1 4215 131 METHYL DEFICIENCY, ALTERATIONS IN GLOBAL HISTONE MODIFICATIONS, AND CARCINOGENESIS. THE METHYL-DEFICIENT MODEL OF ENDOGENOUS HEPATOCARCINOGENESIS IN RODENTS IS UNIQUE IN THAT DIETARY OMISSION RATHER THAN THE ADDITION OF CHEMICAL CARCINOGENS LEADS TO TUMOR FORMATION. THUS, THE BIOCHEMICAL AND MOLECULAR EVENTS PREDISPOSING TO CANCER IN THIS MODEL RESULT FROM CHRONIC METABOLIC STRESS AND PROVIDE AN IDEAL MODEL SYSTEM TO STUDY PROGRESSIVE ALTERATIONS THAT OCCUR DURING CARCINOGENESIS. MOREOVER, EPIGENETIC ALTERATIONS IMPOSED BY THIS DIET ARE BELIEVED TO BE 1 OF THE MAIN MECHANISMS RESPONSIBLE FOR MALIGNANT TRANSFORMATION OF RAT LIVER CELLS. IN THIS STUDY WE EXAMINED THE CHANGES IN GLOBAL HISTONE MODIFICATION PATTERNS IN LIVER DURING HEPATOCARCINOGENESIS INDUCED BY METHYL DEFICIENCY. FEEDING ANIMALS THE METHYL-DEFICIENT DIET (MDD) LED TO PROGRESSIVE LOSS OF HISTONE H4 LYSINE 20 TRIMETHYLATION (H4K20ME3), H3 LYSINE 9 TRIMETHYLATION (H3K9ME3), AND HISTONE H3 LYSINE 9 (H3K9AC) AND HISTONE H4 LYSINE 16 (H4K16AC) ACETYLATION. A CONSIDERABLE DECREASE OF H4K20ME3 AND H3K9AC WAS ALSO DETECTED IN LIVER TUMORS INDUCED BY MDD. IN CONTRAST, LIVER TUMORS DISPLAYED AN INCREASE IN H3K9ME3 AND H4K16AC. TO DETERMINE THE POSSIBLE MECHANISM OF ALTERATIONS OF HISTONE MODIFICATIONS, WE ANALYZED THE EXPRESSION OF HISTONE-MODIFYING ENZYMES IN LIVER DURING HEPATOCARCINOGENESIS. THE EXPRESSION OF SUV4-20H2 AND RIZ1 HISTONE METHYLTRANSFERASES (HMTS) STEADILY DECREASED ALONG WITH THE DEVELOPMENT OF LIVER TUMORS AND REACHED ITS LOWEST LEVEL IN TUMOR TISSUE, WHEREAS THE EXPRESSION OF SUV39-H1 HMT AND HISTONE ACETYLTRANSFERASE 1 (HAT1) SUBSTANTIALLY INCREASED IN TUMORS. THESE RESULTS ILLUSTRATE THE COMPLEXITY AND IMPORTANCE OF HISTONE MODIFICATION CHANGES IN THE ETIOLOGY OF HEPATOCARCINOGENESIS INDUCED BY MDD. 2007 2 4768 31 NUCLEAR EFFECTS OF ETHANOL-INDUCED PROTEASOME INHIBITION IN LIVER CELLS. ALCOHOL INGESTION CAUSES ALTERATION IN SEVERAL CELLULAR MECHANISMS, AND LEADS TO INFLAMMATION, APOPTOSIS, IMMUNOLOGICAL RESPONSE DEFECTS, AND FIBROSIS. THESE PHENOMENA ARE ASSOCIATED WITH SIGNIFICANT CHANGES IN THE EPIGENETIC MECHANISMS, AND SUBSEQUENTLY, TO LIVER CELL MEMORY. THE UBIQUITIN-PROTEASOME PATHWAY IS ONE OF THE VITAL PATHWAYS IN THE CELL THAT BECOMES DYSFUNCTIONAL AS A RESULT OF CHRONIC ETHANOL CONSUMPTION. INHIBITION OF THE PROTEASOME ACTIVITY IN THE NUCLEUS CAUSES CHANGES IN THE TURNOVER OF TRANSCRIPTIONAL FACTORS, HISTONE MODIFYING ENZYMES, AND THEREFORE, AFFECTS EPIGENETIC MECHANISMS. ALCOHOL CONSUMPTION HAS BEEN ASSOCIATED WITH AN INCREASE IN HISTONE ACETYLATION AND A DECREASE IN HISTONE METHYLATION, WHICH LEADS TO GENE EXPRESSION CHANGES. DNA AND HISTONE MODIFICATIONS THAT RESULT FROM ETHANOL-INDUCED PROTEASOME INHIBITION ARE KEY PLAYERS IN REGULATING GENE EXPRESSION, ESPECIALLY GENES INVOLVED IN THE CELL CYCLE, IMMUNOLOGICAL RESPONSES, AND METABOLISM OF ETHANOL. THE PRESENT REVIEW HIGHLIGHTS THE CONSEQUENCES OF ETHANOL-INDUCED PROTEASOME INHIBITION IN THE NUCLEUS OF LIVER CELLS THAT ARE CHRONICALLY EXPOSED TO ETHANOL. 2009 3 2590 39 EPIGENETICS OF PROTEASOME INHIBITION IN THE LIVER OF RATS FED ETHANOL CHRONICALLY. AIM: TO EXAMINE THE EFFECTS OF ETHANOL-INDUCED PROTEASOME INHIBITION, AND THE EFFECTS OF PROTEASOME INHIBITION IN THE REGULATION OF EPIGENETIC MECHANISMS. METHODS: RATS WERE FED ETHANOL FOR 1 MO USING THE TSUKAMOTO-FRENCH MODEL AND WERE COMPARED TO RATS GIVEN THE PROTEASOME INHIBITOR PS-341 (BORTEZOMIB, VELCADE(TM)) BY INTRAPERITONEAL INJECTION. MICROARRAY ANALYSIS AND REAL TIME PCR WERE PERFORMED AND PROTEASOME ACTIVITY ASSAYS AND WESTERN BLOT ANALYSIS WERE PERFORMED USING ISOLATED NUCLEI. RESULTS: CHRONIC ETHANOL FEEDING CAUSED A SIGNIFICANT INHIBITION OF THE UBIQUITIN PROTEASOME PATHWAY IN THE NUCLEUS, WHICH LED TO CHANGES IN THE TURNOVER