1 1158 155 CONTEXT-DEPENDENT EPIGENETIC REGULATION OF NUCLEAR FACTOR OF ACTIVATED T CELLS 1 IN PANCREATIC PLASTICITY. BACKGROUND & AIMS: THE ABILITY OF EXOCRINE PANCREATIC CELLS TO CHANGE THE CELLULAR PHENOTYPE IS REQUIRED FOR TISSUE REGENERATION UPON INJURY, BUT ALSO CONTRIBUTES TO THEIR MALIGNANT TRANSFORMATION AND TUMOR PROGRESSION. WE INVESTIGATED CONTEXT-DEPENDENT SIGNALING AND TRANSCRIPTION MECHANISMS THAT DETERMINE PANCREATIC CELL FATE DECISIONS TOWARD REGENERATION AND MALIGNANCY. IN PARTICULAR, WE STUDIED THE FUNCTION AND REGULATION OF THE INFLAMMATORY TRANSCRIPTION FACTOR NUCLEAR FACTOR OF ACTIVATED T CELLS 1 (NFATC1) IN PANCREATIC CELL PLASTICITY AND TISSUE ADAPTATION. METHODS: WE ANALYZED CELL PLASTICITY DURING PANCREATIC REGENERATION AND TRANSFORMATION IN MICE WITH PANCREAS-SPECIFIC EXPRESSION OF A CONSTITUTIVELY ACTIVE FORM OF NFATC1, OR DEPLETION OF ENHANCER OF ZESTE 2 HOMOLOGUE 2 (EZH2), IN THE CONTEXT OF WILD-TYPE OR CONSTITUTIVELY ACTIVATE KRAS, RESPECTIVELY. ACUTE AND CHRONIC PANCREATITIS WERE INDUCED BY INTRAPERITONEAL INJECTION OF CAERULEIN. EZH2-DEPENDENT REGULATION OF NFATC1 EXPRESSION WAS STUDIED IN MOUSE IN HUMAN PANCREATIC TISSUE AND CELLS BY IMMUNOHISTOCHEMISTRY, IMMUNOBLOTTING, AND QUANTITATIVE REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION. WE USED GENETIC AND PHARMACOLOGIC APPROACHES OF EZH2 AND NFATC1 INHIBITION TO STUDY THE CONSEQUENCES OF PATHWAY DISRUPTION ON PANCREATIC MORPHOLOGY AND FUNCTION. EPIGENETIC MODIFICATIONS ON THE NFATC1 GENE WERE INVESTIGATED BY CHROMATIN IMMUNOPRECIPITATION ASSAYS. RESULTS: NFATC1 WAS RAPIDLY AND TRANSIENTLY INDUCED IN EARLY ADAPTATION TO ACINAR CELL INJURY IN HUMAN SAMPLES AND IN MICE, WHERE IT PROMOTED ACINAR CELL TRANSDIFFERENTIATION AND BLOCKED PROLIFERATION OF METAPLASTIC PANCREATIC CELLS. HOWEVER, IN LATE STAGES OF REGENERATION, NFATC1 WAS EPIGENETICALLY SILENCED BY EZH2-DEPENDENT HISTONE METHYLATION, TO ENABLE ACINAR CELL REDIFFERENTIATION AND PREVENT ORGAN ATROPHY AND EXOCRINE INSUFFICIENCY. IN CONTRAST, ONCOGENIC ACTIVATION OF KRAS SIGNALING IN PANCREATIC DUCTAL ADENOCARCINOMA CELLS REVERSED THE EZH2-DEPENDENT EFFECTS ON THE NFATC1 GENE AND WAS REQUIRED FOR EZH2-MEDIATED TRANSCRIPTIONAL ACTIVATION OF NFATC1. CONCLUSIONS: IN STUDIES OF HUMAN AND MOUSE PANCREATIC CELLS AND TISSUE, WE IDENTIFIED CONTEXT-SPECIFIC EPIGENETIC REGULATION OF NFATC1 ACTIVITY AS AN IMPORTANT MECHANISM OF PANCREATIC CELL PLASTICITY. INHIBITORS OF EZH2 MIGHT THEREFORE INTERFERE WITH ONCOGENIC ACTIVITY OF NFATC1 AND BE USED IN TREATMENT OF PANCREATIC DUCTAL ADENOCARCINOMA. 