1 5695 124 SILENCING UHRF1 ENHANCES CELL AUTOPHAGY TO PREVENT ARTICULAR CHONDROCYTES FROM APOPTOSIS IN OSTEOARTHRITIS THROUGH PI3K/AKT/MTOR SIGNALING PATHWAY. OSTEOARTHRITIS (OA) IS A COMMON CHRONIC DEGENERATIVE JOINT DISEASE, AND CHONDROCYTE APOPTOSIS IS ONE OF MOST IMPORTANT PATHOLOGICAL CHANGES OF OA PATHOGENESIS. GROWING STUDIES HAVE SHOWN THAT UBIQUITIN-LIKE WITH PHD AND RING FINGER DOMAINS 1 (UHRF1) IS AN IMPORTANT EPIGENETIC REGULATORY FACTOR THAT REGULATES CELL PROLIFERATION AND APOPTOSIS OF VARIOUS TUMORS, BUT ITS ROLE IN OA REMAINS ILL-DEFINED. IN THE PRESENT STUDY, WE FOUND THAT UHRF1 EXPRESSION WAS INCREASED IN HUMAN OA CARTILAGE TISSUES, COMPARED WITH NORMAL CARTILAGE TISSUES. INTERLEUKIN-1BETA (IL-1BETA), A MAJOR INFLAMMATORY CYTOKINE THAT PROMOTES CARTILAGE DEGRADATION IN OA, WAS USED TO STIMULATE PRIMARY HUMAN CHONDROCYTES IN VITRO. THE EXPRESSION OF UHRF1 WAS ALSO ENHANCED IN IL-1BETA-INDUCED CHONDROCYTES. MOREOVER, DOWN-REGULATION OF UHRF1 INDUCED AN INCREASE ON CELL PROLIFERATION AND AUTOPHAGY, AND A DECREASE ON APOPTOSIS OF CHONDROCYTES AFTER IL-1BETA TREATMENT. FURTHER DATA INDICATED THAT SILENCING UHRF1 ATTENUATED THE UP-REGULATION OF IL-1BETA ON PHOSPHOINOSITIDE 3-KINASE (PI3K)/PROTEIN KINASE B (AKT)/MAMMALIAN TARGET OF RAPAMYCIN (MTOR) SIGNALING PATHWAY IN CHONDROCYTES. THEN, AN ACTIVATOR OF PI3K WEAKENED THE EFFECT OF UHRF1 SILENCING ON CELL PROLIFERATION, AUTOPHAGY, APOPTOSIS OF IL-1BETA-INDUCED CHONDROCYTES, AND THE CELL AUTOPHAGY SPECIAL INHIBITOR 3-METHYLADENINE (3-MA) ALSO SHOWED A SAME IMPACT ON UHRF1, HENCE SUGGESTING THAT KNOCKDOWN OF UHRF1 ENHANCES CELL AUTOPHAGY TO PROTECT CHONDROCYTES FROM APOPTOSIS IN OA THROUGH PI3K/AKT/MTOR SIGNALING PATHWAY. IN CONCLUSION, OUR STUDY SUGGESTS THAT UHRF1 MAY BE A POTENTIAL REGULATOR OF CHONDROCYTE APOPTOSIS IN THE PATHOGENESIS OF OA. 2020 2 3924 40 LIPOSOMAL UHRF1 SIRNA SHOWS LUNG FIBROSIS TREATMENT POTENTIAL THROUGH REGULATION OF FIBROBLAST ACTIVATION. PULMONARY FIBROSIS IS A CHRONIC AND PROGRESSIVE INTERSTITIAL LUNG DISEASE ASSOCIATED WITH THE DECAY OF PULMONARY FUNCTION, WHICH LEADS TO A FATAL OUTCOME. AS AN ESSENTIAL EPIGENETIC REGULATOR OF DNA METHYLATION, THE INVOLVEMENT OF UBIQUITIN-LIKE CONTAINING PHD AND RING FINGER DOMAINS 1 (UHRF1) IN FIBROBLAST ACTIVATION REMAINS LARGELY UNDEFINED IN PULMONARY FIBROSIS. IN THE PRESENT STUDY, WE FOUND THAT TGF-BETA1-MEDIATED UPREGULATION OF UHRF1 REPRESSED BECLIN 1 VIA METHYLATED INDUCTION OF ITS PROMOTER, WHICH FINALLY RESULTED IN FIBROBLAST ACTIVATION AND LUNG FIBROSIS BOTH IN VITRO AND IN VIVO. MOREOVER, KNOCKDOWN OF UHRF1 SIGNIFICANTLY ARRESTED FIBROBLAST PROLIFERATION AND REACTIVATED BECLIN 1 IN LUNG FIBROBLASTS. THUS, INTRAVENOUS ADMINISTRATION OF UHRF1 SIRNA-LOADED LIPOSOMES SIGNIFICANTLY PROTECTED MICE AGAINST EXPERIMENTAL PULMONARY FIBROSIS. ACCORDINGLY, OUR DATA SUGGEST THAT UHRF1 MIGHT BE A NOVEL POTENTIAL THERAPEUTIC TARGET IN THE PATHOGENESIS OF PULMONARY FIBROSIS. 