1 674 138 BRAHMA-RELATED GENE 1 BRIDGES EPIGENETIC REGULATION OF PROINFLAMMATORY CYTOKINE PRODUCTION TO STEATOHEPATITIS IN MICE. CHRONIC INFLAMMATION, INFLICTED BY THE SPILLOVER OF PROINFLAMMATORY MEDIATORS, LINKS METABOLIC DYSFUNCTION TO NONALCOHOLIC STEATOHEPATITIS (NASH). THE EPIGENETIC MANEUVERINGS THAT UNDERSCORE ACCELERATED SYNTHESIS OF PROINFLAMMATORY MEDIATORS IN RESPONSE TO NUTRITIONAL INPUTS ARE NOT CLEARLY DEFINED. HERE WE REPORT THAT THE ATP-DEPENDENT CHROMATIN REMODELING PROTEINS BRAHMA-RELATED GENE 1 (BRG1) AND BRAHMA (BRM) WERE UP-REGULATED IN VITRO IN CULTURED HEPATOCYTES TREATED WITH FREE FATTY ACID OR GLUCOSE AND IN VIVO IN ANIMAL MODELS OF NASH. OCCUPANCY OF BRG1 AND BRM ON THE PROMOTER REGIONS OF PROINFLAMMATORY GENES WAS INCREASED IN VITRO IN CELLS AND EX VIVO IN LIVER TISSUES. ESTRADIOL SUPPRESSED THE INDUCTION AND RECRUITMENT OF BRG1/BRM BY PALMITATE. RECRUITMENT OF BRG1 AND BRM RELIED ON NUCLEAR FACTOR KAPPA B/P65; RECIPROCALLY, BRG1 AND BRM CONTRIBUTED TO THE STABILIZATION OF P65 BINDING. IMPORTANTLY, OVEREXPRESSION OF BRG1/BRM ENHANCED, WHEREAS KNOCKDOWN OF BRG1/BRM ATTENUATED, THE INDUCTION OF PROINFLAMMATORY MEDIATORS IN HEPATOCYTES CHALLENGED WITH EXCESSIVE NUTRIENT. MECHANISTICALLY, BRG1 AND BRM WERE INVOLVED IN THE MAINTENANCE OF A CHROMATIN MICROENVIRONMENT MARKED BY ACTIVE HISTONE MODIFICATIONS AND FRIENDLY TO THE ACCESS OF THE GENERAL TRANSCRIPTIONAL MACHINERY. FINALLY, DEPLETION OF BRG1/BRM BY SHORT HAIRPIN RNA ATTENUATED THE RELEASE OF PROINFLAMMATORY MEDIATORS IN THE LIVER AND SIGNIFICANTLY AMELIORATED HEPATIC PATHOLOGY IN NASH MICE. CONCLUSION: OUR DATA ILLUSTRATE A BRG1-DEPENDENT PATHWAY THAT CONNECTS THE EPIGENETIC REGULATION OF PROINFLAMMATORY GENES TO THE PATHOGENESIS OF NASH AND POINT TO A POTENTIAL DRUGGABLE TARGET IN THE THERAPEUTIC INTERVENTION OF NASH. 2013 2 673 51 BRAHMA-RELATED GENE 1 (BRG1) EPIGENETICALLY REGULATES CAM ACTIVATION DURING HYPOXIC PULMONARY HYPERTENSION. AIMS: ESTABLISHMENT OF AN INFLAMMATORY MILIEU FOLLOWING ELEVATED LEUKOCYTE ADHESION TO THE VASCULAR ENDOTHELIUM, WHICH IS MEDIATED BY TRANSCRIPTIONAL ACTIVATION OF CELL ADHESION MOLECULES (CAMS), CONTRIBUTES TO THE PATHOGENESIS OF CHRONIC HYPOXIA-INDUCED PULMONARY HYPERTENSION (HPH). THE EPIGENETIC SWITCH THAT DICTATES CAM TRANSACTIVATION IN RESPONSE TO HYPOXIA IN ENDOTHELIAL CELLS LEADING UP TO HPH IS NOT FULLY APPRECIATED. METHODS AND RESULTS: WE REPORT HERE THAT BRAHMA-RELATED GENE 1 (BRG1) AND BRAHMA (BRM), TWO CATALYTIC COMPONENTS OF THE MAMMALIAN CHROMATIN REMODELLING COMPLEX, WERE INDUCED IN CULTURED ENDOTHELIAL CELLS CHALLENGED WITH HYPOXIA IN VITRO AS WELL AS IN PULMONARY ARTERIES IN AN ANIMAL MODEL OF HPH. OVER-EXPRESSION OF BRG1/BRM ENHANCED, WHILE THE DEPLETION OF BRG1/BRM ATTENUATED, CAM TRANSACTIVATION AND ADHESION OF LEUKOCYTES. ENDOTHELIAL-SPECIFIC DELETION OF BRG1/BRM AMELIORATED VASCULAR INFLAMMATION AND HPH IN MICE. CHROMATIN IMMUNOPRECIPITATION (CHIP) AND RE-CHIP ASSAYS REVEALED THAT HYPOXIA UP-REGULATED THE OCCUPANCIES OF BRG1 AND BRM ON CAM PROMOTERS IN A NUCLEAR FACTOR KAPPAB (NF-KAPPAB) -DEPENDENT MANNER. FINALLY, BRG1 AND BRM ACTIVATED CAM TRANSCRIPTION BY ALTERING THE CHROMATIN STRUCTURE SURROUNDING THE CAM PROMOTERS. CONCLUSION: OUR DATA SUGGEST THAT BRG1 PROVIDES THE CRUCIAL EPIGENETIC LINK TO HYPOXIA-INDUCED CAM INDUCTION AND LEUKOCYTE ADHESION THAT ENGENDERS ENDOTHELIAL MALFUNCTION AND PATHOGENESIS OF HPH. AS