1 3725 107 INHIBITION OF GLYCOGEN SYNTHASE KINASE-3 ACTIVITY LEADS TO EPIGENETIC SILENCING OF NUCLEAR FACTOR KAPPAB TARGET GENES AND INDUCTION OF APOPTOSIS IN CHRONIC LYMPHOCYTIC LEUKEMIA B CELLS. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS COMMONLY DEFINED AS A DISEASE OF FAILED APOPTOSIS OF B CELLS AND REMAINS AN INCURABLE DISEASE. THE MECHANISM OF RESISTANCE TO APOPTOSIS IN CLL IS COMPLEX AND INFLUENCED BY NUMEROUS FACTORS, INCLUDING NUCLEAR FACTOR KAPPAB (NFKAPPAB)-MEDIATED EXPRESSION OF ANTIAPOPTOTIC MOLECULES. RECENT EVIDENCE INDICATES THAT GLYCOGEN SYNTHASE KINASE-3BETA (GSK-3BETA) POSITIVELY REGULATES NFKAPPAB-MEDIATED GENE TRANSCRIPTION AND CELL SURVIVAL. USING MALIGNANT B CELLS COLLECTED FROM PATIENTS WITH CLL, WE FIND THAT BOTH GSK-3BETA AND NFKAPPAB ACCUMULATE IN THE NUCLEUS OF CLL B CELLS, AND PHARMACOLOGIC INHIBITION OF GSK-3 RESULTS IN DECREASED EXPRESSION OF TWO NFKAPPAB TARGET GENES BCL-2 AND XIAP AND A SUBSEQUENT INCREASE IN CLL B-CELL APOPTOSIS EX VIVO. FURTHERMORE, WE OBSERVED THAT INHIBITION OF GSK-3 LEADS TO A DECREASE IN NFKAPPAB-MEDIATED GENE TRANSCRIPTION BUT DOES NOT AFFECT THE NUCLEAR ACCUMULATION OF NFKAPPAB IN CLL B CELLS. LAST, USING CHROMATIN IMMUNOPRECIPITATION, WE SHOW THAT GSK-3 INHIBITION ABROGATES NFKAPPAB BINDING TO ITS TARGET GENE PROMOTERS (XIAP, BCL-2), IN PART THROUGH EPIGENETIC MODIFICATION OF HISTONES. OUR RESULTS ESTABLISH THAT INHIBITION OF GSK-3 ABROGATES NFKAPPAB BINDING TO ITS TARGET GENE PROMOTERS THROUGH AN EPIGENETIC MECHANISM, ENHANCES APOPTOSIS IN CLL B CELLS EX VIVO AND IDENTIFIES GSK-3 AS A POTENTIAL THERAPEUTIC TARGET IN THE TREATMENT OF CLL. 2007 2 698 40 BROMODOMAIN CONTAINING PROTEIN 4 (BRD4) REGULATES EXPRESSION OF ITS INTERACTING COACTIVATORS IN THE INNATE RESPONSE TO RESPIRATORY SYNCYTIAL VIRUS. BROMODOMAIN-CONTAINING PROTEIN 4 PLAYS A CENTRAL ROLE IN COORDINATING THE COMPLEX EPIGENETIC COMPONENT OF THE INNATE IMMUNE RESPONSE. PREVIOUS STUDIES IMPLICATED BRD4 AS A COMPONENT OF A CHROMATIN-MODIFYING COMPLEX THAT IS DYNAMICALLY RECRUITED TO A NETWORK OF PROTECTIVE CYTOKINES BY BINDING ACTIVATED TRANSCRIPTION FACTORS, POLYMERASES, AND HISTONES TO TRIGGER THEIR RAPID EXPRESSION VIA TRANSCRIPTIONAL ELONGATION. OUR PREVIOUS STUDY EXTENDED OUR UNDERSTANDING OF THE AIRWAY EPITHELIAL BRD4 INTERACTOME BY IDENTIFYING OVER 100 FUNCTIONALLY IMPORTANT COACTIVATORS AND TRANSCRIPTION FACTORS, WHOSE ASSOCIATION IS INDUCED BY RESPIRATORY SYNCYTIAL VIRUS (RSV) INFECTION. RSV