2022 3 5796 39 STAT3 PROMOTES A YOUTHFUL EPIGENETIC STATE IN ARTICULAR CHONDROCYTES. EPIGENETIC MECHANISMS GUIDING ARTICULAR CARTILAGE REGENERATION AND AGE-RELATED DISEASE SUCH AS OSTEOARTHRITIS (OA) ARE POORLY UNDERSTOOD. STAT3 IS A CRITICAL AGE-PATTERNED TRANSCRIPTION FACTOR HIGHLY ACTIVE IN FETAL AND OA CHONDROCYTES, BUT THE CONTEXT-SPECIFIC ROLE OF STAT3 IN REGULATING THE EPIGENOME OF CARTILAGE CELLS REMAIN ELUSIVE. IN THIS STUDY, DNA METHYLATION PROFILING WAS PERFORMED ACROSS HUMAN CHONDROCYTE ONTOGENY TO BUILD AN EPIGENETIC CLOCK AND ESTABLISH AN ASSOCIATION BETWEEN CPG METHYLATION AND HUMAN CHONDROCYTE AGE. EXPOSURE OF ADULT CHONDROCYTES TO A SMALL MOLECULE STAT3 AGONIST DECREASED DNA METHYLATION, WHILE GENETIC ABLATION OF STAT3 IN FETAL CHONDROCYTES INDUCED GLOBAL HYPERMETHYLATION. CUT&RUN ASSAY AND SUBSEQUENT TRANSCRIPTIONAL VALIDATION REVEALED DNA METHYLTRANSFERASE 3 BETA (DNMT3B) AS ONE OF THE PUTATIVE STAT3 TARGETS IN CHONDROCYTE DEVELOPMENT AND OA. FUNCTIONAL ASSESSMENT OF HUMAN OA CHONDROCYTES SHOWED THE ACQUISITION OF PROGENITOR-LIKE IMMATURE PHENOTYPE BY A SIGNIFICANT SUBSET OF CELLS. FINALLY, CONDITIONAL DELETION OF STAT3 IN CARTILAGE CELLS INCREASED DNMT3B EXPRESSION IN ARTICULAR CHONDROCYTES IN THE KNEE JOINT IN VIVO AND RESULTED IN A MORE PROMINENT OA PROGRESSION IN A POST-TRAUMATIC OA (PTOA) MOUSE MODEL INDUCED BY DESTABILIZATION OF THE MEDIAL MENISCUS (DMM). TAKEN TOGETHER THESE DATA REVEAL A NOVEL ROLE FOR STAT3 IN REGULATING DNA METHYLATION IN CARTILAGE DEVELOPMENT AND DISEASE. OUR FINDINGS ALSO SUGGEST THAT ELEVATED LEVELS OF ACTIVE STAT3 IN OA CHONDROCYTES MAY INDICATE AN INTRINSIC ATTEMPT OF THE TISSUE TO REGENERATE BY PROMOTING A PROGENITOR-LIKE PHENOTYPE. HOWEVER, IT IS LIKELY THAT CHRONIC ACTIVATION OF THIS PATHWAY, INDUCED BY IL-6 CYTOKINES, IS DETRIMENTAL AND LEADS TO TISSUE DEGENERATION. 