OF TRANSCRIPTIONAL FACTORS, HISTONE-MODIFYING ENZYMES, AND, THEREFORE, AFFECTED EPIGENETIC MECHANISMS. CHRONIC ETHANOL FEEDING WAS RELATED TO AN INCREASE IN HISTONE ACETYLATION, AND IT IS HYPOTHESIZED THAT THE PROTEASOME PROTEOLYTIC ACTIVITY REGULATED HISTONE MODIFICATIONS BY CONTROLLING THE STABILITY OF HISTONE MODIFYING ENZYMES, AND, THEREFORE, REGULATED THE CHROMATIN STRUCTURE, ALLOWING EASY ACCESS TO CHROMATIN BY RNA POLYMERASE, AND, THUS, PROPER GENE EXPRESSION. PROTEASOME INHIBITION BY PS-341 INCREASED HISTONE ACETYLATION SIMILAR TO CHRONIC ETHANOL FEEDING. IN ADDITION, PROTEASOME INHIBITION CAUSED DRAMATIC CHANGES IN HEPATIC REMETHYLATION REACTIONS AS THERE WAS A SIGNIFICANT DECREASE IN THE ENZYMES RESPONSIBLE FOR THE REGENERATION OF S-ADENOSYLMETHIONINE, AND, IN PARTICULAR, A SIGNIFICANT DECREASE IN THE BETAINE-HOMOCYSTEINE METHYLTRANSFERASE ENZYME. THIS SUGGESTED THAT HYPOMETHYLATION WAS ASSOCIATED WITH PROTEASOME INHIBITION, AS INDICATED BY THE DECREASE IN HISTONE METHYLATION. CONCLUSION: THE ROLE OF PROTEASOME INHIBITION IN REGULATING EPIGENETIC MECHANISMS, AND ITS LINK TO LIVER INJURY IN ALCOHOLIC LIVER DISEASE, IS THUS A PROMISING APPROACH TO STUDY LIVER INJURY DUE TO CHRONIC ETHANOL CONSUMPTION. 2009 4 3658 39 INDUCTION OF ABERRANT TRIMETHYLATION OF HISTONE H3 LYSINE 27 BY INFLAMMATION IN MOUSE COLONIC EPITHELIAL CELLS. A FIELD FOR CANCERIZATION (FIELD DEFECT), WHERE GENETIC AND EPIGENETIC ALTERATIONS ARE ACCUMULATED IN NORMAL-APPEARING TISSUES, IS INVOLVED IN HUMAN CARCINOGENESIS, ESPECIALLY CANCERS ASSOCIATED WITH CHRONIC INFLAMMATION. ALTHOUGH ABERRANT DNA METHYLATION IS INVOLVED IN THE FIELD DEFECT AND INDUCED BY CHRONIC INFLAMMATION, IT IS STILL UNCLEAR FOR TRIMETHYLATION OF HISTONE H3 LYSINE 27 (H3K27ME3), WHICH IS INVOLVED IN GENE REPRESSION INDEPENDENT OF DNA METHYLATION AND FUNCTIONS AS A PRE-MARK FOR ABERRANT DNA METHYLATION. IN THIS STUDY, USING A MOUSE COLITIS MODEL INDUCED BY DEXTRAN SULFATE SODIUM (DSS), WE AIMED TO CLARIFY WHETHER ABERRANT H3K27ME3 IS INDUCED BY INFLAMMATION AND INVOLVED IN A FIELD DEFECT. CHIP-ON-CHIP ANALYSIS OF COLONIC EPITHELIAL CELLS REVEALED THAT H3K27ME3 LEVELS WERE INCREASED OR DECREASED FOR 266 GENOMIC REGIONS BY AGING, AND MORE EXTENSIVELY (23 INCREASED AND 3574 DECREASED REGIONS) BY COLITIS. SUCH INCREASE OR DECREASE OF H3K27ME3 WAS INDUCED AS EARLY AS 2 WEEKS AFTER THE INITIATION OF DSS TREATMENT, AND PERSISTED AT LEAST FOR 16 WEEKS EVEN AFTER THE INFLAMMATION DISAPPEARED. SOME OF THE ABERRANT H3K27ME3 IN COLONIC EPITHELIAL CELLS WAS CARRIED OVER INTO COLON TUMORS. FURTHERMORE, H3K27ME3 ACQUIRED AT DAPK1 BY COLITIS WAS FOLLOWED BY INCREASED DNA METHYLATION, SUPPORTING ITS FUNCTION AS A PRE-MARK FOR ABERRANT DNA METHYLATION. THESE RESULTS DEMONSTRATED THAT ABERRANT H3K27ME3 CAN BE INDUCED BY EXPOSURE TO A SPECIFIC ENVIRONMENT, SUCH AS COLITIS, AND SUGGESTED THAT ABERRANT HISTONE MODIFICATION, IN ADDITION TO ABERRANT DNA METHYLATION, IS INVOLVED IN THE FORMATION OF A FIELD DEFECT. 2012 5 3360 40 HISTONE H4K20 TRIMETHYLATION IS DECREASED IN MURINE MODELS OF HEART DISEASE. HEART DISEASE IS THE LEADING CAUSE OF DEATH IN THE DEVELOPED WORLD, AND ITS COMORBIDITIES SUCH AS HYPERTENSION, DIABETES, AND HEART FAILURE ARE ACCOMPANIED BY MAJOR TRANSCRIPTOMIC CHANGES IN THE HEART. DURING CARDIAC DYSFUNCTION, WHICH LEADS TO HEART FAILURE, THERE ARE GLOBAL EPIGENETIC ALTERATIONS TO CHROMATIN THAT OCCUR CONCOMITANTLY WITH MORPHOLOGICAL CHANGES IN THE HEART IN RESPONSE TO ACUTE AND CHRONIC STRESS. THESE EPIGENETIC ALTERATIONS INCLUDE THE REVERSIBLE METHYLATION OF LYSINE RESIDUES ON HISTONE PROTEINS. LYSINE METHYLATIONS ON HISTONES H3K4 AND H3K9 WERE AMONG THE FIRST METHYLATED LYSINE RESIDUES IDENTIFIED AND HAVE BEEN LINKED TO GENE ACTIVATION AND SILENCING, RESPECTIVELY. HOWEVER, MUCH LESS IS KNOWN