SUCH, TARGETING BRG1 IN ENDOTHELIAL CELLS MAY YIELD PROMISING STRATEGIES IN THE INTERVENTION AND/OR PREVENTION OF HPH. 2013 3 3946 40 LNCRNA MALAT1 BINDS CHROMATIN REMODELING SUBUNIT BRG1 TO EPIGENETICALLY PROMOTE INFLAMMATION-RELATED HEPATOCELLULAR CARCINOMA PROGRESSION. HEPATOCELLULAR CARCINOMA (HCC) IS ONE TYPE OF CANCERS WHOSE CARCINOGENESIS AND PROGRESSION ARE CLOSELY RELATED TO CHRONIC INFLAMMATION. IDENTIFYING THE MOLECULAR MECHANISMS FOR INFLAMMATION-RELATED HCC PROGRESSION WILL CONTRIBUTE TO IMPROVE THE EFFICACY OF CURRENT THERAPEUTICS FOR HCC PATIENTS. MANY KINDS OF EPIGENETIC FACTORS, INCLUDING LONG NON-CODING RNAS (LNCRNAS), HAVE BEEN DISCOVERED TO BE IMPORTANT IN HCC GROWTH AND METASTASIS. HOWEVER, HOW THE LNCRNAS PROMOTE HCC PROGRESSION AND WHAT'S THE APPLICATION OF LNCRNA SILENCING IN VIVO IN SUPPRESSING HCC REMAIN TO BE FURTHER INVESTIGATED. HERE, WE FOUND THAT LNCRNA METASTASIS ASSOCIATED LUNG ADENOCARCINOMA TRANSCRIPT1 (MALAT1) WAS UPREGULATED IN HCC TUMOR TISSUES, AND KNOCKDOWN OF MALAT1 SUPPRESSED PROLIFERATION, CELL CYCLE AND INVASION OF HCC CELLS IN RESPONSE TO LIPOPOLYSACCHARIDE (LPS) STIMULATION. KNOCKDOWN OF MALAT1 SIGNIFICANTLY INHIBITED LPS-INDUCED PRO-INFLAMMATORY MEDIATORS IL-6 AND CXCL8 EXPRESSION IN HCC CELLS, WHICH COULD BE RESTORED BY OVEREXPRESSING MALAT1. MECHANISTICALLY, MALAT1 RECRUITED BRAHMA-RELATED GENE 1 (BRG1), A CATALYTIC SUBUNIT OF CHROMATIN REMODELING COMPLEX SWITCHING/SUCROSE NON-FERMENTABLE (SWI/SNF), TO THE PROMOTER REGION OF IL-6 AND CXCL8, AND THUS FACILITATED NF-KAPPAB TO INDUCE THE EXPRESSION OF THESE INFLAMMATORY FACTORS. IMPORTANTLY, IN VIVO SILENCING OF MALAT1 IN HCC TISSUES INHIBITED GROWTH OF HCC XENOGRAFTS, AND ALSO SUPPRESSED THE EXPRESSION OF PRO-INFLAMMATORY FACTORS IN HCC TISSUES ACCORDINGLY. OUR RESULTS DEMONSTRATE THAT MALAT1 PROMOTES HCC PROGRESSION BY BINDING BRG1 TO EPIGENETICALLY ENHANCE INFLAMMATORY RESPONSE IN HCC TISSUES, AND SILENCING OF MALAT1 MAY BE A POTENTIAL APPROACH TO THE TREATMENT OF HCC. 2019 4 4171 46 MEGAKARYOCYTIC LEUKEMIA 1 DIRECTS A HISTONE H3 LYSINE 4 METHYLTRANSFERASE COMPLEX TO REGULATE HYPOXIC PULMONARY HYPERTENSION. ENHANCED INTERACTION BETWEEN VASCULAR ENDOTHELIAL CELLS AND CIRCULATING LEUKOCYTES, AS A RESULT OF TRANSCRIPTIONAL ACTIVATION OF CELL ADHESION MOLECULES (CAM), HELPS ESTABLISH A PROINFLAMMATORY MILIEU CONTRIBUTING TO THE PATHOGENESIS OF CHRONIC HYPOXIA-INDUCED PULMONARY HYPERTENSION. THE MOLECULAR SWITCH THAT DICTATES CAM TRANSACTIVATION IS NOT CLEARLY DEFINED. OUR GOAL WAS TO DETERMINE THE INVOLVEMENT OF THE TRANSCRIPTIONAL MODULATOR MEGAKARYOCYTIC LEUKEMIA 1 (MKL1), ALSO KNOWN AS MYOCARDIN-RELATED TRANSCRIPTION FACTOR A (MRTF-A), IN CAM TRANSACTIVATION AND THE UNDERLYING MECHANISM. WE REPORT HERE THAT COMPARED WITH WILD-TYPE LITTERMATES, MKL1/MRTF-A KNOCKOUT MICE WERE MORE RESISTANT TO THE DEVELOPMENT OF HYPOXIA-INDUCED PULMONARY HYPERTENSION WHEN EXPOSED TO LOW OXYGEN PRESSURE. NOTABLY, CAM INDUCTION IN KNOCKOUT MICE WAS SIGNIFICANTLY ATTENUATED WITH A CONCOMITANT REDUCTION OF LEUKOCYTE ADHESION. IN CULTURED VASCULAR ENDOTHELIAL CELLS, OVEREXPRESSION OF MKL1/MRTF-A ENHANCED, WHEREAS DEPLETION OF MKL1/MRTF-A DAMPENED, HYPOXIA-INDUCED CAM TRANSACTIVATION. IN RESPONSE TO HYPOXIA, MKL1/MRTF-A FORMED A COMPLEX WITH NF-KAPPAB ON THE CAM PROMOTERS. OF INTEREST, MKL1/MRTF-A WAS RESPONSIBLE FOR RECRUITING A HISTONE H3 LYSINE 4 METHYLTRANSFERASE COMPLEX TO THE CAM PROMOTERS. FINALLY, ENDOTHELIAL-SPECIFIC SILENCING OF ASH2 AND WDR5, 2 KEY COMPONENTS OF THE HISTONE H3 LYSINE 4 METHYLTRANSFERASE COMPLEX, AMELIORATED HYPOXIA-INDUCED PULMONARY HYPERTENSION IN MICE. IN CONCLUSION, OUR DATA SUGGEST THAT MKL1/MRTF-A, BY COORDINATING KEY EPIGENETIC ALTERATIONS ON CAM PROMOTERS, PROVIDES A CRITICAL LINK TO HYPOXIA-INDUCED ENDOTHELIAL MALFUNCTION AND CONTRIBUTES TO THE PATHOGENESIS OF HYPOXIA-INDUCED PULMONARY HYPERTENSION. 