2023 4 2384 35 EPIGENETIC REGULATOR UHRF1 ORCHESTRATES PROINFLAMMATORY GENE EXPRESSION IN RHEUMATOID ARTHRITIS IN A SUPPRESSIVE MANNER. RHEUMATOID ARTHRITIS (RA) IS CHARACTERIZED BY CHRONIC SYNOVIAL INFLAMMATION WITH ABERRANT EPIGENETIC ALTERATIONS, EVENTUALLY LEADING TO JOINT DESTRUCTION. HOWEVER, THE EPIGENETIC REGULATORY MECHANISMS UNDERLYING RA PATHOGENESIS REMAIN LARGELY UNKNOWN. HERE, WE SHOWED THAT UBIQUITIN-LIKE CONTAINING PHD AND RING FINGER DOMAINS 1 (UHRF1) IS A CENTRAL EPIGENETIC REGULATOR THAT ORCHESTRATES MULTIPLE PATHOGENESES IN RA IN A SUPPRESSIVE MANNER. UHRF1 EXPRESSION WAS REMARKABLY UPREGULATED IN SYNOVIAL FIBROBLASTS (SFS) FROM ARTHRITIS MODEL MICE AND PATIENTS WITH RA. MICE WITH SF-SPECIFIC UHRF1 CONDITIONAL KNOCKOUT SHOWED MORE SEVERE ARTHRITIC PHENOTYPES THAN LITTERMATE CONTROLS. UHRF1-DEFICIENT SFS ALSO EXHIBITED ENHANCED APOPTOSIS RESISTANCE AND UPREGULATED EXPRESSION OF SEVERAL CYTOKINES, INCLUDING CCL20. IN PATIENTS WITH RA, DAS28, CRP, AND TH17 ACCUMULATION AND APOPTOSIS RESISTANCE WERE NEGATIVELY CORRELATED WITH UHRF1 EXPRESSION IN SYNOVIUM. FINALLY, RYUVIDINE ADMINISTRATION STABILIZED UHRF1 AMELIORATED ARTHRITIS PATHOGENESES IN A MOUSE MODEL OF RA. THIS STUDY DEMONSTRATED THAT UHRF1 EXPRESSED IN RA SFS CAN CONTRIBUTE TO NEGATIVE FEEDBACK MECHANISMS THAT SUPPRESS MULTIPLE PATHOGENIC EVENTS IN ARTHRITIS, SUGGESTING THAT TARGETING UHRF1 COULD BE ONE OF THE THERAPEUTIC STRATEGIES FOR RA. 2022 5 6611 36 UHRF1 REGULATES GERMINAL CENTER B CELL EXPANSION AND AFFINITY MATURATION TO CONTROL VIRAL INFECTION. THE PRODUCTION OF HIGH-AFFINITY ANTIBODY IS ESSENTIAL FOR PATHOGEN CLEARANCE. ANTIBODY AFFINITY IS INCREASED THROUGH GERMINAL CENTER (GC) AFFINITY MATURATION, WHICH RELIES ON BCR SOMATIC HYPERMUTATION (SHM) FOLLOWED BY ANTIGEN-BASED SELECTION. GC B CELL PROLIFERATION IS ESSENTIALLY INVOLVED IN THESE PROCESSES; IT PROVIDES ENOUGH TEMPLATES FOR SHM AND ALSO SERVES AS A CRITICAL MECHANISM OF POSITIVE SELECTION. IN THIS STUDY, WE SHOW THAT EXPRESSION OF EPIGENETIC REGULATOR UBIQUITIN-LIKE WITH PHD AND RING FINGER DOMAINS 1 (UHRF1) WAS MARKEDLY UP-REGULATED BY C-MYC-AP4 IN GC B CELLS, AND IT WAS REQUIRED FOR GC RESPONSE. UHRF1 REGULATES CELL PROLIFERATION-ASSOCIATED GENES INCLUDING CDKN1A, SLFN1, AND SLFN2 BY DNA METHYLATION, AND ITS DEFICIENCY INHIBITED THE GC B CELL CYCLE AT G1-S PHASE. SUBSEQUENTLY, GC B CELL SHM AND AFFINITY MATURATION WERE IMPAIRED, AND UHRF1 GC B KNOCKOUT MICE WERE UNABLE TO CONTROL CHRONIC VIRUS INFECTION. COLLECTIVELY, OUR DATA SUGGEST THAT UHRF1 REGULATES GC B CELL PROLIFERATION AND AFFINITY MATURATION, AND ITS EXPRESSION IN GC B CELLS IS REQUIRED FOR VIRUS CLEARANCE. 