REGARDING OTHER METHYLATED HISTONE RESIDUES, INCLUDING HISTONE H4K20. TRIMETHYLATION OF HISTONE H4K20 HAS BEEN SHOWN TO REPRESS GENE EXPRESSION; HOWEVER, THIS MODIFICATION HAS NEVER BEEN EXAMINED IN THE HEART. HERE, WE UTILIZED IMMUNOBLOTTING AND MASS SPECTROMETRY TO QUANTIFY HISTONE H4K20 TRIMETHYLATION IN THREE MODELS OF CARDIAC DYSFUNCTION. OUR RESULTS SHOW THAT LYSINE METHYLATION AT THIS SITE IS DIFFERENTIALLY REGULATED IN THE CARDIOMYOCYTE, LEADING TO INCREASED H4K20 TRIMETHYLATION DURING ACUTE HYPERTROPHIC STRESS IN CELL MODELS AND DECREASED H4K20 TRIMETHYLATION DURING SUSTAINED ISCHEMIC INJURY AND CARDIAC DYSFUNCTION IN ANIMAL MODELS. IN ADDITION, WE EXAMINED PUBLICLY AVAILABLE DATA SETS TO ANALYZE ENZYMES THAT REGULATE H4K20 METHYLATION AND IDENTIFIED TWO DEMETHYLASES (KDM7B AND KDM7C) AND TWO METHYLTRANSFERASES (KMT5A AND SMYD5) THAT WERE ALL DIFFERENTIALLY EXPRESSED IN HEART FAILURE PATIENTS. THIS IS THE FIRST STUDY TO EXAMINE HISTONE H4K20 TRIMETHYLATION IN THE HEART AND TO DETERMINE HOW THIS POST-TRANSLATIONAL MODIFICATION IS DIFFERENTIALLY REGULATED IN MULTIPLE MODELS OF CARDIAC DISEASE. 2022 6 3240 34 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 7 4004 32 LOSS OF THE POLYCOMB MARK FROM BIVALENT PROMOTERS LEADS TO ACTIVATION OF CANCER-PROMOTING GENES IN COLORECTAL TUMORS. IN COLON TUMORS, THE TRANSCRIPTION OF MANY GENES BECOMES DEREGULATED BY POORLY DEFINED EPIGENETIC MECHANISMS THAT HAVE BEEN STUDIED MAINLY IN ESTABLISHED CELL LINES. IN THIS STUDY, WE USED FROZEN HUMAN COLON TISSUES TO ANALYZE PATTERNS OF HISTONE MODIFICATION AND DNA CYTOSINE METHYLATION IN CANCER AND MATCHED NORMAL MUCOSA SPECIMENS. DNA METHYLATION IS STRONGLY TARGETED TO BIVALENT H3K4ME3- AND H3K27ME3-ASSOCIATED PROMOTERS, WHICH LOSE BOTH HISTONE MARKS AND ACQUIRE DNA METHYLATION. HOWEVER, WE FOUND THAT LOSS OF THE POLYCOMB MARK H3K27ME3 FROM BIVALENT PROMOTERS WAS ACCOMPANIED OFTEN BY ACTIVATION OF GENES ASSOCIATED WITH CANCER PROGRESSION, INCLUDING NUMEROUS STEM CELL REGULATORS, ONCOGENES, AND PROLIFERATION-ASSOCIATED GENES. INDEED, WE FOUND MANY OF THESE SAME GENES WERE ALSO ACTIVATED IN PATIENTS WITH ULCERATIVE COLITIS WHERE CHRONIC INFLAMMATION PREDISPOSES THEM TO COLON CANCER. BASED ON OUR FINDINGS, WE PROPOSE THAT A LOSS OF POLYCOMB REPRESSION AT BIVALENT GENES COMBINED WITH AN ENSUING SELECTION FOR TUMOR-DRIVING EVENTS PLAYS A MAJOR ROLE IN CANCER PROGRESSION. 2014 8 4497 34 MORPHINE LEADS TO GLOBAL GENOME CHANGES IN H3K27ME3 LEVELS VIA A POLYCOMB REPRESSIVE COMPLEX 2 (PRC2) SELF-REGULATORY MECHANISM IN MESCS. BACKGROUND: ENVIRONMENTALLY INDUCED EPIGENETIC CHANGES CAN LEAD TO HEALTH PROBLEMS OR DISEASE, BUT THE MECHANISMS INVOLVED REMAIN UNCLEAR. MORPHINE CAN PASS THROUGH THE PLACENTAL BARRIER LEADING TO ABNORMAL EMBRYO DEVELOPMENT. HOWEVER, THE MECHANISM BY WHICH MORPHINE CAUSES THESE EFFECTS AND HOW THEY SOMETIMES PERSIST INTO ADULTHOOD IS NOT WELL KNOWN. TO UNRAVEL THE MORPHINE-INDUCED CHROMATIN ALTERATIONS INVOLVED IN ABERRANT EMBRYO DEVELOPMENT, WE EXPLORED THE ROLE OF THE H3K27ME3/PRC2 REPRESSIVE COMPLEX IN GENE EXPRESSION AND ITS TRANSMISSION ACROSS CELLULAR GENERATIONS IN RESPONSE TO MORPHINE. RESULTS: USING MOUSE EMBRYONIC STEM CELLS AS A MODEL SYSTEM, WE FOUND THAT CHRONIC MORPHINE TREATMENT INDUCES A GLOBAL DOWNREGULATION OF THE HISTONE MODIFICATION H3K27ME3. CONVERSELY, CHIP-SEQ SHOWED A REMARKABLE INCREASE IN H3K27ME3 LEVELS AT SPECIFIC GENOMIC SITES, PARTICULARLY PROMOTERS, DISRUPTING SELECTIVE TARGET GENES RELATED TO EMBRYO DEVELOPMENT, CELL CYCLE AND METABOLISM. THROUGH A SELF-REGULATORY MECHANISM, MORPHINE DOWNREGULATED THE TRANSCRIPTION OF PRC2 COMPONENTS RESPONSIBLE FOR H3K27ME3 BY ENRICHING HIGH H3K27ME3 LEVELS AT THE PROMOTER REGION. DOWNREGULATION OF PRC2 COMPONENTS PERSISTED FOR AT LEAST 48 H (4 CELL CYCLES) FOLLOWING