IS AN ETIOLOGICAL AGENT OF RECURRENT RESPIRATORY TRACT INFECTIONS ASSOCIATED WITH EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE. USING A HIGHLY SELECTIVE SMALL-MOLECULE BRD4 INHIBITOR (ZL0454) DEVELOPED BY US, WE EXTEND THESE FINDINGS TO IDENTIFY THE GENE REGULATORY NETWORK DEPENDENT ON BRD4 BROMODOMAIN (BD) INTERACTIONS. HUMAN SMALL AIRWAY EPITHELIAL CELLS WERE INFECTED IN THE ABSENCE OR PRESENCE OF ZL0454, AND GENE EXPRESSION PROFILING WAS PERFORMED. A HIGHLY REPRODUCIBLE DATASET WAS OBTAINED WHICH INDICATED THAT BRD4 MEDIATES BOTH ACTIVATION AND REPRESSION OF RSV-INDUCIBLE GENE REGULATORY NETWORKS CONTROLLING CYTOKINE EXPRESSION, INTERFERON (IFN) PRODUCTION, AND EXTRACELLULAR MATRIX REMODELING. INDEX GENES OF FUNCTIONALLY SIGNIFICANT CLUSTERS WERE VALIDATED INDEPENDENTLY. WE DISCOVER THAT BRD4 REGULATES THE EXPRESSION OF ITS OWN GENE DURING THE INNATE IMMUNE RESPONSE. INTERESTINGLY, BRD4 ACTIVATES THE EXPRESSION OF NFKAPPAB/RELA, A COACTIVATOR THAT BINDS TO BRD4 IN A BD-DEPENDENT MANNER. WE EXTEND THIS FINDING TO SHOW THAT BRD4 ALSO REGULATES OTHER COMPONENTS OF ITS FUNCTIONAL INTERACTOME, INCLUDING THE MEDIATOR (MED) COACTIVATOR COMPLEX AND THE SWI/SNF-RELATED, MATRIX-ASSOCIATED, ACTIN-DEPENDENT REGULATOR OF CHROMATIN (SMARC) SUBUNITS. TO PROVIDE FURTHER INSIGHT INTO MECHANISMS FOR BRD4 IN RSV EXPRESSION, WE MAPPED 7,845 RSV-INDUCIBLE TN5 TRANSPOSASE PEAKS ONTO THE BRD4-DEPENDENT GENE BODIES. THESE WERE LOCATED IN PROMOTERS AND INTRONS OF CYTOSTRUCTURAL AND EXTRACELLULAR MATRIX (ECM) FORMATION GENES. THESE DATA INDICATE THAT BRD4 MEDIATES THE DYNAMIC RESPONSE OF AIRWAY EPITHELIAL CELLS TO RNA INFECTION BY MODULATING THE EXPRESSION OF ITS COACTIVATORS, CONTROLLING THE EXPRESSION OF HOST DEFENSE MECHANISMS AND REMODELING GENES THROUGH CHANGES IN PROMOTER ACCESSIBILITY. 2021 3 2425 26 EPIGENETIC SILENCING OF IRF1 DYSREGULATES TYPE III INTERFERON RESPONSES TO RESPIRATORY VIRUS INFECTION IN EPITHELIAL TO MESENCHYMAL TRANSITION. CHRONIC OXIDATIVE INJURY PRODUCED BY AIRWAY DISEASE TRIGGERS A TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA)-MEDIATED EPIGENETIC REPROGRAMMING KNOWN AS THE EPITHELIAL-MESENCHYMAL TRANSITION (EMT). WE OBSERVE THAT EMT SILENCES PROTECTIVE MUCOSAL INTERFERON (IFN)-I AND III PRODUCTION ASSOCIATED WITH ENHANCED RHINOVIRUS (RV) AND RESPIRATORY SYNCYTIAL VIRUS (RSV) REPLICATION. MESENCHYMAL TRANSITIONED CELLS ARE DEFECTIVE IN INDUCIBLE INTERFERON REGULATORY FACTOR 1 (IRF1) EXPRESSION BY OCCLUDING