2018 6 3527 33 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 7 2065 31 EPIGENETIC CONTROL OF INTESTINAL BARRIER FUNCTION AND INFLAMMATION IN ZEBRAFISH. THE INTESTINAL EPITHELIUM FORMS A BARRIER PROTECTING THE ORGANISM FROM MICROBES AND OTHER PROINFLAMMATORY STIMULI. THE INTEGRITY OF THIS BARRIER AND THE PROPER RESPONSE TO INFECTION REQUIRES PRECISE REGULATION OF POWERFUL IMMUNE HOMING SIGNALS SUCH AS TUMOR NECROSIS FACTOR (TNF). DYSREGULATION OF TNF LEADS TO INFLAMMATORY BOWEL DISEASES (IBD), BUT THE MECHANISM CONTROLLING THE EXPRESSION OF THIS POTENT CYTOKINE AND THE EVENTS THAT TRIGGER THE ONSET OF CHRONIC INFLAMMATION ARE UNKNOWN. HERE, WE SHOW THAT LOSS OF FUNCTION OF THE EPIGENETIC REGULATOR UBIQUITIN-LIKE PROTEIN CONTAINING PHD AND RING FINGER DOMAINS 1 (UHRF1) IN ZEBRAFISH LEADS TO A REDUCTION IN TNFA PROMOTER METHYLATION AND THE INDUCTION OF TNFA EXPRESSION IN INTESTINAL EPITHELIAL CELLS (IECS). THE INCREASE IN IEC TNFA LEVELS IS MICROBE-DEPENDENT AND RESULTS IN IEC SHEDDING AND APOPTOSIS, IMMUNE CELL RECRUITMENT, AND BARRIER DYSFUNCTION, CONSISTENT WITH CHRONIC INFLAMMATION. IMPORTANTLY, TNFA KNOCKDOWN IN UHRF1 MUTANTS RESTORES IEC MORPHOLOGY, REDUCES CELL SHEDDING, AND IMPROVES BARRIER FUNCTION. WE PROPOSE THAT LOSS OF EPIGENETIC REPRESSION AND TNF INDUCTION IN THE INTESTINAL EPITHELIUM CAN LEAD TO IBD ONSET. 2015 8 911 31 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 3795 33 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 10 4284 28 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 11 2380 29 EPIGENETIC REGULATION OF WNT SIGNALING IN CHRONIC LYMPHOCYTIC LEUKEMIA. CERTAIN WNT AND WNT NETWORK TARGET GENES ARE EXPRESSED AT HIGHER OR LOWER LEVELS IN CHRONIC LYMPHOCYTIC LEUKEMIA COMPARED WITH NORMAL B-CELLS. THIS INCLUDES UPREGULATION OF NUCLEAR COMPLEX GENES, AS WELL AS GENES FOR CYTOPLASMIC PROTEINS AND WNT LIGANDS AND THEIR COGNATE RECEPTORS. IN ADDITION, EPIGENETIC SILENCING OF SEVERAL NEGATIVE REGULATORS OF THE WNT PATHWAY HAVE BEEN IDENTIFIED. THE BALANCE BETWEEN EPIGENETIC DOWNREGULATION OF NEGATIVE EFFECTOR GENES AND INCREASED EXPRESSION OF POSITIVE EFFECTOR GENES DEMONSTRATE THAT THE EPIGENETIC DOWNREGULATION OF WNT ANTAGONISTS IS ONE MECHANISM, PERHAPS THE MAIN MECHANISM, THAT IS PERMISSIVE TO ACTIVE WNT SIGNALING IN CHRONIC LYMPHOCYTIC LEUKEMIA. MOREOVER, CONSTITUTIVE ACTIVATION OF THE WNT NETWORK AND TARGET GENES IS LIKELY TO IMPACT ON ADDITIONAL INTERACTING SIGNALING PATHWAYS. BASED ON PUBLISHED STUDIES, WE PROPOSE A MODEL OF WNT SIGNALING THAT INVOLVES MAINLY PERMISSIVE EXPRESSION, AND SOMETIMES OVEREXPRESSION, OF POSITIVE EFFECTORS AND DOWNREGULATION OF NEGATIVE REGULATORS IN THE NETWORK. IN THIS MODEL, DNA METHYLATION, HISTONE MODIFICATIONS AND ALTERED EXPRESSION OF MICRORNA MOLECULES INTERACT TO ALLOW CONTINUOUS WNT SIGNALING. 