MORPHINE REMOVAL, THOUGH PROMOTER H3K27ME3 LEVELS RETURNED TO CONTROL LEVELS. CONCLUSIONS: MORPHINE INDUCES TARGETING OF THE PRC2 COMPLEX TO SELECTED PROMOTERS, INCLUDING THOSE OF PRC2 COMPONENTS, LEADING TO CHARACTERISTIC CHANGES IN GENE EXPRESSION AND A GLOBAL REDUCTION IN H3K27ME3. FOLLOWING MORPHINE REMOVAL, ENHANCED PROMOTER H3K27ME3 LEVELS REVERT TO NORMAL SOONER THAN GLOBAL H3K27ME3 OR PRC2 COMPONENT TRANSCRIPT LEVELS. WE SUGGEST THAT H3K27ME3 IS INVOLVED IN INITIATING MORPHINE-INDUCED CHANGES IN GENE EXPRESSION, BUT NOT IN THEIR MAINTENANCE. MODEL OF POLYCOMB REPRESSIVE COMPLEX 2 (PRC2) AND H3K27ME3 ALTERATIONS INDUCED BY CHRONIC MORPHINE EXPOSURE. MORPHINE INDUCES H3K27ME3 ENRICHMENT AT PROMOTERS OF GENES ENCODING CORE MEMBERS OF THE PRC2 COMPLEX AND IS ASSOCIATED WITH THEIR TRANSCRIPTIONAL DOWNREGULATION. 2020 9 5067 27 PHYSICAL ACTIVITY AND DNA METHYLATION IN HUMANS. PHYSICAL ACTIVITY IS A STRONG STIMULUS INFLUENCING THE OVERALL PHYSIOLOGY OF THE HUMAN BODY. EXERCISES LEAD TO BIOCHEMICAL CHANGES IN VARIOUS TISSUES AND EXERT AN IMPACT ON GENE EXPRESSION. EXERCISE-INDUCED CHANGES IN GENE EXPRESSION MAY BE MEDIATED BY EPIGENETIC MODIFICATIONS, WHICH REARRANGE THE CHROMATIN STRUCTURE AND THEREFORE MODULATE ITS ACCESSIBILITY FOR TRANSCRIPTION FACTORS. ONE OF SUCH EPIGENETIC MARK IS DNA METHYLATION THAT INVOLVES AN ATTACHMENT OF A METHYL GROUP TO THE FIFTH CARBON OF CYTOSINE RESIDUE PRESENT IN CG DINUCLEOTIDES (CPG). DNA METHYLATION IS CATALYZED BY A FAMILY OF DNA METHYLTRANSFERASES. THIS REVERSIBLE DNA MODIFICATION RESULTS IN THE RECRUITMENT OF PROTEINS CONTAINING METHYL BINDING DOMAIN AND FURTHER TRANSCRIPTIONAL CO-REPRESSORS LEADING TO THE SILENCING OF GENE EXPRESSION. THE ACCUMULATION OF CPG DINUCLEOTIDES, REFERRED AS CPG ISLANDS, OCCURS AT THE PROMOTER REGIONS IN A GREAT MAJORITY OF HUMAN GENES. THEREFORE, CHANGES IN DNA METHYLATION PROFILE AFFECT THE TRANSCRIPTION OF MULTIPLE GENES. A GROWING BODY OF EVIDENCE INDICATES THAT EXERCISE TRAINING MODULATES DNA METHYLATION IN MUSCLES AND ADIPOSE TISSUE. SOME OF THESE EPIGENETIC MARKERS WERE ASSOCIATED WITH A REDUCED RISK OF CHRONIC DISEASES. THIS REVIEW SUMMARIZES THE CURRENT KNOWLEDGE ABOUT THE INFLUENCE OF PHYSICAL ACTIVITY ON THE DNA METHYLATION STATUS IN HUMANS. 2021 10 4900 40 OXIDATIVE STRESS-INDUCED EPIGENETIC CHANGES ASSOCIATED WITH MALIGNANT TRANSFORMATION OF HUMAN KIDNEY EPITHELIAL CELLS. RENAL CELL CARCINOMA (RCC) IN HUMANS IS POSITIVELY INFLUENCED BY OXIDATIVE STRESS STATUS IN KIDNEYS. WE RECENTLY REPORTED THAT ADAPTIVE RESPONSE TO LOW LEVEL OF CHRONIC OXIDATIVE STRESS INDUCES MALIGNANT TRANSFORMATION OF IMMORTALIZED HUMAN RENAL TUBULAR EPITHELIAL CELLS. EPIGENETIC ALTERATIONS IN HUMAN RCC ARE WELL DOCUMENTED, BUT ITS ROLE IN OXIDATIVE STRESS-INDUCED MALIGNANT TRANSFORMATION OF KIDNEY CELLS IS NOT KNOWN. THEREFORE, THE OBJECTIVE OF THIS STUDY WAS TO EVALUATE THE POTENTIAL ROLE OF EPIGENETIC CHANGES IN CHRONIC OXIDATIVE STRESS-INDUCED MALIGNANT TRANSFORMATION OF HK-2, HUMAN RENAL TUBULAR EPITHELIAL CELLS. THE RESULTS REVEALED ABERRANT EXPRESSION OF EPIGENETIC REGULATORY GENES INVOLVED IN DNA METHYLATION (DNMT1, DNMT3A AND MBD4) AND HISTONE MODIFICATIONS (HDAC1, HMT1 AND HAT1) IN HK-2 CELLS MALIGNANTLY TRANSFORMED BY CHRONIC OXIDATIVE STRESS. ADDITIONALLY, BOTH IN VITRO SOFT AGAR ASSAY AND IN VIVO NUDE MICE STUDY SHOWING DECREASED TUMORIGENIC POTENTIAL OF MALIGNANTLY TRANSFORMED HK-2 CELLS FOLLOWING TREATMENT WITH DNA DE-METHYLATING AGENT 5-AZA 2' DC FURTHER CONFIRMED THE CRUCIAL ROLE OF DNA HYPERMETHYALTION IN OXIDATIVE STRESS-INDUCED MALIGNANT TRANSFORMATION. CHANGES OBSERVED IN GLOBAL HISTONE H3 ACETYLATION (H3K9, H3K18, H3K27 AND H3K14) AND DECREASE IN PHOSPHO-H2AX (SER139) ALSO SUGGEST POTENTIAL ROLE OF HISTONE MODIFICATIONS IN INCREASED SURVIVAL AND MALIGNANT TRANSFORMATION OF HK-2 CELLS BY OXIDATIVE STRESS. IN SUMMARY, THE RESULTS OF THIS STUDY SUGGEST THAT EPIGENETIC REPROGRAMMING INDUCED BY LOW LEVELS OF OXIDATIVE STRESS ACT AS DRIVER FOR MALIGNANT TRANSFORMATION OF KIDNEY EPITHELIAL CELLS. FINDINGS OF THIS STUDY ARE HIGHLY RELEVANT IN POTENTIAL CLINICAL APPLICATION OF EPIGENETIC-BASED THERAPEUTICS FOR TREATMENTS OF KIDNEY CANCERS. 