECIMENS, AS WELL AS QUANTITATIVE ANALYSIS. BASED ON THESE FINDINGS, DRUG VALIDATION OF SOME TARGETS INVOLVED IN THE EPIGENETIC MECHANISM OF LIVER DISEASE IS GRADUALLY BEING CARRIED OUT CLINICALLY. 2020 17 3240 38 HEPATIC LIPID ACCUMULATION ALTERS GLOBAL HISTONE H3 LYSINE 9 AND 4 TRIMETHYLATION IN THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA NETWORK. RECENT DATA SUGGEST THAT THE ETIOLOGY OF SEVERAL METABOLIC DISEASES IS CLOSELY ASSOCIATED WITH TRANSCRIPTOME ALTERATION BY ABERRANT HISTONE METHYLATION. WE PERFORMED DNA MICROARRAY AND CHIP-ON-CHIP ANALYSES TO EXAMINE TRANSCRIPTOME PROFILING AND TRIMETHYLATION ALTERATIONS TO IDENTIFY THE GENOMIC SIGNATURE OF NONALCOHOLIC FATTY LIVER DISEASE (NAFLD), THE MOST COMMON FORM OF CHRONIC LIVER DISEASE. TRANSCRIPTOME ANALYSIS SHOWED THAT STEATOTIC LIVERS IN HIGH-FAT DIET-FED APOLIPOPROTEIN E2 MICE SIGNIFICANTLY ALTERED THE EXPRESSION OF APPROXIMATELY 70% OF TOTAL GENES COMPARED WITH NORMAL DIET-FED CONTROL LIVERS, SUGGESTING THAT HEPATIC LIPID ACCUMULATION INDUCES DRAMATIC ALTERATIONS IN GENE EXPRESSION IN VIVO. ALSO, PATHWAY ANALYSIS SUGGESTED THAT GENES ENCODING CHROMATIN-REMODELING ENZYMES, SUCH AS JUMONJI C-DOMAIN-CONTAINING HISTONE DEMETHYLASES THAT REGULATE HISTONE H3K9 AND H3K4 TRIMETHYLATION (H3K9ME3, H3K4ME3), WERE SIGNIFICANTLY ALTERED IN STEATOTIC LIVERS. THUS, WE FURTHER INVESTIGATED THE GLOBAL H3K9ME3 AND H3K4ME3 STATUS IN LIPID-ACCUMULATED MOUSE PRIMARY HEPATOCYTES BY CHIP-ON-CHIP ANALYSIS. RESULTS SHOWED THAT HEPATIC LIPID ACCUMULATION INDUCED ABERRANT H3K9ME3 AND H3K4ME3 STATUS IN PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA AND HEPATIC LIPID CATABOLISM NETWORK GENES, REDUCING THEIR MRNA EXPRESSION COMPARED WITH NON-TREATED CONTROL HEPATOCYTES. THIS STUDY PROVIDES THE FIRST EVIDENCE THAT EPIGENETIC REGULATION BY H3K9ME3 AND H3K4ME3 IN HEPATOCYTES MAY BE INVOLVED IN HEPATIC STEATOSIS AND THE PATHOGENESIS OF NAFLD. THUS, CONTROL OF H3K9ME3 AND H3K4ME3 REPRESENTS A POTENTIAL NOVEL NAFLD PREVENTION AND TREATMENT STRATEGY. 2012 18 4284 31 MICRORNA CIRCUITS REGULATE THE CANCER-INFLAMMATION LINK. GENETIC AND EPIGENETIC PERTURBATIONS ARE REQUIRED TO TRANSFORM NORMAL CELLS INTO CANCER CELLS. INFLAMMATORY SIGNALING PATHWAYS ARE ACTIVATED IN VARIOUS CANCERS, LINKING CHRONIC INFLAMMATION TO ONCOGENESIS. HOWEVER, THE MOLECULAR CIRCUITS THAT RESULT IN SUSTAINED ACTIVATION OF THESE INFLAMMATORY FACTORS ARE NOT YET WELL UNDERSTOOD. IN THE 28 JANUARY 2014 ISSUE OF SCIENCE SIGNALING, XIANG ET AL. IDENTIFIED A MICRORNA-MEDIATED ANTI-INFLAMMATORY CIRCUIT THAT IS REPRESSED EPIGENETICALLY IN RECEPTOR-NEGATIVE BREAST CANCERS. A HIGH-THROUGHPUT SCREEN FOR SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 (STAT3)-REGULATED MICRORNAS REVEALED MICRORNA MIR-146B AS A DIRECT STAT3 TARGET IN MAMMARY EPITHELIAL CELLS, BUT DNA METHYLATION IN ITS PROMOTER AREA SUPPRESSED MIR-146B EXPRESSION IN CANCER CELLS. OVEREXPRESSION OF MIR-146B SUPPRESSED NUCLEAR FACTOR KAPPAB (NF-KAPPAB)-DEPENDENT EXPRESSION OF IL6 AND SUBSEQUENT STAT3 ACTIVATION AND DECREASED THE STAT3-INDUCED INVASIVENESS AND MESENCHYMAL PHENOTYPE OF BREAST CANCER CELLS. OVERALL, THIS STUDY CONTRIBUTES TO OUR UNDERSTANDING OF HOW INFLAMMATION IS INVOLVED IN ONCOGENIC TRANSFORMATION. FURTHER STUDIES COULD EVALUATE THE THERAPEUTIC POTENTIAL OF TARGETING THIS CIRCUIT IN ESTROGEN RECEPTOR-NEGATIVE BREAST CANCERS. 