2015 5 3527 32 IL-6 ENHANCES THE NUCLEAR TRANSLOCATION OF DNA CYTOSINE-5-METHYLTRANSFERASE 1 (DNMT1) VIA PHOSPHORYLATION OF THE NUCLEAR LOCALIZATION SEQUENCE BY THE AKT KINASE. THE EPIGENETIC PROGRAMMING OF GENOMIC DNA IS ACCOMPLISHED, IN PART, BY SEVERAL DNA CYTOSINE-5-METHYLTRANSFERASES THAT ACT BY COVALENTLY MODIFYING CYTOSINES WITH THE ADDITION OF A METHYL GROUP. THIS COVALENT MODIFICATION IS MAINTAINED BY THE DNA CYTOSINE-5-METHYLTRANSFERASE-1 ENZYME (DNMT1), WHICH IS CAPABLE OF ACTING IN CONCERT WITH OTHER SIMILAR ENZYMES TO SILENCE IMPORTANT TUMOR SUPPRESSOR GENES. IL-6 IS A MULTIFUNCTIONAL MEDIATOR OF INFLAMMATION, ACTING THROUGH SEVERAL MAJOR SIGNALING CASCADES, INCLUDING THE PHOSPHATIDYLINOSITOL-3-KINASE PATHWAY (PI-3-K), WHICH ACTIVATES PROTEIN KINASE B (AKT/PKB) DOWNSTREAM. HERE, WE SHOW THAT THE SUBCELLULAR LOCALIZATION OF DNMT1 CAN BE ALTERED BY THE ADDITION OF IL-6, INCREASING THE RATE OF NUCLEAR TRANSLOCATION OF THE ENZYME FROM THE CYTOSOLIC COMPARTMENT. THE MECHANISM OF NUCLEAR TRANSLOCATION OF DNMT1 IS GREATLY ENHANCED BY PHOSPHORYLATION OF THE DNMT1 NUCLEAR LOCALIZATION SIGNAL (NLS) BY PKB/AKT KINASE. MUTAGENIC ALTERATION OF THE TWO AKT TARGET AMINO ACIDS WITHIN THE NLS RESULTS IN A MAJOR LOSS OF DNMT1 NUCLEAR TRANSLOCATION, WHILE THE CREATION OF A "PHOSPHO-MIMIC" AMINO ACID (MUTATION TO ACIDIC RESIDUES) RESTORES THIS COMPARTMENTATION ABILITY. THESE OBSERVATIONS SUGGEST AN INTERESTING HYPOTHESIS REGARDING HOW MEDIATORS OF CHRONIC INFLAMMATION MAY DISTURB THE DELICATE BALANCE OF CELLULAR COMPARTMENTALIZATION OF IMPORTANT PROTEINS, AND REVEALS A POTENTIAL MECHANISM FOR THE INDUCTION OR ENHANCEMENT OF TUMOR GROWTH VIA ALTERATION OF THE COMPONENTS INVOLVED IN THE EPIGENETIC PROGRAMMING OF A CELL. 2007 6 2002 28 EPIGENETIC AND POST-TRANSCRIPTIONAL REPRESSION SUPPORT METABOLIC SUPPRESSION IN CHRONICALLY HYPOXIC GOLDFISH. GOLDFISH ENTER A HYPOMETABOLIC STATE TO SURVIVE CHRONIC HYPOXIA. WE RECENTLY DESCRIBED TISSUE-SPECIFIC CONTRIBUTIONS OF MEMBRANE LIPID COMPOSITION REMODELING AND MITOCHONDRIAL FUNCTION TO METABOLIC SUPPRESSION ACROSS DIFFERENT GOLDFISH TISSUES. HOWEVER, THE MOLECULAR AND ESPECIALLY EPIGENETIC FOUNDATIONS OF HYPOXIA TOLERANCE IN GOLDFISH UNDER METABOLIC SUPPRESSION ARE NOT WELL UNDERSTOOD. HERE WE SHOW THAT COMPONENTS OF THE MOLECULAR OXYGEN-SENSING MACHINERY ARE ROBUSTLY ACTIVATED ACROSS TISSUES IRRESPECTIVE OF HYPOXIA DURATION. INDUCTION OF GENE EXPRESSION OF ENZYMES INVOLVED IN DNA METHYLATION TURNOVER AND MICRORNA BIOGENESIS SUGGEST A ROLE FOR EPIGENETIC TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL SUPPRESSION OF GENE EXPRESSION IN THE HYPOXIA-ACCLIMATED BRAIN. CONVERSELY, MECHANISTIC TARGET OF RAPAMYCIN-DEPENDENT TRANSLATIONAL MACHINERY ACTIVITY IS NOT REDUCED IN LIVER AND WHITE MUSCLE, SUGGESTING THIS PATHWAY DOES NOT CONTRIBUTE TO LOWERING CELLULAR ENERGY EXPENDITURE. FINALLY, MOLECULAR EVIDENCE SUPPORTS PREVIOUSLY REPORTED CHRONIC HYPOXIA-DEPENDENT CHANGES IN MEMBRANE