2017 11 1731 34 DYSREGULATION OF THE HISTONE DEMETHYLASE KDM6B IN ALCOHOL DEPENDENCE IS ASSOCIATED WITH EPIGENETIC REGULATION OF INFLAMMATORY SIGNALING PATHWAYS. EPIGENETIC ENZYMES OVERSEE LONG-TERM CHANGES IN GENE EXPRESSION BY INTEGRATING GENETIC AND ENVIRONMENTAL CUES. WHILE THERE ARE HUNDREDS OF ENZYMES THAT CONTROL HISTONE AND DNA MODIFICATIONS, THEIR POTENTIAL ROLES IN SUBSTANCE ABUSE AND ALCOHOL DEPENDENCE REMAIN UNDEREXPLORED. A FEW RECENT STUDIES HAVE SUGGESTED THAT EPIGENETIC PROCESSES COULD UNDERLIE TRANSCRIPTOMIC AND BEHAVIORAL HALLMARKS OF ALCOHOL ADDICTION. IN THE PRESENT STUDY, WE SOUGHT TO IDENTIFY EPIGENETIC ENZYMES IN THE BRAIN THAT ARE DYSREGULATED DURING PROTRACTED ABSTINENCE AS A CONSEQUENCE OF CHRONIC AND INTERMITTENT ALCOHOL EXPOSURE. THROUGH QUANTITATIVE MRNA EXPRESSION ANALYSIS OF OVER 100 EPIGENETIC ENZYMES, WE IDENTIFIED 11 THAT ARE SIGNIFICANTLY ALTERED IN ALCOHOL-DEPENDENT RATS COMPARED WITH CONTROLS. FOLLOW-UP STUDIES OF ONE OF THESE ENZYMES, THE HISTONE DEMETHYLASE KDM6B, SHOWED THAT THIS ENZYME EXHIBITS REGION-SPECIFIC DYSREGULATION IN THE PREFRONTAL CORTEX AND NUCLEUS ACCUMBENS OF ALCOHOL-DEPENDENT RATS. KDM6B WAS ALSO UPREGULATED IN THE HUMAN ALCOHOLIC BRAIN. UPREGULATION OF KDM6B PROTEIN IN ALCOHOL-DEPENDENT RATS WAS ACCOMPANIED BY A DECREASE OF TRIMETHYLATION LEVELS AT HISTONE H3, LYSINE 27 (H3K27ME3), CONSISTENT WITH THE KNOWN DEMETHYLASE SPECIFICITY OF KDM6B. SUBSEQUENT EPIGENETIC (CHROMATIN IMMUNOPRECIPITATION [CHIP]-SEQUENCING) ANALYSIS SHOWED THAT ALCOHOL-INDUCED CHANGES IN H3K27ME3 WERE SIGNIFICANTLY ENRICHED AT GENES IN THE IL-6 SIGNALING PATHWAY, CONSISTENT WITH THE WELL-CHARACTERIZED ROLE OF KDM6B IN MODULATION OF INFLAMMATORY RESPONSES. KNOCKDOWN OF KDM6B IN CULTURED MICROGLIAL CELLS DIMINISHED IL-6 INDUCTION IN RESPONSE TO AN INFLAMMATORY STIMULUS. OUR FINDINGS IMPLICATE A NOVEL KDM6B-MEDIATED EPIGENETIC SIGNALING PATHWAY INTEGRATED WITH INFLAMMATORY SIGNALING PATHWAYS THAT ARE KNOWN TO UNDERLIE THE DEVELOPMENT OF ALCOHOL ADDICTION. 2021 12 5438 24 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 13 5279 31 PROMOTER-SPECIFIC RELEVANCE OF HISTONE MODIFICATIONS INDUCED BY DEXAMETHASONE DURING THE REGULATION OF PRO-INFLAMMATORY MEDIATORS. GLUCOCORTICOSTEROIDS (GCS) ARE WIDELY USED TO TREAT DIFFERENT KINDS OF CHRONIC INFLAMMATORY AND IMMUNE DISEASES THROUGH TRANSCRIPTIONAL REGULATION OF INFLAMMATORY GENES. MODULATION OF GENE EXPRESSION BY GCS IS KNOWN TO OCCUR THROUGH DIVERSE MECHANISMS OF VARYING RELEVANCE TO SPECIFIC CLASSES OF GENES. EPIGENETIC MODIFICATIONS ARE INDEED A PIVOTAL REGULATORY FEATURE OF GLUCOCORTICOID RECEPTOR AND OTHER TRANSCRIPTION FACTORS. IN THIS STUDY, HISTONE POST-TRANSLATIONAL MODIFICATIONS WERE INVESTIGATED FOR THEIR INVOLVEMENT IN THE REGULATION OF SELECTED PRO-INFLAMMATORY GENES - EXPRESSED IN HUMAN MONOCYTE-DERIVED MACROPHAGES - IN RESPONSE TO TREATMENT WITH SYNTHETIC GC DEXAMETHASONE (DEX). WE SHOW THAT HISTONE TAIL ACETYLATION STATUS IS MODIFIED FOLLOWING DEX ADMINISTRATION, THROUGH DISTINCT AND ALTERNATIVE MECHANISMS AT THE PROMOTERS OF INTERLEUKIN-8 AND INTERLEUKIN-23. IN ADDITION TO HISTONE H3 ACETYLATION, OUR RESULTS DEMONSTRATE THAT H3 LYSINE 4 TRIMETHYLATION IS AFFECTED FOLLOWING DRUG TREATMENT. 