2010 12 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 13 141 38 ABERRANT DNA METHYLATION OF MTOR PATHWAY GENES PROMOTES INFLAMMATORY ACTIVATION OF IMMUNE CELLS IN DIABETIC KIDNEY DISEASE. DNA METHYLATION HAS BEEN IMPLICATED IN THE PATHOGENESIS OF DIABETIC KIDNEY DISEASE (DKD), BUT THE UNDERLYING MECHANISMS REMAIN UNCLEAR. IN THIS STUDY, WE TESTED THE HYPOTHESIS THAT ABERRANT DNA METHYLATION IN PERIPHERAL IMMUNE CELLS CONTRIBUTES TO DKD PROGRESSION. WE SHOWED THAT LEVELS OF DNA METHYLTRANSFERASE 1 (DNMT1), A KEY ENZYME FOR DNA METHYLATION, WERE INCREASED ALONG WITH INFLAMMATORY ACTIVITY OF PERIPHERAL BLOOD MONONUCLEAR CELLS IN DKD PATIENTS. INHIBITION OF DNMT1 WITH 5-AZA-2'-DEOXYCYTIDINE (5-AZA) MARKEDLY INCREASED THE PROPORTION OF CD4(+)CD25(+) REGULATORY T CELLS IN PERIPHERAL BLOOD MONONUCLEAR CELLS IN CULTURE AND IN DIABETIC ANIMALS. ADOPTIVE TRANSFER OF IMMUNE CELLS FROM 5-AZA-TREATED ANIMALS SHOWED BENEFICIAL EFFECTS ON THE HOST IMMUNE SYSTEM, RESULTING IN A SIGNIFICANT IMPROVEMENT OF DKD. USING GENOME-WIDE DNA METHYLATION ASSAYS, WE IDENTIFIED THE DIFFERENTIALLY METHYLATED CYTOSINES IN THE PROMOTER REGIONS OF MAMMALIAN TARGET OF RAPAMYCIN (MTOR) REGULATORS IN PERIPHERAL BLOOD MONONUCLEAR CELLS OF DIABETIC PATIENTS. FURTHER, MRNA ARRAYS CONFIRMED THE CONSISTENT INDUCTION OF GENES EXPRESSED IN THE MTOR PATHWAY. IMPORTANTLY, DOWN-REGULATION OF DNMT1 EXPRESSION VIA RNA INTERFERENCE RESULTED IN PROMINENT CYTOSINE DEMETHYLATION OF MTOR NEGATIVE REGULATORS AND SUBSEQUENT DECREASE OF MTOR ACTIVITY. LASTLY, MODULATION OF MTOR RESULTED IN CHANGES IN THE EFFECT OF 5-AZA ON DIABETIC IMMUNE CELLS. THUS, UP-REGULATION OF DNMT1 IN DIABETIC IMMUNE CELLS INDUCES ABERRANT CYTOSINE METHYLATION OF THE UPSTREAM REGULATORS OF MTOR, LEADING TO PATHOGENIC ACTIVATION OF THE MTOR PATHWAY AND CONSEQUENT INFLAMMATION IN DIABETIC KIDNEYS. HENCE, THIS STUDY HIGHLIGHTS THERAPEUTIC POTENTIAL OF TARGETING EPIGENETIC EVENTS IN IMMUNE SYSTEM FOR TREATING DKD. 2019 14 5795 36 STAT3 INDUCTION OF MIR-146B FORMS A FEEDBACK LOOP TO INHIBIT THE NF-KAPPAB TO IL-6 SIGNALING AXIS AND STAT3-DRIVEN CANCER PHENOTYPES. INTERLEUKIN-6 (IL-6)-MEDIATED ACTIVATION OF SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 (STAT3) IS A MECHANISM BY WHICH CHRONIC INFLAMMATION CAN CONTRIBUTE TO CANCER AND IS A COMMON ONCOGENIC EVENT. WE DISCOVERED A PATHWAY, THE LOSS OF WHICH IS ASSOCIATED WITH PERSISTENT STAT3 ACTIVATION IN HUMAN CANCER. WE FOUND THAT THE GENE ENCODING THE TUMOR SUPPRESSOR MICRORNA MIR-146B IS A DIRECT STAT3 TARGET GENE, AND ITS EXPRESSION WAS INCREASED IN NORMAL BREAST EPITHELIAL CELLS BUT DECREASED IN TUMOR CELLS. METHYLATION OF THE MIR-146B