CHOLESTEROL, LIPID METABOLISM AND MITOCHONDRIAL FUNCTION VIA CHANGES IN TRANSCRIPTS INVOLVED IN CHOLESTEROL BIOSYNTHESIS, BETA-OXIDATION, AND MITOCHONDRIAL FUSION IN MULTIPLE TISSUES. OVERALL, THIS STUDY SHOWS THAT CHRONIC HYPOXIA ROBUSTLY INDUCES EXPRESSION OF OXYGEN-SENSING MACHINERY ACROSS TISSUES, INDUCES REPRESSIVE TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL EPIGENETIC MARKS ESPECIALLY IN THE CHRONIC HYPOXIA-ACCLIMATED BRAIN AND SUPPORTS A ROLE FOR MEMBRANE REMODELING AND MITOCHONDRIAL FUNCTION AND DYNAMICS IN PROMOTING METABOLIC SUPPRESSION. 2022 7 4772 34 NUCLEAR SIRTUINS AND INFLAMMATORY SIGNALING PATHWAYS. THE REGULATION OF CHRONIC INFLAMMATION HAS RECEIVED CONSIDERABLE RESEARCH ATTENTION IN RECENT YEARS BECAUSE OF ITS CONTRIBUTION TO THE PATHOGENESIS OF CHRONIC DISEASES SUCH AS ARTHRITIS, DIABETES, METABOLIC SYNDROME AND OBESITY. THUS, STRATEGIES THAT INHIBIT THE INFLAMMATORY STATE MAY BE BENEFICIAL IN IMPROVING THE PATHOPHYSIOLOGY OF SEVERAL INFLAMMATION-RELATED DISORDERS. SIRTUINS ARE A FAMILY OF HISTONE DEACETYLASES THAT CONTAIN SEVEN ENZYMATIC ACTIVITIES IN MAMMALS (SIRT1-SIRT7) AND FUNCTION TO SUPPRESS GENE TRANSCRIPTION BY EPIGENETIC MECHANISMS. NUCLEAR SIRTUINS (SIRT 1, 2, 6 AND 7) IN PARTICULAR MAY PLAY AN IMPORTANT ROLE IN THE REGULATION OF INFLAMMATORY RESPONSES. IN THE PRESENT REVIEW, WE ASSESSED THE ROLES OF NUCLEAR SIRTUINS IN INFLAMMATORY REACTIONS: SIRT1 HAS BEEN SHOWN TO SUPPRESS NF-KAPPAB ACTIVITY, THE MASTER REGULATOR OF CELLULAR INFLAMMATORY RESPONSE, DECREASE COX-2 AND INOS PRODUCTION, AND INCREASE ANTIOXIDANT GENE EXPRESSION THAT SUPPRESSED INFLAMMATION. SIRT2 ACTIVITY INCLUDED THE DEACETYLATION OF P65 SUBUNIT OF NF-KAPPABETA AND RIP-1, WHILE SIRT6 HAS BEEN SHOWN TO INTERACT WITH P65/RELA BOUND TO THE NF-KAPPABETA PROMOTER REGION AND REPRESS TRANSCRIPTIONAL ACTIVITY. FURTHERMORE, RECENT STUDIES HAVE SHOWN THAT THE ABSENCE OF SIRT7 PRODUCED AN INCREASE IN INFLAMMATION, ILLUSTRATING THAT SIRT7 ALSO FUNCTIONED TO DECREASE INFLAMMATION. GIVEN THEIR SIGNIFICANT ROLES IN THE REGULATION OF CHRONIC INFLAMMATION, NUCLEAR SIRTUINS REPRESENT POTENTIAL THERAPEUTIC TARGETS IN THE CONTROL OF CHRONIC INFLAMMATORY DISEASES. 2017 8 911 26 CHRONIC EXPOSURE TO TNF REPROGRAMS CELL SIGNALING PATHWAYS IN FIBROBLAST-LIKE SYNOVIOCYTES BY ESTABLISHING LONG-TERM INFLAMMATORY MEMORY. FIBROBLAST-LIKE SYNOVIOCYTES (FLS) PLAY A CRITICAL ROLE IN THE PATHOGENESIS OF RHEUMATOID ARTHRITIS (RA). CHRONIC INFLAMMATION INDUCES TRANSCRIPTOMIC AND EPIGENETIC MODIFICATIONS THAT IMPARTS A PERSISTENT CATABOLIC PHENOTYPE TO THE FLS, DESPITE THEIR DISSOCIATION FROM THE INFLAMMATORY ENVIRONMENT. WE ANALYZED HIGH THROUGHPUT GENE EXPRESSION AND CHROMATIN ACCESSIBILITY DATA FROM HUMAN AND MOUSE FLS FROM OUR AND OTHER STUDIES AVAILABLE ON PUBLIC REPOSITORIES, WITH THE GOAL OF IDENTIFYING THE PERSISTENTLY REPROGRAMMED SIGNALING PATHWAYS DRIVEN BY CHRONIC INFLAMMATION. WE FOUND THAT THE GENE EXPRESSION CHANGES INDUCED BY SHORT-TERM TUMOR NECROSIS FACTOR-ALPHA (TNF) TREATMENT WERE LARGELY SUSTAINED IN THE FLS EXPOSED TO CHRONIC INFLAMMATION. THESE CHANGES THAT INCLUDED BOTH ACTIVATION AND REPRESSION OF GENE EXPRESSION, WERE ACCOMPANIED BY THE REMODELING OF CHROMATIN ACCESSIBILITY. THE SUSTAINED ACTIVATED GENES (SAGS) INCLUDED ESTABLISHED PRO-INFLAMMATORY SIGNALING COMPONENTS KNOWN TO ACT AT MULTIPLE LEVELS OF NF-KAPPAB, STAT AND AP-1 SIGNALING CASCADES. INTERESTINGLY, THE SUSTAINED REPRESSED GENES (SRGS) INCLUDED CRITICAL MEDIATORS AND TARGETS OF THE BMP SIGNALING PATHWAY. WE THUS IDENTIFIED SUSTAINED REPRESSION OF BMP SIGNALING AS A UNIQUE CONSTITUENT OF THE LONG-TERM INFLAMMATORY MEMORY INDUCED BY CHRONIC INFLAMMATION. WE POSTULATE THAT SIMULTANEOUS TARGETING OF THESE ACTIVATED AND REPRESSED SIGNALING PATHWAYS MAY BE NECESSARY TO COMBAT RA PERSISTENCE. 