RELA AND IRF3 ACCESS TO THE PROMOTER. IRF1 IS NECESSARY FOR THE EXPRESSION OF TYPE III IFNS (IFNLS 1 AND 2/3). INDUCED BY THE EMT, ZINC FINGER E-BOX BINDING HOMEOBOX 1 (ZEB1) BINDS AND SILENCES IRF1. ECTOPIC ZEB1 IS SUFFICIENT FOR IRF1 SILENCING, WHEREAS ZEB1 KNOCKDOWN PARTIALLY RESTORES IRF1-IFNL UPREGULATION. ZEB1 SILENCES IRF1 THROUGH THE CATALYTIC ACTIVITY OF THE ENHANCER OF ZESTE 2 POLYCOMB REPRESSIVE COMPLEX 2 SUBUNIT (EZH2), FORMING REPRESSIVE H3K27(ME3) MARKS. WE OBSERVE THAT IRF1 EXPRESSION IS MEDIATED BY ZEB1 DE-REPRESSION, AND OUR STUDY DEMONSTRATES HOW AIRWAY REMODELLING/FIBROSIS IS ASSOCIATED WITH A DEFECTIVE MUCOSAL ANTIVIRAL RESPONSE THROUGH ZEB1-INITIATED EPIGENETIC SILENCING. 2017 4 1730 22 DYSREGULATION OF STEM CELL SIGNALING NETWORK DUE TO GERMLINE MUTATION, SNP, HELICOBACTER PYLORI INFECTION, EPIGENETIC CHANGE AND GENETIC ALTERATION IN GASTRIC CANCER. GENETIC FACTORS, HELICOBACTER PYLORI INFECTION, SALT OVER-UPTAKE, DECREASED VEGETABLE/FRUIT CONSUMPTION, SMOKING, AND METABOLIC SYNDROME ARE RISK FACTORS OF HUMAN GASTRIC CANCER. GERMLINE MUTATIONS OF CDH1 GENE, AND SNPS OF PTPN11 (SHP2), TLR4, IL1B, TNFA, BMP6, GDF15 AND RUNX3 GENES ARE ASSOCIATED WITH GASTRIC CANCER. HELICOBACTER PYLORI ACTIVATES CAGA-SHP2-ERK AND PEPTIDOGLYCAN-NOD1-NFKAPPAB SIGNALING CASCADES IN GASTRIC EPITHELIAL CELLS USING TYPE IV SECRETION SYSTEM, AND ALSO TRAF6-MAP3K7-NFKAPPAB AND TRAF6-MAP3K7-AP-1 SIGNALING CASCADES IN EPITHELIAL AND IMMUNE CELLS THROUGH LIPOPOLYSACCHARIDE RECOGNITION BY TLR2 OR TLR4. IL-1BETA, IL-6, IL-8, TNFALPHA AND IFNGAMMA ARE ELEVATED IN GASTRIC MUCOSA WITH HELICOBACTER PYLORI INFECTION. IL-6 AND TNFALPHA INDUCE UPREGULATION OF WNT5A AND WNT10B, RESPECTIVELY. WNT SIGNALS ARE TRANSDUCED TO BETA-CATENIN-TCF/LEF, RHOA, JNK, PKC, NFAT, AND NLK SIGNALING CASCADES. WNT-BETA-CATENIN-TCF/LEF SIGNALING INDUCES UPREGULATION OF MYC, CCND1, WISP1, FGF20, JAG1 AND DKK1 GENES. NOTCH SIGNALS ARE TRANSDUCED TO CSL-NICD-MAML AND NFKAPPAB SIGNALING CASCADES. FGF SIGNALS ARE TRANSDUCED TO ERK, PI3K-AKT, PKC, AND NFAT SIGNALING CASCADES. HELICOBACTER PYLORI INFECTION INDUCES SHH UPREGULATION IN PARIETAL CELL LINEAGE, WHILE BMP SIGNALS INDUCE IHH UPREGULATION IN PIT CELL LINEAGE. HEDGEHOG SIGNALS INDUCE UPREGULATION OF GLI1, PTCH1, CCND2, FOXL1, JAG2 AND SFRP1 GENES. JAG1 AND JAG2 ACTIVATE NOTCH SIGNALING, WHILE DKK1 AND SFRP1 INHIBIT WNT SIGNALING. STEM CELL SIGNALING NETWORK, CONSISTING OF WNT, NOTCH, FGF, HEDGEHOG AND BMP