2017 2 1035 47 CLASS I HISTONE DEACETYLASE INHIBITION IMPROVES PANCREATITIS OUTCOME BY LIMITING LEUKOCYTE RECRUITMENT AND ACINAR-TO-DUCTAL METAPLASIA. BACKGROUND AND PURPOSE: PANCREATITIS IS A COMMON INFLAMMATION OF THE PANCREAS WITH RISING INCIDENCE IN MANY COUNTRIES. DESPITE IMPROVEMENTS IN DIAGNOSTIC TECHNIQUES, THE DISEASE IS ASSOCIATED WITH HIGH RISK OF SEVERE MORBIDITY AND MORTALITY AND THERE IS AN URGENT NEED FOR NEW THERAPEUTIC INTERVENTIONS. IN THIS STUDY, WE EVALUATED WHETHER HISTONE DEACETYLASES (HDACS), KEY EPIGENETIC REGULATORS OF GENE TRANSCRIPTION, ARE INVOLVED IN THE DEVELOPMENT OF THE DISEASE. EXPERIMENTAL APPROACH: WE ANALYSED HDAC REGULATION DURING CERULEIN-INDUCED ACUTE, CHRONIC AND AUTOIMMUNE PANCREATITIS USING DIFFERENT TRANSGENIC MOUSE MODELS. THE FUNCTIONAL RELEVANCE OF CLASS I HDACS WAS TESTED WITH THE SELECTIVE INHIBITOR MS-275 IN VIVO UPON PANCREATITIS INDUCTION AND IN VITRO IN ACTIVATED MACROPHAGES AND PRIMARY ACINAR CELL EXPLANTS. KEY RESULTS: HDAC EXPRESSION AND ACTIVITY WERE UP-REGULATED IN A TIME-DEPENDENT MANNER FOLLOWING INDUCTION OF PANCREATITIS, WITH THE HIGHEST ABUNDANCE OBSERVED FOR CLASS I HDACS. CLASS I HDAC INHIBITION DID NOT PREVENT THE INITIAL ACINAR CELL DAMAGE. HOWEVER, IT EFFECTIVELY REDUCED THE INFILTRATION OF INFLAMMATORY CELLS, INCLUDING MACROPHAGES AND T CELLS, IN BOTH ACUTE AND CHRONIC PHASES OF THE DISEASE, AND DIRECTLY DISRUPTED MACROPHAGE ACTIVATION. IN ADDITION, MS-275 TREATMENT REDUCED DNA DAMAGE IN ACINAR CELLS AND LIMITED ACINAR DE-DIFFERENTIATION INTO ACINAR-TO-DUCTAL METAPLASIA IN A CELL-AUTONOMOUS MANNER BY IMPEDING THE EGF RECEPTOR SIGNALLING AXIS. CONCLUSIONS AND IMPLICATIONS: THESE RESULTS DEMONSTRATE THAT CLASS I HDACS ARE CRITICALLY INVOLVED IN THE DEVELOPMENT OF ACUTE AND CHRONIC FORMS OF PANCREATITIS AND SUGGEST THAT BLOCKADE OF CLASS I HDAC ISOFORMS IS A PROMISING TARGET TO IMPROVE THE OUTCOME OF THE DISEASE. 2017 3 3795 42 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 4 2380 32 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 5 141 36 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 6 4284 35 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 7 4004 36 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 8 925 41 CHRONIC INFLAMMATION INDUCES A NOVEL EPIGENETIC PROGRAM THAT IS CONSERVED IN INTESTINAL ADENOMAS AND IN COLORECTAL CANCER. CHRONIC INFLAMMATION REPRESENTS A MAJOR RISK FACTOR FOR TUMOR FORMATION, BUT THE UNDERLYING MECHANISMS HAVE