2020 9 4284 26 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 10 2780 27 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 11 2228 26 EPIGENETIC MODIFICATIONS OF HISTONES IN PERIODONTAL DISEASE. PERIODONTITIS IS A CHRONIC INFECTIOUS DISEASE DRIVEN BY DYSBIOSIS, AN IMBALANCE BETWEEN COMMENSAL BACTERIA AND THE HOST ORGANISM. PERIODONTITIS IS A LEADING CAUSE OF TOOTH LOSS IN ADULTS AND OCCURS IN ABOUT 50% OF THE US POPULATION. IN ADDITION TO THE CLINICAL CHALLENGES ASSOCIATED WITH TREATING PERIODONTITIS, THE PROGRESSION AND CHRONIC NATURE OF THIS DISEASE SERIOUSLY AFFECT HUMAN HEALTH. EMERGING EVIDENCE SUGGESTS THAT PERIODONTITIS IS ASSOCIATED WITH MECHANISMS BEYOND BACTERIA-INDUCED PROTEIN AND TISSUE DEGRADATION. HERE, WE HYPOTHESIZE THAT BACTERIA ARE ABLE TO INDUCE EPIGENETIC MODIFICATIONS IN ORAL EPITHELIAL CELLS MEDIATED BY HISTONE MODIFICATIONS. IN THIS STUDY, WE FOUND THAT DYSBIOSIS IN VIVO LED TO EPIGENETIC MODIFICATIONS, INCLUDING ACETYLATION OF HISTONES AND DOWNREGULATION OF DNA METHYLTRANSFERASE 1. IN ADDITION, IN VITRO EXPOSURE OF ORAL EPITHELIAL CELLS TO LIPOPOLYSACCHARIDES RESULTED IN HISTONE MODIFICATIONS, ACTIVATION OF TRANSCRIPTIONAL COACTIVATORS, SUCH AS P300/CBP, AND ACCUMULATION OF NUCLEAR FACTOR-KAPPAB (NF-KAPPAB). GIVEN THAT ORAL EPITHELIAL CELLS ARE THE FIRST LINE OF DEFENSE FOR THE PERIODONTIUM AGAINST BACTERIA, WE ALSO EVALUATED WHETHER ACTIVATION OF PATHOGEN RECOGNITION RECEPTORS INDUCED HISTONE MODIFICATIONS. WE FOUND THAT ACTIVATION OF THE TOLL-LIKE RECEPTORS 1, 2, AND 4 AND THE NUCLEOTIDE-BINDING OLIGOMERIZATION DOMAIN PROTEIN 1 INDUCED HISTONE ACETYLATION IN ORAL EPITHELIAL CELLS. OUR FINDINGS CORROBORATE THE EMERGING CONCEPT THAT EPIGENETIC MODIFICATIONS PLAY A ROLE IN THE DEVELOPMENT OF PERIODONTITIS. 2016 12 3322 31 HISTONE ACETYLTRANSFERASE P300 INDUCES DE NOVO SUPER-ENHANCERS TO DRIVE CELLULAR SENESCENCE. ACCUMULATION OF SENESCENT CELLS DURING AGING CONTRIBUTES TO CHRONIC INFLAMMATION AND AGE-RELATED DISEASES. WHILE SENESCENCE IS ASSOCIATED WITH PROFOUND ALTERATIONS OF THE EPIGENOME, A SYSTEMATIC VIEW OF EPIGENETIC FACTORS IN REGULATING SENESCENCE IS LACKING. HERE, WE CURATED A LIBRARY OF SHORT HAIRPIN RNAS FOR TARGETED SILENCING OF ALL KNOWN EPIGENETIC PROTEINS AND PERFORMED A HIGH-THROUGHPUT SCREEN TO IDENTIFY KEY CANDIDATES WHOSE DOWNREGULATION CAN DELAY REPLICATIVE SENESCENCE OF PRIMARY HUMAN CELLS. THIS SCREEN IDENTIFIED MULTIPLE NEW PLAYERS INCLUDING THE HISTONE ACETYLTRANSFERASE P300 THAT WAS FOUND TO BE A PRIMARY DRIVER OF THE SENESCENT PHENOTYPE. P300, BUT NOT THE PARALOGOUS CBP, INDUCES A DYNAMIC HYPER-ACETYLATED CHROMATIN STATE AND PROMOTES THE FORMATION OF ACTIVE ENHANCER ELEMENTS IN THE NON-CODING GENOME, LEADING TO A SENESCENCE-SPECIFIC GENE EXPRESSION PROGRAM. OUR WORK ILLUSTRATES A CAUSAL ROLE OF HISTONE ACETYLTRANSFERASES AND ACETYLATION IN SENESCENCE AND SUGGESTS P300 AS A POTENTIAL THERAPEUTIC TARGET FOR SENESCENCE AND AGE-RELATED DISEASES. 