SIGNALING PATHWAYS, IS ACTIVATED DURING CHRONIC HELICOBACTER PYLORI INFECTION. EPIGENETIC SILENCING OF SFRP1 GENE OCCURS IN THE EARLIER STAGE OF CARCINOGENESIS IN THE STOMACH, WHILE AMPLIFICATION AND OVEREXPRESSION OF FGFR2 GENE IN THE LATER STAGE. DYSREGULATION OF THE STEM CELL SIGNALING NETWORK DUE TO THE ACCUMULATION OF GERMLINE MUTATION, SNP, HELICOBACTER PYLORI INFECTION, EPIGENETIC CHANGE AND GENETIC ALTERATION GIVES RISE TO GASTRIC CANCER. SNP TYPING AND CUSTOM-MADE MICROARRAY ANALYSES ON GENES ENCODING STEM CELL SIGNALING MOLECULES COULD BE UTILIZED FOR THE PERSONALIZED MEDICINE. 2007 5 699 22 BROMODOMAIN PROTEIN 4 IS A KEY MOLECULAR DRIVER OF TGFBETA1-INDUCED HEPATIC STELLATE CELL ACTIVATION. LIVER FIBROSIS IS CHARACTERIZED BY THE EXCESSIVE DEPOSITION OF EXTRACELLULAR MATRIX IN LIVER. CHRONIC LIVER INJURY INDUCES THE ACTIVATION OF HEPATIC STELLATE CELL (HSCS), A KEY STEP IN LIVER FIBROGENESIS. THE ACTIVATED HSC IS THE PRIMARY SOURCE OF ECM AND CONTRIBUTES SIGNIFICANTLY TO LIVER FIBROSIS. TGFBETA1 IS THE MOST POTENT PRO-FIBROTIC CYTOKINE. BROMODOMAIN PROTEIN 4 (BRD4), AN EPIGENETIC READER OF HISTONE ACETYLATION MARKS, WAS CRUCIAL FOR PROFIBROTIC GENE EXPRESSION IN HSCS. THE PRESENT STUDY AIMED TO INVESTIGATE THE ROLES OF BRD4 IN TGFBETA1-DEPENDENT HSC ACTIVATION AND LIVER FIBROSIS, FOCUSING ON TGFBETA1-INDUCED ALTERATIONS OF THE LEVELS OF THE FIBROTIC-RELATED IMPORTANT PROTEINS IN HSCS BY EMPLOYING THE HETEROZYGOUS TGFBETA1 KNOCKOUT MICE AND BRD4 KNOCKDOWN IN VIVO AND IN VITRO. RESULTS REVEALED THAT BRD4 PROTEIN LEVEL WAS SIGNIFICANTLY UPREGULATED BY TGFBETA1 AND BRD4 KNOCKDOWN REDUCED TGFBETA1-INDUCED HSC ACTIVATION AND LIVER FIBROSIS. BRD4 WAS REQUIRED FOR THE INFLUENCES OF TGFBETA1 ON PDGFBETA RECEPTOR AND ON THE PATHWAYS OF SMAD3, STAT3, AND AKT. BRD4 ALSO MEDIATED TGFBETA1-INDUCED INCREASES IN HISTONE ACETYLTRANSFERASE P300, THE PIVOTAL PRO-INFLAMMATORY NFKB P65, AND TISSUE INHIBITOR OF METALLOPROTEINASE 1 WHEREAS BRD4 REDUCED CASPASE-3 PROTEIN LEVELS IN HSCS DURING LIVER INJURY, INDEPENDENT OF TGFBETA1. FURTHER EXPERIMENTS INDICATED THE INTERACTION BETWEEN TGFBETA1-INDUCED BRD4 AND NFKB P65 IN HSCS AND IN LIVER OF TAA-INDUCED LIVER INJURY. HUMAN CIRRHOTIC LIVERS WERE DEMONSTRATED A PARALLEL INCREASE IN THE PROTEIN LEVELS OF BRD4 AND NFKB P65 IN HSCS. THIS STUDY REVEALED THAT BRD4 WAS A KEY MOLECULAR DRIVER OF TGFBETA1-INDUCED HSC ACTIVATION AND LIVER FIBROSIS. 