REMAINED LARGELY UNKNOWN. EPIGENETIC MECHANISMS CAN RECORD THE EFFECTS OF ENVIRONMENTAL CHALLENGES ON THE GENOME LEVEL AND COULD THEREFORE PLAY AN IMPORTANT ROLE IN THE PATHOGENESIS OF INFLAMMATION-ASSOCIATED TUMORS. USING SINGLE-BASE METHYLATION MAPS AND TRANSCRIPTOME ANALYSES OF A COLITIS-INDUCED MOUSE COLON CANCER MODEL, WE IDENTIFIED A NOVEL EPIGENETIC PROGRAM THAT IS CHARACTERIZED BY HYPERMETHYLATION OF DNA METHYLATION VALLEYS THAT ARE CHARACTERIZED BY LOW CPG DENSITY AND ACTIVE CHROMATIN MARKS. THIS PROGRAM IS CONSERVED AND FUNCTIONAL IN MOUSE INTESTINAL ADENOMAS AND RESULTS IN SILENCING OF ACTIVE INTESTINAL GENES THAT ARE INVOLVED IN GASTROINTESTINAL HOMEOSTASIS AND INJURY RESPONSE. FURTHER ANALYSES REVEAL THAT THE PROGRAM REPRESENTS A PROMINENT FEATURE OF HUMAN COLORECTAL CANCER AND CAN BE USED TO CORRECTLY CLASSIFY COLORECTAL CANCER SAMPLES WITH HIGH ACCURACY. TOGETHER, OUR RESULTS SHOW THAT INFLAMMATORY SIGNALS ESTABLISH A NOVEL EPIGENETIC PROGRAM THAT SILENCES A SPECIFIC SET OF GENES THAT CONTRIBUTE TO INFLAMMATION-INDUCED CELLULAR TRANSFORMATION. 2015 9 1336 26 DESCRIBING A TRANSCRIPTION FACTOR DEPENDENT REGULATION OF THE MICRORNA TRANSCRIPTOME. WHILE THE TRANSCRIPTION REGULATION OF PROTEIN CODING GENES WAS EXTENSIVELY STUDIED, LITTLE IS KNOWN ON HOW TRANSCRIPTION FACTORS ARE INVOLVED IN TRANSCRIPTION OF NON-CODING RNAS, SPECIFICALLY OF MICRORNAS. HERE, WE PROPOSE A STRATEGY TO STUDY THE POTENTIAL ROLE OF TRANSCRIPTION FACTOR IN REGULATING TRANSCRIPTION OF MICRORNAS USING PUBLICALLY AVAILABLE DATA, COMPUTATIONAL RESOURCES AND HIGH THROUGHPUT DATA. WE USE THE H3K4ME3 EPIGENETIC SIGNATURE TO IDENTIFY MICRORNA PROMOTERS AND CHROMATIN IMMUNOPRECIPITATION (CHIP)-SEQUENCING DATA FROM THE ENCODE PROJECT TO IDENTIFY MICRORNA PROMOTERS THAT ARE ENRICHED WITH TRANSCRIPTION FACTOR BINDING SITES. BY TRANSFECTING CELLS OF INTEREST WITH SHRNA TARGETING A TRANSCRIPTION FACTOR OF INTEREST AND SUBJECTING THE CELLS TO MICRORNA ARRAY, WE STUDY THE EFFECT OF THIS TRANSCRIPTION FACTOR ON THE MICRORNA TRANSCRIPTOME. AS AN ILLUSTRATIVE EXAMPLE WE USE OUR STUDY ON THE EFFECT OF STAT3 ON THE MICRORNA TRANSCRIPTOME OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) CELLS. 