2019 13 5872 30 SUSTAINED TNF-ALPHA STIMULATION LEADS TO TRANSCRIPTIONAL MEMORY THAT GREATLY ENHANCES SIGNAL SENSITIVITY AND ROBUSTNESS. TRANSCRIPTIONAL MEMORY ALLOWS CERTAIN GENES TO RESPOND TO PREVIOUSLY EXPERIENCED SIGNALS MORE ROBUSTLY. HOWEVER, WHETHER AND HOW THE KEY PROINFLAMMATORY CYTOKINE TNF-ALPHA MEDIATES TRANSCRIPTIONAL MEMORY ARE POORLY UNDERSTOOD. USING HEK293F CELLS AS A MODEL SYSTEM, WE REPORT THAT SUSTAINED TNF-ALPHA STIMULATION INDUCES TRANSCRIPTIONAL MEMORY DEPENDENT ON TET ENZYMES. THE HYPOMETHYLATED STATUS OF TRANSCRIPTIONAL REGULATORY REGIONS CAN BE INHERITED, FACILITATING NF-KAPPAB BINDING AND MORE ROBUST SUBSEQUENT ACTIVATION. A HIGH INITIAL METHYLATION LEVEL AND CPG DENSITY AROUND KAPPAB SITES ARE CORRELATED WITH THE FUNCTIONAL POTENTIAL OF TRANSCRIPTIONAL MEMORY MODULES. INTERESTINGLY, THE CALCB GENE, ENCODING THE PROVEN MIGRAINE THERAPEUTIC TARGET CGRP, EXHIBITS THE BEST TRANSCRIPTIONAL MEMORY. A NEIGHBORING PRIMATE-SPECIFIC ENDOGENOUS RETROVIRUS STIMULATES MORE RAPID, MORE STRONG, AND AT LEAST 100-FOLD MORE SENSITIVE CALCB INDUCTION IN SUBSEQUENT TNF-ALPHA STIMULATION. OUR STUDY REVEALS THAT TNF-ALPHA-MEDIATED TRANSCRIPTIONAL MEMORY IS GOVERNED BY ACTIVE DNA DEMETHYLATION AND GREATLY SENSITIZES MEMORY GENES TO MUCH LOWER DOSES OF INFLAMMATORY CUES. 2020 14 1615 27 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 15 1479 26 DIVERSE TARGETS OF THE TRANSCRIPTION FACTOR STAT3 CONTRIBUTE TO T CELL PATHOGENICITY AND HOMEOSTASIS. STAT3, AN ESSENTIAL TRANSCRIPTION FACTOR WITH PLEIOTROPIC FUNCTIONS, PLAYS CRITICAL ROLES IN THE PATHOGENESIS OF AUTOIMMUNITY. DESPITE RECENT DATA LINKING STAT3 WITH INFLAMMATORY BOWEL DISEASE, EXACTLY HOW IT CONTRIBUTES TO CHRONIC INTESTINAL INFLAMMATION IS NOT KNOWN. USING A T CELL TRANSFER MODEL OF COLITIS, WE FOUND THAT STAT3 EXPRESSION IN T CELLS WAS ESSENTIAL FOR THE INDUCTION OF BOTH COLITIS AND SYSTEMIC INFLAMMATION. STAT3 WAS CRITICAL IN MODULATING THE BALANCE OF T HELPER 17 (TH17) AND REGULATORY T (TREG) CELLS, AS WELL AS IN PROMOTING CD4(+) T CELL PROLIFERATION. WE USED CHROMATIN IMMUNOPRECIPITATION AND MASSIVE PARALLEL SEQUENCING (CHIP-SEQ) TO DEFINE THE GENOME-WIDE TARGETS OF STAT3 IN CD4(+) T CELLS. WE FOUND THAT STAT3 BOUND TO MULTIPLE GENES INVOLVED IN TH17 CELL DIFFERENTIATION, CELL ACTIVATION, PROLIFERATION, AND SURVIVAL, REGULATING BOTH EXPRESSION AND EPIGENETIC MODIFICATIONS. THUS, STAT3 ORCHESTRATES MULTIPLE CRITICAL ASPECTS OF T CELL FUNCTION IN INFLAMMATION AND HOMEOSTASIS. 2010 16 4969 36 PATHOLOGICAL NEUROINFLAMMATORY CONVERSION OF REACTIVE ASTROCYTES IS INDUCED BY MICROGLIA AND INVOLVES CHROMATIN REMODELING. FOLLOWING BRAIN INJURY OR IN NEURODEGENERATIVE DISEASES, ASTROCYTES BECOME REACTIVE AND MAY SUFFER PATHOLOGICAL REMODELING, FEATURES OF WHICH ARE THE LOSS OF THEIR HOMEOSTATIC FUNCTIONS AND A PRO-INFLAMMATORY GAIN OF FUNCTION THAT FACILITATES NEURODEGENERATION. PHARMACOLOGICAL INTERVENTION TO MODULATE THIS ASTROGLIAL RESPONSE AND NEUROINFLAMMATION IS AN INTERESTING NEW THERAPEUTIC RESEARCH STRATEGY, BUT IT STILL REQUIRES A DEEPER UNDERSTANDING OF THE UNDERLYING CELLULAR AND MOLECULAR MECHANISMS OF THE PHENOMENON. BASED ON THE KNOWN MICROGLIAL-ASTROGLIAL INTERACTION, THE PROMINENT ROLE OF THE NUCLEAR FACTOR KAPPA B (NF-KAPPAB) PATHWAY IN MEDIATING ASTROGLIAL PATHOLOGICAL PRO-INFLAMMATORY GAIN OF FUNCTION, AND ITS ABILITY TO RECRUIT CHROMATIN-REMODELING ENZYMES, WE FIRST EXPLORED THE MICROGLIAL ROLE IN THE INITIATION OF ASTROGLIAL PRO-INFLAMMATORY CONVERSION AND