PROMOTER, WHICH INHIBITED STAT3-MEDIATED INDUCTION OF EXPRESSION, WAS INCREASED IN PRIMARY BREAST CANCERS. MOREOVER, WE FOUND THAT MIR-146B INHIBITED NUCLEAR FACTOR KAPPAB (NF-KAPPAB)-DEPENDENT PRODUCTION OF IL-6, SUBSEQUENT STAT3 ACTIVATION, AND IL-6/STAT3-DRIVEN MIGRATION AND INVASION IN BREAST CANCER CELLS, THEREBY ESTABLISHING A NEGATIVE FEEDBACK LOOP. IN ADDITION, HIGHER EXPRESSION OF MIR-146B WAS POSITIVELY CORRELATED WITH PATIENT SURVIVAL IN BREAST CANCER SUBTYPES WITH INCREASED IL6 EXPRESSION AND STAT3 PHOSPHORYLATION. OUR RESULTS IDENTIFY AN EPIGENETIC MECHANISM OF CROSSTALK BETWEEN STAT3 AND NF-KAPPAB RELEVANT TO CONSTITUTIVE STAT3 ACTIVATION IN MALIGNANCY AND THE ROLE OF INFLAMMATION IN ONCOGENESIS. 2014 15 5975 31 TET1 IS AN IMPORTANT TRANSCRIPTIONAL ACTIVATOR OF TNFALPHA EXPRESSION IN MACROPHAGES. ACTIVATION OF MACROPHAGES AND OVEREXPRESSION OF TNFALPHA IS ASSOCIATED WITH THE PATHOGENESIS OF CHRONIC INFLAMMATORY DISEASES. HOWEVER, THE MECHANISMS LEADING TO TNFALPHA OVEREXPRESSION ARE STILL UNKNOWN. 5-METHYLOCYTOSINE (5-MC) IS AN EPIGENETIC MODIFICATION THAT IS ASSOCIATED WITH SILENCED GENES. RECENT STUDIES SHOWED THAT IT IS CONVERTED TO 5-HYDROXYLMETHYLOCYTOSINE (5-HMC) AND REACTIVATES GENE EXPRESSION THROUGH THE ACTION OF THE FAMILY OF TEN-ELEVEN-TRANSLOCATION (TET1-3) ENZYMES. IN THIS STUDY, WE SHOW THAT 5-HMC LEVELS ARE INCREASED GLOBALLY AND SPECIFICALLY IN THE TNFALPHA PROMOTER DURING THE DIFFERENTIATION OF MONOCYTES TO MACROPHAGES. IN ADDITION, THE LEVELS OF 5-HMC ARE INCREASED UPON LPS STIMULATION OF MACROPHAGES. FURTHERMORE, CRIPSR STABLE KNOCKOUT OF TET1 DECREASES THE EXPRESSION OF TNFALPHA AND OTHER PRO-INFLAMMATORY CYTOKINES. IN CONCLUSION, WE SHOWED THAT TET1 CONTRIBUTES TO THE ACTIVATION OF MACROPHAGES POSSIBLY THROUGH REGULATION OF 5-HYDROXYMETHYLATION IN THE PROMOTER OF PRO-INFLAMMATORY CYTOKINE GENES. THE TET1 ENZYME COULD BE A PROMISING THERAPEUTIC TARGET TO INHIBIT THE PERSISTENT INFLAMMATION CAUSED BY MACROPHAGES IN CHRONIC INFLAMMATORY DISEASES. 2019 16 5972 29 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 17 2748 38 EXPRESSION AND FUNCTION OF EZH2 IN SYNOVIAL FIBROBLASTS: EPIGENETIC REPRESSION OF THE WNT INHIBITOR SFRP1 IN RHEUMATOID ARTHRITIS. OBJECTIVES: TO STUDY THE EXPRESSION, REGULATION AND FUNCTION OF THE HISTONE METHYLTRANSFERASE ENHANCER OF ZESTE HOMOLOGUE 2 (EZH2) IN SYNOVIAL FIBROBLASTS (SF) FROM PATIENTS WITH RHEUMATOID ARTHRITIS (RA) AND OSTEOARTHRITIS (OA). METHODS: SF WERE OBTAINED FROM RA AND OA PATIENTS UNDERGOING JOINT SURGERY. EXPRESSION LEVELS WERE ASSESSED BY QUANTITATIVE REAL-TIME PCR