2023 6 1945 39 EPIGALLOCATECHIN-3-GALLATE, A HISTONE ACETYLTRANSFERASE INHIBITOR, INHIBITS EBV-INDUCED B LYMPHOCYTE TRANSFORMATION VIA SUPPRESSION OF RELA ACETYLATION. BECAUSE THE P300/CBP-MEDIATED HYPERACETYLATION OF RELA (P65) IS CRITICAL FOR NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) ACTIVATION, THE ATTENUATION OF P65 ACETYLATION IS A POTENTIAL MOLECULAR TARGET FOR THE PREVENTION OF CHRONIC INFLAMMATION. DURING OUR ONGOING SCREENING STUDY TO IDENTIFY NATURAL COMPOUNDS WITH HISTONE ACETYLTRANSFERASE INHIBITOR (HATI) ACTIVITY, WE IDENTIFIED EPIGALLOCATECHIN-3-GALLATE (EGCG) AS A NOVEL HATI WITH GLOBAL SPECIFICITY FOR THE MAJORITY OF HAT ENZYMES BUT WITH NO ACTIVITY TOWARD EPIGENETIC ENZYMES INCLUDING HDAC, SIRT1, AND HMTASE. AT A DOSE OF 100 MICROMOL/L, EGCG ABROGATES P300-INDUCED P65 ACETYLATION IN VITRO AND IN VIVO, INCREASES THE LEVEL OF CYTOSOLIC IKAPPABALPHA, AND SUPPRESSES TUMOR NECROSIS FACTOR ALPHA (TNFALPHA)-INDUCED NF-KAPPAB ACTIVATION. WE ALSO SHOWED THAT EGCG PREVENTS TNFALPHA-INDUCED P65 TRANSLOCATION TO THE NUCLEUS, CONFIRMING THAT HYPERACETYLATION IS CRITICAL FOR NF-KAPPAB TRANSLOCATION AS WELL AS ACTIVITY. FURTHERMORE, EGCG TREATMENT INHIBITED THE ACETYLATION OF P65 AND THE EXPRESSION OF NF-KAPPAB TARGET GENES IN RESPONSE TO DIVERSE STIMULI. FINALLY, EGCG REDUCED THE BINDING OF P300 TO THE PROMOTER REGION OF INTERLEUKIN-6 GENE WITH AN INCREASED RECRUITMENT OF HDAC3, WHICH HIGHLIGHTS THE IMPORTANCE OF THE BALANCE BETWEEN HATS AND HISTONE DEACETYLASES IN THE NF-KAPPAB-MEDIATED INFLAMMATORY SIGNALING PATHWAY. IMPORTANTLY, EGCG AT 50 MICROMOL/L DOSE COMPLETELY BLOCKS EBV INFECTION-INDUCED CYTOKINE EXPRESSION AND SUBSEQUENTLY THE EBV-INDUCED B LYMPHOCYTE TRANSFORMATION. THESE RESULTS SHOW THE CRUCIAL ROLE OF ACETYLATION IN THE DEVELOPMENT OF INFLAMMATORY-RELATED DISEASES. 2009 7 5920 31 TARGETING CHROMATIN REMODELING IN INFLAMMATION AND FIBROSIS. MUCOSAL SURFACES OF THE HUMAN BODY ARE LINED BY A CONTIGUOUS EPITHELIAL CELL SURFACE THAT FORMS A BARRIER TO AEROSOLIZED PATHOGENS. SPECIALIZED PATTERN RECOGNITION RECEPTORS DETECT THE PRESENCE OF VIRAL PATHOGENS AND INITIATE PROTECTIVE HOST RESPONSES BY TRIGGERING ACTIVATION OF THE NUCLEAR FACTOR KAPPAB (NFKAPPAB)/RELA TRANSCRIPTION FACTOR AND FORMATION OF A COMPLEX WITH THE POSITIVE TRANSCRIPTION ELONGATION FACTOR (P-TEFB)/CYCLIN-DEPENDENT KINASE (CDK)9 AND BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) EPIGENETIC READER. THE RELA.BRD4.P-TEFB COMPLEX PRODUCES ACUTE INFLAMMATION BY REGULATING TRANSCRIPTIONAL