THEN MONITORED THE PROGRESSION OF EPIGENETIC CHANGES IN THE ASTROCYTIC CHROMATIN. DIFFERENT CONFIGURATIONS OF PRIMARY GLIAL CULTURE WERE USED TO MODULATE MICROGLIA-ASTROCYTE CROSSTALK WHILE INDUCING PRO-INFLAMMATORY GAIN OF FUNCTION BY LIPOPOLYSACCHARIDE (LPS) EXPOSURE. IN VIVO, BRAIN ISCHEMIA BY CORTICAL DEVASCULARIZATION (PIAL DISRUPTION) WAS PERFORMED TO VERIFY THE PRESENCE OF EPIGENETIC MARKS IN REACTIVE ASTROCYTES. OUR RESULTS SHOWED THAT 1) MICROGLIA IS REQUIRED TO INITIATE THE PATHOLOGICAL CONVERSION OF ASTROCYTES BY TRIGGERING THE NF-KAPPAB SIGNALING PATHWAY; 2) THIS INTERACTION IS MEDIATED BY SOLUBLE FACTORS AND INDUCES STABLE ASTROGLIAL PHENOTYPIC CHANGES; 3) THE PATHOLOGICAL CONVERSION PROMOTES CHROMATIN REMODELING WITH STABLE INCREASE IN H3K9K14AC, TEMPORARY INCREASE IN H3K27AC, AND TEMPORARY REDUCTION IN HETEROCHROMATIN MARK H3K9ME3; AND 4) IN VIVO REACTIVE ASTROCYTES SHOW INCREASED H3K27AC MARK IN THE NEUROINFLAMMATORY MILIEU FROM THE ISCHEMIC PENUMBRA. OUR FINDINGS INDICATE THAT ASTROGLIAL PATHOLOGICAL PRO-INFLAMMATORY GAIN OF FUNCTION IS ASSOCIATED WITH PROFOUND CHANGES IN THE CONFIGURATION OF ASTROCYTIC CHROMATIN, WHICH IN TURN ARE INITIATED BY MICROGLIA-DERIVED CUES. THESE RESULTS OPEN A NEW AVENUE IN THE STUDY OF POTENTIAL PHARMACOLOGICAL INTERVENTIONS THAT MODIFY THE INITIATION AND STABILIZATION OF ASTROGLIAL PATHOLOGICAL REMODELING, WHICH WOULD BE USEFUL IN ACUTE AND CHRONIC CNS INJURY. EPIGENETIC CHANGES REPRESENT A PLAUSIBLE PHARMACOLOGICAL TARGET TO INTERFERE WITH THE STABILIZATION OF THE PATHOLOGICAL ASTROGLIAL PHENOTYPE. 2021 17 4574 38 MYOCARDIN-RELATED TRANSCRIPTION FACTOR A EPIGENETICALLY REGULATES RENAL FIBROSIS IN DIABETIC NEPHROPATHY. DIABETIC NEPHROPATHY (DN) IS ONE OF THE MOST COMMON COMPLICATIONS ASSOCIATED WITH DIABETES AND CHARACTERIZED BY RENAL MICROVASCULAR INJURY ALONG WITH ACCELERATED SYNTHESIS OF EXTRACELLULAR MATRIX PROTEINS CAUSING TUBULOINTERSTITIAL FIBROSIS. PRODUCTION OF TYPE I COLLAGEN, THE MAJOR COMPONENT OF EXTRACELLULAR MATRIX, IS AUGMENTED DURING RENAL FIBROSIS AFTER CHRONIC EXPOSURE TO HYPERGLYCEMIA. HOWEVER, THE TRANSCRIPTIONAL MODULATOR RESPONSIBLE FOR THE EPIGENETIC MANIPULATION LEADING TO INDUCTION OF TYPE I COLLAGEN GENES IS NOT CLEARLY DEFINED. WE SHOW HERE THAT TUBULOINTERSTITIAL FIBROSIS AS A RESULT OF DN WAS DIMINISHED IN MYOCARDIN-RELATED TRANSCRIPTION FACTOR A (MRTF-A) -DEFICIENT MICE. IN CULTURED RENAL TUBULAR EPITHELIAL CELLS AND THE KIDNEYS OF MICE WITH DN, MRTF-A WAS INDUCED BY GLUCOSE AND SYNERGIZED WITH GLUCOSE TO ACTIVATE COLLAGEN TRANSCRIPTION. NOTABLY, MRTF-A SILENCING LED TO THE DISAPPEARANCE OF PROMINENT HISTONE MODIFICATIONS INDICATIVE OF TRANSCRIPTIONAL ACTIVATION, INCLUDING ACETYLATED HISTONE H3K18/K27 AND TRIMETHYLATED HISTONE H3K4. DETAILED ANALYSIS REVEALED THAT MRTF-A RECRUITED P300, A HISTONE ACETYLTRANSFERASE, AND WD REPEAT-CONTAINING PROTEIN 5 (WDR5), A KEY COMPONENT OF THE HISTONE H3K4 METHYLTRANSFERASE COMPLEX, TO THE COLLAGEN PROMOTERS AND ENGAGED THESE PROTEINS IN TRANSCRIPTIONAL ACTIVATION. ESTRADIOL SUPPRESSED COLLAGEN PRODUCTION BY DAMPENING THE EXPRESSION AND BINDING ACTIVITY OF MRTF-A AND INTERFERING WITH THE INTERACTION BETWEEN P300 AND WDR5 IN RENAL EPITHELIAL CELLS. THEREFORE, TARGETING THE MRTF-A-ASSOCIATED EPIGENETIC MACHINERY MIGHT YIELD INTERVENTIONAL STRATEGIES AGAINST DN-ASSOCIATED RENAL FIBROSIS. 