AND WESTERN BLOT. KINASE INHIBITORS AND REPORTER GENE ASSAYS WERE EMPLOYED TO STUDY SIGNALLING PATHWAYS. FUNCTIONAL ANALYSES INCLUDED EZH2 OVEREXPRESSION BY PLASMID TRANSFECTION AND GENE SILENCING BY SMALL INTERFERING RNA. CHROMATIN IMMUNOPRECIPITATION ASSAY WAS USED TO ANALYSE HISTONE METHYLATION WITHIN DISTINCT PROMOTER REGIONS. RESULTS: BY STUDYING THE EXPRESSION AND FUNCTION OF EZH2 IN SF THE AUTHORS FOUND THAT EZH2 IS OVEREXPRESSED IN RHEUMATOID ARTHRITIS SYNOVIAL FIBROBLASTS (RASF) AND FURTHER INDUCED BY TUMOUR NECROSIS FACTOR ALPHA THROUGH THE NUCLEAR FACTOR KAPPA B AND JUN KINASE PATHWAYS. AS A TARGET GENE OF EZH2 THE AUTHORS IDENTIFIED SECRETED FRIZZLED-RELATED PROTEIN 1 (SFRP1), AN INHIBITOR OF WNT SIGNALLING, WHICH IS ASSOCIATED WITH THE ACTIVATION OF RASF, AND SHOW THAT SFRP1 EXPRESSION CORRELATES WITH THE OCCUPATION OF ITS PROMOTER WITH ACTIVATING AND SILENCING HISTONE MARKS. CONCLUSIONS: THESE DATA STRONGLY SUGGEST THAT THE CHRONIC INFLAMMATORY ENVIRONMENT OF THE RA JOINT INDUCES EZH2 AND THUS MIGHT CAUSE CHANGES IN THE EPIGENETIC PROGRAMMES OF SF. 2011 18 3791 37 INTERLEUKIN 6 SUPPORTS THE MAINTENANCE OF P53 TUMOR SUPPRESSOR GENE PROMOTER METHYLATION. A STRONG ASSOCIATION EXISTS BETWEEN STATES OF CHRONIC INFLAMMATION AND CANCER, AND IT IS BELIEVED THAT MEDIATORS OF INFLAMMATION MAY BE RESPONSIBLE FOR THIS PHENOMENON. INTERLEUKIN 6 (IL-6) IS AN INFLAMMATORY CYTOKINE KNOWN TO PLAY A ROLE IN THE GROWTH AND SURVIVAL OF MANY TYPES OF TUMORS, YET THE MECHANISMS EMPLOYED BY THIS PLEOMORPHIC CYTOKINE TO ACCOMPLISH THIS FEAT ARE STILL POORLY UNDERSTOOD. ANOTHER IMPORTANT FACTOR IN TUMOR DEVELOPMENT SEEMS TO BE THE HYPERMETHYLATION OF CPG ISLANDS LOCATED WITHIN THE PROMOTER REGIONS OF TUMOR SUPPRESSOR GENES. THIS COMMON EPIGENETIC ALTERATION ENABLES TUMOR CELLS TO REDUCE OR INACTIVATE THE EXPRESSION OF IMPORTANT TUMOR SUPPRESSOR AND CELL CYCLE REGULATORY GENES. HERE WE SHOW THAT IN THE IL-6-RESPONSIVE HUMAN MULTIPLE MYELOMA CELL LINE KAS 6/1, THE PROMOTER REGION OF P53 IS EPIGENETICALLY MODIFIED BY METHYLTRANSFERASES, RESULTING IN DECREASED LEVELS OF EXPRESSION. FURTHERMORE, CELLS TREATED WITH IL-6 EXHIBIT AN INCREASE IN THE EXPRESSION OF THE DNA MAINTENANCE METHYLATION ENZYME, DNMT-1. THE DNA METHYLTRANSFERASE INHIBITOR ZEBULARINE REVERSES THE METHYLATION OF THE P53 PROMOTER, ALLOWING THE RESUMPTION OF ITS EXPRESSION. HOWEVER, WHEN ZEBULARINE IS WITHDRAWN FROM THE CELLS, THE REESTABLISHMENT OF THE ORIGINAL CPG ISLAND METHYLATION WITHIN THE P53 PROMOTER DOES NOT OCCUR IN THE ABSENCE OF IL-6, AND CELLS WHICH DO NOT RECEIVE IL-6 EVENTUALLY