2016 10 3791 40 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 11 3720 42 INHIBITION OF CLASS I HISTONE DEACETYLASES ABROGATES TUMOR GROWTH FACTOR BETA EXPRESSION AND DEVELOPMENT OF FIBROSIS DURING CHRONIC PANCREATITIS. PANCREATIC FIBROSIS IS THE HALLMARK OF CHRONIC PANCREATITIS, A HIGHLY DEBILITATING DISEASE FOR WHICH THERE IS CURRENTLY NO CURE. THE KEY EVENT AT THE BASIS OF PANCREATIC FIBROSIS IS THE DEPOSITION OF EXTRACELLULAR MATRIX PROTEINS BY ACTIVATED PANCREATIC STELLATE CELLS (PSCS). TRANSFORMING GROWTH FACTOR BETA (TGFBETA) IS A POTENT PROFIBROTIC FACTOR IN THE PANCREAS AS IT PROMOTES THE ACTIVATION OF PSC; THUS, PHARMACOLOGIC INTERVENTIONS THAT EFFECTIVELY REDUCE TGFBETA EXPRESSION HARBOR CONSIDERABLE THERAPEUTIC POTENTIAL IN THE TREATMENT OF CHRONIC PANCREATITIS. IN THIS STUDY, WE INVESTIGATED WHETHER TGFBETA EXPRESSION IS REDUCED BY PHARMACOLOGIC INHIBITION OF THE EPIGENETIC MODIFIERS HISTONE DEACETYLASES (HDACS). TO ADDRESS THIS AIM, CHRONIC PANCREATITIS WAS INDUCED IN C57BL/6 MICE WITH SERIAL INJECTIONS OF CERULEIN, AND THE SELECTIVE CLASS 1 HDAC INHIBITOR MS-275 WAS ADMINISTERED IN VIVO IN A PREVENTIVE AND THERAPEUTIC MANNER. BOTH MS-275 REGIMENS POTENTLY REDUCED DEPOSITION OF EXTRACELLULAR MATRIX AND DEVELOPMENT OF FIBROSIS IN THE PANCREAS AFTER 4 WEEKS OF CHRONIC PANCREATITIS. REDUCED PANCREATIC FIBROSIS WAS CONCOMITANT WITH LOWER EXPRESSION OF PANCREATIC TGFBETA AND CONSEQUENT REDUCED PSC ACTIVATION. IN SEARCH OF THE CELL TYPES TARGETED BY THE INHIBITOR, WE FOUND THAT MS-275 TREATMENT ABROGATED THE EXPRESSION OF TGFBETA IN ACINAR CELLS STIMULATED BY CERULEIN TREATMENT. OUR STUDY DEMONSTRATES THAT MS-275 IS AN EFFECTIVE ANTIFIBROTIC AGENT IN THE CONTEXT OF EXPERIMENTAL CHRONIC PANCREATITIS AND THUS MAY CONSTITUTE A VALID THERAPEUTIC INTERVENTION FOR THIS SEVERE DISEASE. 2018 12 2493 39 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 13 5795 40 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 14 926 41 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 15 1479 33 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 2114 41 EPIGENETIC HETEROCHROMATIN MARKERS DISTINGUISH TERMINALLY DIFFERENTIATED LEUKOCYTES FROM INCOMPLETELY DIFFERENTIATED LEUKEMIA CELLS IN HUMAN BLOOD. OBJECTIVE: DURING TERMINAL CELL DIFFERENTIATION, NUCLEAR CHROMATIN BECOMES CONDENSED AND THE REPERTOIRE OF EPIGENTIC HETEROCHROMATIN PROTEINS RESPONSIBLE FOR CHROMATIN CONDENSATION IS DRAMATICALLY CHANGED. IN ORDER TO IDENTIFY THE CHROMATIN REGULATORY FACTORS ASSOCIATED WITH INCOMPLETE CELL DIFFERENTIATION AND IMPAIRED CHROMATIN CONDENSATION IN HEMATOLOGICAL MALIGNANCIES, WE EXAMINED EXPRESSION LEVELS OF MAJOR HETEROCHROMATIN PROTEINS IN NORMAL BLOOD CELLS AND CELLS DERIVED FROM A NUMBER OF CHRONIC AND ACUTE MYELOID LEUKEMIA PATIENTS EXHIBITING DIFFERENT DEGREES OF DIFFERENTIATION. METHODS: WE USED IMMUNOBLOTTING AND IMMUNOFLUORESCENCE TO EXAMINE THE LEVELS AND LOCALIZATION OF EPIGENETIC HETEROCHROMATIN FACTORS IN ISOLATED CELL NUCLEI AND FRACTIONATED PERIPHERAL BLOOD CELLS. RESULTS: WHILE THE MAJOR EPIGENETIC HETEROCHROMATIN FACTOR, HISTONE H3 METHYLATED AT LYSINE 9, IS PRESENT IN ALL CELL TYPES, ITS MAIN COUNTERPARTS, NONHISTONE PROTEINS, HETEROCHROMATIN PROTEINS 1 (HP1) ALPHA, BETA, AND GAMMA, ARE DRAMATICALLY REDUCED IN PERIPHERAL BLOOD LEUKOCYTES OF NORMAL DONORS AND CHRONIC MYELOID LEUKEMIA PATIENTS, BUT ARE SUBSTANTIALLY INCREASED IN THE BLOOD OF ACCELERATED PHASE AND BLAST CRISIS PATIENTS. IN THE TERMINALLY DIFFERENTIATED CELLS, NUCLEAR CHROMATIN ACCUMULATES A NUCLEOCYTOPLASMIC SERPIN, MONOCYTE AND NEUTROPHIL ELASTASE INHIBITOR (MNEI). HP1 AND MNEI LEVELS INVERSELY CORRELATE IN A NUMBER OF NORMAL AND LEUKEMIA MYELOID CELLS AND SHOW STRIKINGLY OPPOSITE COORDINATED CHANGES DURING DIFFERENTIATION OF U937 CELL LINE INDUCED BY RETINOIC ACID. CONCLUSIONS: OUR RESULTS SUGGEST THAT REPRESSION OF HP1 AND ACCUMULATION OF MNEI ARE LINKED TO TERMINAL CELL DIFFERENTIATION AND THAT THEIR LEVELS MAY BE MONITORED IN BLOOD CELL POPULATIONS TO DETECT TRANSITIONS IN CELL DIFFERENTIATION ASSOCIATED WITH LEUKEMIA PROGRESSION AND TREATMENT. 2006 17 1656 33 DOUBLE STRAND BREAKS CAN INITIATE GENE SILENCING AND SIRT1-DEPENDENT ONSET OF DNA METHYLATION IN AN EXOGENOUS PROMOTER CPG ISLAND. CHRONIC EXPOSURE TO INDUCERS OF DNA BASE OXIDATION AND SINGLE AND DOUBLE STRAND BREAKS CONTRIBUTE TO TUMORIGENESIS. IN ADDITION TO THE GENETIC CHANGES CAUSED BY THIS DNA DAMAGE, SUCH TUMORS OFTEN CONTAIN EPIGENETICALLY SILENCED GENES WITH ABERRANT PROMOTER REGION CPG ISLAND DNA HYPERMETHYLATION. WE HEREIN EXPLORE THE RELATIONSHIPS BETWEEN SUCH DNA DAMAGE AND EPIGENETIC GENE SILENCING USING AN EXPERIMENTAL MODEL IN WHICH WE INDUCE A DEFINED DOUBLE STRAND BREAK IN AN EXOGENOUS PROMOTER CONSTRUCT OF THE E-CADHERIN CPG ISLAND, WHICH IS FREQUENTLY ABERRANTLY DNA HYPERMETHYLATED IN EPITHELIAL CANCERS. FOLLOWING THE ONSET OF REPAIR OF THE BREAK, WE OBSERVE RECRUITMENT TO THE SITE OF DAMAGE OF KEY PROTEINS INVOLVED IN ESTABLISHING AND MAINTAINING TRANSCRIPTIONAL REPRESSION, NAMELY SIRT1, EZH2, DNMT1, AND DNMT3B, AND THE APPEARANCE OF THE SILENCING HISTONE MODIFICATIONS, HYPOACETYL H4K16, H3K9ME2 AND ME3, AND H3K27ME3. ALTHOUGH IN MOST CELLS SELECTED AFTER THE BREAK, DNA REPAIR OCCURS FAITHFULLY WITH PRESERVATION OF ACTIVITY OF THE PROMOTER, A SMALL PERCENTAGE OF THE PLATED CELLS DEMONSTRATE INDUCTION OF