2015 18 1326 20 DEPLETION OF NUCLEAR HISTONE H2A VARIANTS IS ASSOCIATED WITH CHRONIC DNA DAMAGE SIGNALING UPON DRUG-EVOKED SENESCENCE OF HUMAN SOMATIC CELLS. CELLULAR SENESCENCE IS ASSOCIATED WITH GLOBAL CHROMATIN CHANGES, ALTERED GENE EXPRESSION, AND ACTIVATION OF CHRONIC DNA DAMAGE SIGNALING. THESE EVENTS ULTIMATELY LEAD TO MORPHOLOGICAL AND PHYSIOLOGICAL TRANSFORMATIONS IN PRIMARY CELLS. IN THIS STUDY, WE SHOW THAT CHRONIC DNA DAMAGE SIGNALS CAUSED BY GENOTOXIC STRESS IMPACT THE EXPRESSION OF HISTONES H2A FAMILY MEMBERS AND LEAD TO THEIR DEPLETION IN THE NUCLEI OF SENESCENT HUMAN FIBROBLASTS. OUR DATA REINFORCE THE HYPOTHESIS THAT PROGRESSIVE CHROMATIN DESTABILIZATION MAY LEAD TO THE LOSS OF EPIGENETIC INFORMATION AND IMPAIRED CELLULAR FUNCTION ASSOCIATED WITH CHRONIC DNA DAMAGE UPON DRUG-EVOKED SENESCENCE. WE PROPOSE THAT CHANGES IN THE HISTONE BIOSYNTHESIS AND CHROMATIN ASSEMBLY MAY DIRECTLY CONTRIBUTE TO CELLULAR AGING. IN ADDITION, WE ALSO OUTLINE THE METHOD THAT ALLOWS FOR QUANTITATIVE AND UNBIASED MEASUREMENT OF THESE CHANGES. 2012 19 5972 27 TET REPRESSION AND INCREASED DNMT ACTIVITY SYNERGISTICALLY INDUCE ABERRANT DNA METHYLATION. CHRONIC INFLAMMATION IS DEEPLY INVOLVED IN VARIOUS HUMAN DISORDERS, SUCH AS CANCER, NEURODEGENERATIVE DISORDERS, AND METABOLIC DISORDERS. INDUCTION OF EPIGENETIC ALTERATIONS, ESPECIALLY ABERRANT DNA METHYLATION, IS ONE OF THE MAJOR MECHANISMS, BUT HOW IT IS INDUCED IS STILL UNCLEAR. HERE, WE FOUND THAT EXPRESSION OF TET GENES, METHYLATION ERASERS, WAS DOWNREGULATED IN INFLAMED MOUSE AND HUMAN TISSUES, AND THAT THIS WAS CAUSED BY UPREGULATION OF TET-TARGETING MIRNAS SUCH AS MIR20A, MIR26B, AND MIR29C, LIKELY DUE TO ACTIVATION OF NF-KAPPAB SIGNALING DOWNSTREAM OF IL-1BETA AND TNF-ALPHA. HOWEVER, TET KNOCKDOWN INDUCED ONLY MILD ABERRANT METHYLATION. NITRIC OXIDE (NO), PRODUCED BY NOS2, ENHANCED ENZYMATIC ACTIVITY OF DNA METHYLTRANSFERASES (DNMTS), METHYLATION WRITERS, AND NO EXPOSURE INDUCED MINIMAL ABERRANT METHYLATION. IN CONTRAST, A COMBINATION OF TET KNOCKDOWN AND NO EXPOSURE SYNERGISTICALLY INDUCED ABERRANT METHYLATION, INVOLVING GENOMIC REGIONS NOT METHYLATED BY EITHER ALONE. THE RESULTS SHOWED THAT A VICIOUS COMBINATION OF TET REPRESSION, DUE TO NF-KAPPAB ACTIVATION, AND DNMT ACTIVATION, DUE TO NO PRODUCTION, IS RESPONSIBLE FOR ABERRANT METHYLATION INDUCTION IN HUMAN TISSUES. 2020 20 2055 25 EPIGENETIC CONTROL DURING LYMPHOID DEVELOPMENT AND IMMUNE RESPONSES: ABERRANT REGULATION, VIRUSES, AND CANCER. METHYLATION OF CYTOSINES CONTROLS A NUMBER OF BIOLOGIC PROCESSES SUCH AS IMPRINTING AND X CHROMOSOMAL INACTIVATION. DNA HYPERMETHYLATION IS CLOSELY ASSOCIATED WITH TRANSCRIPTIONAL SILENCING, WHILE DNA HYPOMETHYLATION IS ASSOCIATED WITH TRANSCRIPTIONAL ACTIVATION. HYPOACETYLATION OF HISTONES LEADS TO COMPACT CHROMATIN WITH REDUCED ACCESSIBILITY TO THE TRANSCRIPTIONAL MACHINERY. METHYL-CPG BINDING PROTEINS CAN RECRUIT COREPRESSORS AND HISTONE DEACETYLASES; THUS, THE INTERPLAY BETWEEN THESE EPIGENETIC MECHANISMS REGULATES GENE ACTIVATION. METHYLATION HAS BEEN IMPLICATED AS AN IMPORTANT MECHANISM DURING IMMUNE DEVELOPMENT, CONTROLLING VDJ RECOMBINATION, LINEAGE-SPECIFIC EXPRESSION OF CELL SURFACE ANTIGENS, AND TRANSCRIPTIONAL REGULATION OF CYTOKINE GENES DURING IMMUNE RESPONSES. ABERRATIONS IN EPIGENETIC MACHINERY, EITHER BY GENETIC MUTATIONS OR BY SOMATIC CHANGES SUCH AS VIRAL INFECTIONS, ARE ASSOCIATED WITH EARLY ALTERATIONS IN CHRONIC DISEASES SUCH AS IMMUNODEFICIENCY AND CANCER. 2003