2014 19 1615 33 DNA METHYLTRANSFERASE 3B PLAYS A PROTECTIVE ROLE AGAINST HEPATOCARCINOGENESIS CAUSED BY CHRONIC INFLAMMATION VIA MAINTAINING MITOCHONDRIAL HOMEOSTASIS. MOST HEPATOCELLULAR CARCINOMAS (HCCS) DEVELOP ON THE BASIS OF CHRONIC HEPATITIS, BUT THE MECHANISM OF EPIGENETIC REGULATION IN INFLAMMATORY HEPATOCARCINOGENESIS HAS YET TO BE ELUCIDATED. AMONG DE NOVO DNA METHYLTRANSFERASES (DNMTS), DNMT3B HAS LATELY BEEN REPORTED TO ACT SPECIFICALLY ON ACTIVELY TRANSCRIBED GENES, SUGGESTING THE POSSIBILITY THAT IT PLAYS A ROLE IN THE PATHOGENESIS OF CANCER. WE CONFIRMED THAT DNMT3B ISOFORMS LACKING ITS CATALYTIC DOMAIN WERE HIGHLY EXPRESSED IN HCCS COMPARED WITH NON-TUMOROUS LIVER TISSUE. TO ELUCIDATE THE ROLE OF DNMT3B IN HEPATOCARCINOGENESIS, WE GENERATED A GENETICALLY ENGINEERED MOUSE MODEL WITH HEPATOCYTE-SPECIFIC DNMT3B DELETION. THE LIVER OF THE DNMT3B-DEFICIENT MICE EXHIBITED AN EXACERBATION OF THIOACETAMIDE-INDUCED HEPATITIS, PROGRESSION OF LIVER FIBROSIS AND A HIGHER INCIDENCE OF HCC COMPARED WITH THE LIVER OF THE CONTROL MICE. WHOLE-GENOME BISULFITE SEQUENCING VERIFIED A LOWER CG METHYLATION LEVEL IN THE DNMT3B-DEFICIENT LIVER, DEMONSTRATING DIFFERENTIALLY METHYLATED REGIONS THROUGHOUT THE GENOME. TRANSCRIPTOME ANALYSIS REVEALED DECREASED EXPRESSION OF GENES RELATED TO OXIDATIVE PHOSPHORYLATION IN THE DNMT3B-DEFICIENT LIVER. MOREOVER, PRIMARY HEPATOCYTES ISOLATED FROM THE DNMT3B-DEFICIENT MICE SHOWED REDUCED MITOCHONDRIAL RESPIRATORY CAPACITY, LEADING TO THE ENHANCEMENT OF OXIDATIVE STRESS IN THE LIVER TISSUE. OUR FINDINGS SUGGEST THE PROTECTIVE ROLE OF DNMT3B AGAINST CHRONIC INFLAMMATION AND HCC DEVELOPMENT VIA MAINTAINING MITOCHONDRIAL HOMEOSTASIS. 2020 20 6372 26 THE ROLE OF MIR-29A IN THE REGULATION, FUNCTION, AND SIGNALING OF LIVER FIBROSIS. BOTH FIBROSIS AND CIRRHOSIS OF THE LIVER ARE THE END RESULTS OF MOST KINDS OF CHRONIC LIVER DAMAGE AND REPRESENT A COMMON BUT DIFFICULT CLINICAL CHALLENGE THROUGHOUT THE WORLD. THE INHIBITION OF THE FIBROGENIC, PROLIFERATIVE, AND MIGRATORY EFFECTS OF HEPATIC STELLATE CELLS (HSCS) HAS BECOME AN EXPERIMENTAL THERAPY FOR PREVENTING AND EVEN REVERSING HEPATIC FIBROSIS. FURTHERMORE, A COMPLETE UNDERSTANDING OF THE FUNCTION OF NON-CODING RNA-MEDIATED EPIGENETIC MECHANISMS IN HSC ACTIVATION MAY IMPROVE OUR PERCEPTION OF LIVER FIBROSIS PATHOGENESIS. THIS REVIEW FOCUSES ON THE EVOLVING VIEW OF THE MOLECULAR MECHANISMS BY WHICH HSC ACTIVATION BY MIR-29A SIGNALING MAY MODERATE THE PROFIBROGENIC PHENOTYPE OF THESE CELLS, THUS SUPPORTING THE USE OF MIR-29A AGONISTS AS A POTENTIAL THERAPY FOR TREATING LIVER FIBROSIS IN THE FUTURE. 2018