HERITABLE SILENCING. THE CHROMATIN AROUND THE BREAK SITE IN SUCH A SILENT CLONE IS ENRICHED FOR MOST OF THE ABOVE SILENT CHROMATIN PROTEINS AND HISTONE MARKS, AND THE REGION HARBORS THE APPEARANCE OF INCREASING DNA METHYLATION IN THE CPG ISLAND OF THE PROMOTER. DURING THE ACUTE BREAK, SIRT1 APPEARS TO BE REQUIRED FOR THE TRANSIENT RECRUITMENT OF DNMT3B AND SUBSEQUENT METHYLATION OF THE PROMOTER IN THE SILENT CLONES. TAKEN TOGETHER, OUR DATA SUGGEST THAT NORMAL REPAIR OF A DNA BREAK CAN OCCASIONALLY CAUSE HERITABLE SILENCING OF A CPG ISLAND-CONTAINING PROMOTER BY RECRUITMENT OF PROTEINS INVOLVED IN SILENCING. FURTHERMORE, WITH CONTRIBUTION OF THE STRESS-RELATED PROTEIN SIRT1, THE BREAK CAN LEAD TO THE ONSET OF ABERRANT CPG ISLAND DNA METHYLATION, WHICH IS FREQUENTLY ASSOCIATED WITH TIGHT GENE SILENCING IN CANCER. 2008 18 6764 41 ZINC DEFICIENCY ENHANCED INFLAMMATORY RESPONSE BY INCREASING IMMUNE CELL ACTIVATION AND INDUCING IL6 PROMOTER DEMETHYLATION. SCOPE: ZINC DEFICIENCY RESULTS IN IMMUNE DYSFUNCTION AND PROMOTES SYSTEMIC INFLAMMATION. THE OBJECTIVE OF THIS STUDY WAS TO EXAMINE THE EFFECTS OF ZINC DEFICIENCY ON CELLULAR IMMUNE ACTIVATION AND EPIGENETIC MECHANISMS THAT PROMOTE INFLAMMATION. THIS WORK IS POTENTIALLY RELEVANT TO THE AGING POPULATION GIVEN THAT AGE-RELATED IMMUNE DEFECTS, INCLUDING CHRONIC INFLAMMATION, COINCIDE WITH DECLINING ZINC STATUS. METHODS AND RESULTS: AN IN VITRO CELL CULTURE SYSTEM AND THE AGED MOUSE MODEL WERE USED TO CHARACTERIZE IMMUNE ACTIVATION AND DNA METHYLATION PROFILES THAT MAY CONTRIBUTE TO THE ENHANCED PROINFLAMMATORY RESPONSE MEDIATED BY ZINC DEFICIENCY. ZINC DEFICIENCY UPREGULATED CELL ACTIVATION MARKERS ICAM1, MHC CLASS II, AND CD86 IN THP1 CELLS, WHICH COINCIDED WITH INCREASED IL1BETA AND IL6 RESPONSES FOLLOWING LPS STIMULATION. A DECREASED ZINC STATUS IN AGED MICE WAS SIMILARLY ASSOCIATED WITH INCREASED ICAM1 AND IL6 GENE EXPRESSION. REDUCED IL6 PROMOTER METHYLATION WAS OBSERVED IN ZINC-DEFICIENT THP1 CELLS, AS WELL AS IN AGED MICE AND HUMAN LYMPHOBLASTOID CELL LINES DERIVED FROM AGED INDIVIDUALS. CONCLUSION: ZINC DEFICIENCY INDUCED INFLAMMATORY RESPONSE IN PART BY ELICITING ABERRANT IMMUNE CELL ACTIVATION AND ALTERED PROMOTER METHYLATION. OUR RESULTS SUGGESTED POTENTIAL INTERACTIONS BETWEEN ZINC STATUS, EPIGENETICS, AND IMMUNE FUNCTION, AND HOW THEIR DYSREGULATION COULD CONTRIBUTE TO CHRONIC INFLAMMATION. 2015 19 4900 34 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 20 2228 31 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