2014 14 2417 32 EPIGENETIC SIGNATURE OF CHRONIC CEREBRAL HYPOPERFUSION AND BENEFICIAL EFFECTS OF S-ADENOSYLMETHIONINE IN RATS. CHRONIC CEREBRAL HYPOPERFUSION IS ASSOCIATED WITH COGNITIVE DECLINE IN AGING AND AGE-RELATED NEURODEGENERATIVE DISEASE. EPIGENETIC MECHANISMS ARE INVOLVED IN THE MAINTENANCE OF LONG-TERM HYPOXIA-ADAPTED CELLULAR PHENOTYPES. IN THE PRESENT STUDY, THE EPIGENETIC SIGNATURES SUCH AS DNA METHYLATION AND HISTONE ACETYLATION, AS WELL AS S-ADENOSYLMETHIONINE (SAM) CYCLE USING CHRONIC CEREBRAL HYPOPERFUSION RAT MODEL WERE EXPLORED. CHRONIC CEREBRAL HYPOXIA-INDUCED GLOBAL DNA HYPERMETHYLATION ASSOCIATED WITH THE INCREASE OF DNA METHYLTRANSFERASE (DNMT) 3A AS WELL AS ALTERATION OF SAM CYCLE. MEANWHILE, AN ENHANCED LEVEL OF GLOBAL HISTONE H4 ACETYLATION ACCOMPANIED WITH THE UPREGULATION OF HISTONE ACETYLTRANSFERASE, P300/CREB-BINDING PROTEIN (CBP), AND THE DOWNREGULATION OF HISTONE DEACETYLASES (HDACS), WAS ALSO OBSERVED. SAM COULD IMPROVE SPATIAL CAPACITY THROUGH THE UPREGULATION OF ACETYLCHOLINE AND BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) RATHER THAN ALTERATION OF DNA METHYLATION LEVELS. IN CONCLUSION, WE HAVE DEMONSTRATED A GENOME-WIDE ADJUSTMENT OF DNA METHYLATION AND HISTONE ACETYLATION UNDER CHRONIC CEREBRAL HYPOXIC CONDITIONS IN A RAT'S BRAIN. THESE EPIGENETIC SIGNATURES MAY REPRESENT AN ADDITIONAL MECHANISM TO PROMOTE AND MAINTAIN A HYPOXIC-ADAPTED CELLULAR RESPONDS WITH A POTENTIAL ROLE IN MEMORY DEFICITS. 2014 15 2493 32 EPIGENETICS AND CHROMATIN REMODELING PLAY A ROLE IN LUNG DISEASE. EPIGENETICS IS DEFINED AS HERITABLE CHANGES THAT AFFECT GENE EXPRESSION WITHOUT ALTERING THE DNA SEQUENCE. EPIGENETIC REGULATION OF GENE EXPRESSION IS FACILITATED THROUGH DIFFERENT MECHANISMS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS AND RNA-ASSOCIATED SILENCING BY SMALL NON-CODING RNAS. ALL THESE MECHANISMS ARE CRUCIAL FOR NORMAL DEVELOPMENT, DIFFERENTIATION AND TISSUE-SPECIFIC GENE EXPRESSION. THESE THREE SYSTEMS INTERACT AND STABILIZE ONE ANOTHER AND CAN INITIATE AND SUSTAIN EPIGENETIC SILENCING, THUS DETERMINING HERITABLE CHANGES IN GENE EXPRESSION. HISTONE ACETYLATION REGULATES DIVERSE CELLULAR FUNCTIONS INCLUDING INFLAMMATORY GENE EXPRESSION, DNA REPAIR AND CELL PROLIFERATION. TRANSCRIPTIONAL COACTIVATORS POSSESS INTRINSIC HISTONE ACETYLTRANSFERASE ACTIVITY AND THIS ACTIVITY DRIVES INFLAMMATORY GENE EXPRESSION. ELEVEN CLASSICAL HISTONE DEACETYLASES (HDACS) ACT TO REGULATE THE EXPRESSION OF DISTINCT SUBSETS OF INFLAMMATORY/IMMUNE GENES. THUS, LOSS OF HDAC ACTIVITY OR THE PRESENCE OF HDAC INHIBITORS CAN FURTHER ENHANCE INFLAMMATORY GENE EXPRESSION BY PRODUCING A GENE-SPECIFIC CHANGE IN HAT ACTIVITY. FOR EXAMPLE, HDAC2 EXPRESSION AND ACTIVITY ARE REDUCED IN LUNG MACROPHAGES, BIOPSY SPECIMENS, AND BLOOD CELLS FROM PATIENTS WITH SEVERE ASTHMA AND SMOKING ASTHMATICS, AS WELL AS IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). THIS MAY ACCOUNT, AT LEAST IN PART, FOR THE ENHANCED INFLAMMATION AND REDUCED STEROID RESPONSIVENESS SEEN IN THESE PATIENTS. OTHER PROTEINS, PARTICULARLY TRANSCRIPTION FACTORS, ARE ALSO ACETYLATED AND ARE TARGETS FOR DEACETYLATION BY HDACS AND SIRTUINS, A RELATED FAMILY OF 7 PREDOMINANTLY PROTEIN DEACETYLASES. THUS THE ACETYLATION/DEACETYLATION STATUS OF NF-KAPPAB AND THE GLUCOCORTICOID RECEPTOR CAN ALSO AFFECT THE OVERALL EXPRESSION PATTERN OF INFLAMMATORY GENES AND REGULATE THE INFLAMMATORY RESPONSE. UNDERSTANDING AND TARGETING SPECIFIC ENZYMES INVOLVED IN THIS PROCESS MIGHT LEAD TO NEW THERAPEUTIC AGENTS, PARTICULARLY IN SITUATIONS IN WHICH CURRENT ANTI-INFLAMMATORY THERAPIES ARE SUBOPTIMAL. 