DIE, AS P53 EXPRESSION CONTINUES UNCHECKED BY REMETHYLATION. INTERESTINGLY, THIS LOSS OF VIABILITY SEEMS TO INVOLVE NOT THE WITHDRAWAL OF CYTOKINE, BUT THE INABILITY OF THE CELL TO RESILENCE THE PROMOTER. CONSISTENT WITH THIS MODEL, WHEN CELLS THAT EXPRESS IL-6 IN AN AUTOCRINE FASHION ARE SUBJECTED TO IDENTICAL TREATMENT, P53 EXPRESSION IS REDUCED SHORTLY AFTER WITHDRAWAL OF ZEBULARINE. THEREFORE, IT SEEMS IL-6 IS CAPABLE OF MAINTAINING PROMOTER METHYLATION THUS REPRESENTING ONE OF THE POSSIBLE MECHANISMS USED BY INFLAMMATORY MEDIATORS IN THE GROWTH AND SURVIVAL OF TUMORS. 2005 19 926 32 CHRONIC INFLAMMATION PATHWAY NF-KAPPAB COOPERATES WITH EPIGENETIC REPROGRAMMING TO DRIVE THE MALIGNANT PROGRESSION OF GLIOBLASTOMA. WITHOUT AN EFFECTIVE STRATEGY FOR TARGETED THERAPY, GLIOBLASTOMA IS STILL INCURABLE WITH A MEDIAN SURVIVAL OF ONLY 15 MONTHS. BOTH CHRONIC INFLAMMATION AND EPIGENETIC REPROGRAMMING ARE HALLMARKS OF CANCER. HOWEVER, THE MECHANISMS AND CONSEQUENCES OF THEIR COOPERATION IN GLIOBLASTOMA REMAIN UNKNOWN. HERE, WE DISCOVER THAT CHRONIC INFLAMMATION GOVERNS H3K27ME3 REPROGRAMMING IN GLIOBLASTOMA THROUGH THE CANONICAL NF-KAPPAB PATHWAY TO TARGET EZH2. BEING A CRUCIAL MEDIATOR OF CHRONIC INFLAMMATION, THE CANONICAL NF-KAPPAB SIGNALLING SPECIFICALLY DIRECTS THE EXPRESSION AND REDISTRIBUTION OF H3K27ME3 BUT NOT H3K4ME3, H3K9ME3 AND H3K36ME3. USING RNA-SEQ SCREENING TO FOCUS ON GENES ENCODING METHYLTRANSFERASES AND DEMETHYLASES OF HISTONE, WE IDENTIFY EZH2 AS A KEY METHYLTRANSFERASE TO CONTROL INFLAMMATION-TRIGGERED EPIGENETIC REPROGRAMMING IN GLIOMAGENESIS. MECHANISTICALLY, NF-KAPPAB SELECTIVELY DRIVES THE EXPRESSION OF EZH2 BY ACTIVATING ITS TRANSCRIPTION, CONSEQUENTLY RESULTING IN A GLOBAL CHANGE IN H3K27ME3 EXPRESSION AND DISTRIBUTION. FURTHERMORE, WE FIND THAT CO-ACTIVATION OF NF-KAPPAB AND EZH2 CONFERS THE POOREST CLINICAL OUTCOME, AND THAT THE RISK FOR GLIOBLASTOMA CAN BE ACCURATELY MOLECULARLY STRATIFIED BY NF-KAPPAB AND EZH2. IT IS NOTABLE THAT NF-KAPPAB CAN POTENTIALLY COOPERATE WITH EZH2 IN MORE THAN ONE WAY, AND MOST IMPORTANTLY, WE DEMONSTRATE A SYNERGISTIC EFFECT OF CANCER CELLS INDUCED BY COMBINATORY INHIBITION OF NF-KAPPAB AND EZH2, WHICH BOTH ARE FREQUENTLY OVER-ACTIVATED IN GLIOBLASTOMA. IN SUMMARY, WE UNCOVER A FUNCTIONAL COOPERATION BETWEEN CHRONIC INFLAMMATION AND EPIGENETIC REPROGRAMMING IN GLIOBLASTOMA, COMBINED TARGETING OF WHICH BY INHIBITORS GUARANTEED IN SAFETY AND AVAILABILITY FURNISHES A POTENT STRATEGY FOR EFFECTIVE TREATMENT OF THIS FATAL DISEASE. 2022 20 4772 32 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