2011 16 2280 33 EPIGENETIC REGULATION IN DRUG ADDICTION. THE INTERACTION BETWEEN ENVIRONMENTAL SIGNALS AND GENES HAS NOW TAKEN ON A CLEAR MOLECULAR FORM AS DEMONSTRATED BY STABLE CHANGES IN CHROMATIN STRUCTURE. THESE CHANGES OCCUR THROUGH ACTIVATION OR REPRESSION OF SPECIFIC GENE PROGRAMMES BY A COMBINATION OF CHROMATIN REMODELLING, ACTIVATION AND ENZYMATIC MODIFICATION OF DNA AND HISTONES AS WELL AS NUCLEOSOMAL SUBUNIT EXCHANGE. RECENT RESEARCH INVESTIGATING THE MOLECULAR MECHANISMS CONTROLLING DRUG-INDUCED TRANSCRIPTIONAL, BEHAVIOURAL AND SYNAPTIC ACTIVITY HAS SHOWN A DIRECT ROLE FOR CHROMATIN REMODELLING--TERMED AS EPIGENETIC REGULATION--OF NEURONAL GENE PROGRAMMES AND SUBSEQUENT ADDICTIVE BEHAVIOUR ARISING FROM IT. RECENT DATA SUGGEST THAT REPEATED EXPOSURE TO CERTAIN DRUGS PROMOTES CHANGES IN LEVELS OF HISTONE ACETYLATION, PHOSPHORYLATION AND METHYLATION, TOGETHER WITH ALTERATIONS IN DNA METHYLATION LEVELS IN THE NEURONS OF THE BRAIN REWARD CENTRE, LOCALISED IN THE NUCLEUS ACCUMBENS (NAC) REGION OF THE LIMBIC SYSTEM. THE COMBINATION OF ACETYLATING, PHOSPHORYLATING AND METHYLATING H3 AND H4 HISTONE TAILS ALTER CHROMATIN COMPACTION THEREBY PROMOTING ALTERED LEVELS OF CELLULAR GENE EXPRESSION. HISTONE MODIFICATIONS, WHICH WEAKEN HISTONE INTERACTION WITH DNA OR THAT PROMOTE RECRUITMENT OF TRANSCRIPTIONAL ACTIVATING COMPLEXES, CORRELATE WITH PERMISSIVE GENE EXPRESSION. HISTONE DEACETYLATION, (WHICH STRENGTHEN HISTONE: DNA CONTACTS), OR HISTONE METHYLATION, (WHICH RECRUITS REPRESSIVE COMPLEXES TO CHROMATIN), PROMOTE A STATE OF TRANSCRIPTIONAL REPRESSION. USING ANIMAL MODELS, ACUTE COCAINE TREATMENT INCREASES H4 ACETYLATION AT ACUTELY REGULATED GENE PROMOTERS, WHEREAS H3 ACETYLATION APPEARS TO PREDOMINATE AT CHRONICALLY INDUCED PROMOTERS. CHRONIC COCAINE AND ALCOHOL TREATMENT ACTIVATE AND REPRESS MANY GENES SUCH AS FOSB, CDK5, AND BDNF, WHERE THEIR DYSREGULATION, AT THE CHROMATIN LEVEL, CONTRIBUTE TO THE DEVELOPMENT AND MAINTENANCE OF ADDICTION. FOLLOWING DRUG EXPOSURE, IT IS STILL UNKNOWN, HOWVER, HOW LONG THESE CHANGES IN CHROMATIN STRUCTURE PERSIST IN AFFECTING NEURONAL FUNCTION, BUT SOME DO SO FOR LIFE. 2012 17 2119 36 EPIGENETIC HISTONE MODIFICATION REGULATES DEVELOPMENTAL LEAD EXPOSURE INDUCED HYPERACTIVITY IN RATS. LEAD (PB) EXPOSURE WAS COMMONLY CONSIDERED AS A HIGH ENVIRONMENTAL RISK FACTOR FOR THE DEVELOPMENT OF ATTENTION-DEFICIT/HYPERACTIVITY DISORDER (ADHD). HOWEVER, THE MOLECULAR BASIS OF THIS PATHOLOGICAL PROCESS STILL REMAINS ELUSIVE. IN LIGHT OF THE ROLE OF EPIGENETICS IN MODULATING THE NEUROLOGICAL DISEASE AND THE CAUSATIVE ENVIRONMENT, THE ALTERATIONS OF HISTONE MODIFICATIONS IN THE HIPPOCAMPUS OF RATS EXPOSED BY VARIOUS DOSES OF LEAD, ALONG WITH CONCOMITANT BEHAVIORAL DEFICITS, WERE INVESTIGATED IN THIS STUDY. ACCORDING TO THE FREE AND FORCED OPEN FIELD TEST, THERE SHOWED THAT IN A DOSAGE-DEPENDENT MANNER, LEAD EXPOSURE COULD RESULT IN THE INCREASED LOCOMOTOR ACTIVITY OF RATS, THAT IS, HYPERACTIVITY: A SUBTYPE OF ADHD. WESTERN BLOTTING ASSAYS REVEALED THAT THE LEVELS OF HISTONE ACETYLATION INCREASED SIGNIFICANTLY IN THE HIPPOCAMPUS BY CHRONIC LEAD EXPOSURE, WHILE NO DRAMATIC CHANGES WERE DETECTED IN TERMS OF EXPRESSION YIELDS OF ADHD-RELATED DOPAMINERGIC PROTEINS, INDICATING THAT HISTONE ACETYLATION PLAYS ESSENTIAL ROLES IN THIS TOXICANT-INVOLVED PATHOGENESIS. IN ADDITION, THE INCREASED LEVEL OF HISTONE ACETYLATION MIGHT BE ATTRIBUTED TO THE ENZYMATIC ACTIVITY OF P300, A TYPICAL HISTONE ACETYLTRANSFERASE, AS THE TRANSCRIPTIONAL LEVEL OF P300 WAS SIGNIFICANTLY INCREASED UPON HIGHER-DOSE PB EXPOSURE. IN SUMMARY, THIS STUDY FIRST DISCOVERED THE EPIGENETIC MECHANISM BRIDGING THE ENVIRONMENTAL INFLUENCE (PB) AND THE DISEASE ITSELF (ADHD) IN THE HISTONE MODIFICATION LEVEL, PAVING THE WAY FOR THE COMPREHENSIVE UNDERSTANDING OF ADHD'S ETIOLOGY AND IN FURTHER STEPS, ESTABLISHING THE THERAPY STRATEGY OF THIS WIDESPREAD NEUROLOGICAL DISORDER. 2014 18 1615 31 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 19 476 38 ARSENIC INDUCES FIBROGENIC CHANGES IN HUMAN KIDNEY EPITHELIAL CELLS POTENTIALLY THROUGH EPIGENETIC ALTERATIONS IN DNA METHYLATION. ARSENIC CONTAMINATION IS A SIGNIFICANT PUBLIC HEALTH ISSUE, AND KIDNEY IS ONE OF THE TARGET ORGAN FOR ARSENIC-INDUCED ADVERSE EFFECTS. RENAL FIBROSIS IS A WELL-KNOWN PATHOLOGICAL STAGE FREQUENTLY OBSERVED IN PROGRESSIVE CHRONIC KIDNEY DISEASE (CKD). EPIDEMIOLOGICAL STUDIES IMPLICATE ARSENIC EXPOSURE TO CKD, BUT THE ROLE OF ARSENIC IN KIDNEY FIBROSIS AND THE UNDERLYING MECHANISM IS STILL UNCLEAR. IT IS IN THIS CONTEXT THAT THE CURRENT STUDY EVALUATED THE EFFECTS OF LONG-TERM ARSENIC EXPOSURE ON THE CELLULAR RESPONSE IN MORPHOLOGY, AND MARKER GENES EXPRESSION WITH RESPECT TO FIBROSIS USING HUMAN KIDNEY 2 (HK-2) EPITHELIAL CELLS. RESULTS OF THIS STUDY REVEALED THAT IN ADDITION TO INCREASED GROWTH, HK-2 CELLS UNDERWENT PHENOTYPIC, BIOCHEMICAL AND MOLECULAR CHANGES INDICATIVE OF EPITHELIAL-MESENCHYMAL TRANSITION (EMT) IN RESPONSE TO THE EXPOSURE TO ARSENIC. MOST IMPORTANTLY, THE ARSENIC-EXPOSED CELLS ACQUIRED THE PATHOGENIC FEATURES OF FIBROSIS AS SUPPORTED BY INCREASED EXPRESSION OF MARKERS FOR FIBROSIS, SUCH AS COLLAGEN I, FIBRONECTIN, TRANSFORMING GROWTH FACTOR BETA, AND ALPHA-SMOOTH MUSCLE ACTIN. UPREGULATION OF FIBROSIS ASSOCIATED SIGNALING MOLECULES SUCH AS TISSUE INHIBITOR OF METALLOPROTEINASES-3 AND MATRIX METALLOPROTEINASE-2 AS WELL AS ACTIVATION OF AKT WAS ALSO OBSERVED. ADDITIONALLY, THE EXPRESSION OF EPIGENETIC GENES (DNA METHYLTRANSFERASES 3A AND 3B; METHYL-CPG BINDING DOMAIN 4) WAS INCREASED IN ARSENIC-EXPOSED CELLS. TREATMENT WITH DNA METHYLATION INHIBITOR 5-AZA-2'-DC REVERSED THE EMT PROPERTIES AND RESTORED THE LEVEL OF PHOSPHO-AKT. TOGETHER, THESE DATA FOR THE FIRST TIME SUGGEST THAT LONG-TERM EXPOSURE TO ARSENIC CAN INCREASE THE RISK OF KIDNEY FIBROSIS. ADDITIONALLY, OUR DATA SUGGEST THAT THE ARSENIC-INDUCED FIBROTIC CHANGES ARE, AT LEAST IN PART, MEDIATED BY DNA METHYLATION AND THEREFORE POTENTIALLY CAN BE REVERSED BY EPIGENETIC THERAPEUTICS. 2019 20 3795 34 INTERLEUKIN-6 CONTRIBUTES TO GROWTH IN CHOLANGIOCARCINOMA CELLS BY ABERRANT PROMOTER METHYLATION AND GENE EXPRESSION. THE ASSOCIATION BETWEEN CHRONIC INFLAMMATION AND THE DEVELOPMENT AND PROGRESSION OF MALIGNANCY IS EXEMPLIFIED IN THE BILIARY TRACT WHERE PERSISTENT INFLAMMATION STRONGLY PREDISPOSES TO CHOLANGIOCARCINOMA. THE INFLAMMATORY CYTOKINE INTERLEUKIN-6 (IL-6) ENHANCES TUMOR GROWTH IN CHOLANGIOCARCINOMA BY ALTERED GENE EXPRESSION VIA AUTOCRINE MECHANISMS. IL-6 CAN REGULATE THE ACTIVITY OF DNA METHYLTRANSFERASES, AND MOREOVER, ABERRANT DNA METHYLATION CAN CONTRIBUTE TO CARCINOGENESIS. WE THEREFORE INVESTIGATED THE EFFECT OF CHRONIC EXPOSURE TO IL-6 ON METHYLATION-DEPENDENT GENE EXPRESSION AND TRANSFORMED CELL GROWTH IN HUMAN CHOLANGIOCARCINOMA. THE RELATIONSHIP BETWEEN AUTOCRINE IL-6 PATHWAYS, DNA METHYLATION, AND TRANSFORMED CELL GROWTH WAS ASSESSED USING MALIGNANT CHOLANGIOCYTES STABLY TRANSFECTED TO OVEREXPRESS IL-6. TREATMENT WITH THE DNA METHYLATION INHIBITOR 5-AZA-2'-DEOXYCYTIDINE DECREASED CELL PROLIFERATION, GROWTH IN SOFT AGAR, AND METHYLCYTOSINE CONTENT OF MALIGNANT CHOLANGIOCYTES. HOWEVER, THIS EFFECT WAS NOT OBSERVED IN IL-6-OVEREXPRESSING CELLS. IL-6 OVEREXPRESSION RESULTED IN THE ALTERED EXPRESSION AND PROMOTER METHYLATION OF SEVERAL GENES, INCLUDING THE EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR). EGFR PROMOTER METHYLATION WAS DECREASED AND GENE AND PROTEIN EXPRESSION WAS INCREASED BY IL-6. THUS, EPIGENETIC REGULATION OF GENE EXPRESSION BY IL-6 CAN CONTRIBUTE TO TUMOR PROGRESSION BY ALTERING PROMOTER METHYLATION AND GENE EXPRESSION OF GROWTH-REGULATORY PATHWAYS, SUCH AS THOSE INVOLVING EGFR. MOREOVER, ENHANCED IL-6 EXPRESSION MAY DECREASE THE SENSITIVITY OF TUMOR CELLS TO THERAPEUTIC TREATMENTS USING METHYLATION INHIBITORS. THESE OBSERVATIONS HAVE IMPORTANT IMPLICATIONS FOR CANCER TREATMENT AND PROVIDE A MECHANISM BY WHICH PERSISTENT CYTOKINE STIMULATION CAN PROMOTE TUMOR GROWTH. 2006