ELONGATION, WHICH PRODUCES A RAPID GENOMIC RESPONSE BY INACTIVE GENES MAINTAINED IN AN OPEN CHROMATIN CONFIGURATION ENGAGED WITH HYPOPHOSPHORYLATED RNA POLYMERASE II. WE DESCRIBE RECENT STUDIES THAT HAVE LINKED PROLONGED ACTIVATION OF THE RELA-BRD4 PATHWAY WITH THE EPITHELIAL-MESENCHYMAL TRANSITION (EMT) BY INDUCING A CORE OF EMT COREPRESSORS, STIMULATING SECRETION OF GROWTH FACTORS PROMOTING AIRWAY FIBROSIS. THE MESENCHYMAL STATE PRODUCES REWIRING OF THE KINOME AND REPROGRAMMING OF INNATE RESPONSES TOWARD INFLAMMATION. IN ADDITION, THE CORE REGULATOR ZINC FINGER E-BOX HOMEODOMAIN 1 (ZEB1) SILENCES THE EXPRESSION OF THE INTERFERON RESPONSE FACTOR 1 (IRF1), REQUIRED FOR TYPE III IFN EXPRESSION. THIS EPIGENETIC SILENCING IS MEDIATED BY THE ENHANCER OF ZESTE 2 (EZH2) HISTONE METHYLTRANSFERASE. BECAUSE OF THEIR POTENTIAL APPLICATIONS IN CANCER AND INFLAMMATION, SMALL-MOLECULE INHIBITORS OF NFKAPPAB/RELA, CDK9, BRD4, AND EZH2 HAVE BEEN THE TARGETS OF MEDICINAL CHEMISTRY EFFORTS. WE SUGGEST THAT DISRUPTION OF THE RELA.BRD4.P-TEFB PATHWAY AND EZH2 METHYLTRANSFERASE HAS IMPORTANT IMPLICATIONS FOR REVERSING FIBROSIS AND RESTORING NORMAL MUCOSAL IMMUNITY IN CHRONIC INFLAMMATORY DISEASES. 2017 8 3204 35 HDAC3 REGULATES GINGIVAL FIBROBLAST INFLAMMATORY RESPONSES IN PERIODONTITIS. HISTONE DEACETYLASES (HDACS) ARE IMPORTANT REGULATORS OF GENE EXPRESSION THAT ARE ABERRANTLY REGULATED IN SEVERAL INFLAMMATORY AND INFECTIOUS DISEASES. HDAC INHIBITORS (HDACI) SUPPRESS INFLAMMATORY ACTIVATION OF VARIOUS CELL TYPES THROUGH EPIGENETIC AND NON-EPIGENETIC MECHANISMS, AND AMELIORATE PATHOLOGY IN A MOUSE MODEL OF PERIODONTITIS. ACTIVATION OF GINGIVAL FIBROBLASTS (GFS) SIGNIFICANTLY CONTRIBUTES TO THE DEVELOPMENT OF PERIODONTITIS AND THE ANAEROBIC BACTERIUM PORPHYROMONAS GINGIVALIS PLAYS A KEY ROLE IN DRIVING CHRONIC INFLAMMATION. HERE, WE ANALYZED THE ROLE OF HDACS IN INFLAMMATORY RESPONSES OF GFS. PAN-HDACI SUBEROYLANILIDE HYDROXAMIC ACID (SAHA) AND/OR ITF2357 (GIVINOSTAT) SIGNIFICANTLY REDUCED TNFALPHA- AND P. GINGIVALIS-INDUCIBLE EXPRESSION AND/OR PRODUCTION OF A CLUSTER OF INFLAMMATORY MEDIATORS IN HEALTHY DONOR GFS (IL1B, CCL2, CCL5, CXCL10, COX2, AND MMP3) WITHOUT AFFECTING CELL VIABILITY. SELECTIVE INHIBITION OF HDAC3/6, BUT NOT SPECIFIC HDAC1, HDAC6, OR HDAC8 INHIBITION, REPRODUCED THE SUPPRESSIVE EFFECTS OF PAN-HDACI ON THE INFLAMMATORY GENE EXPRESSION PROFILE INDUCED BY TNFALPHA AND P. GINGIVALIS, SUGGESTING A CRITICAL ROLE FOR HDAC3 IN GF INFLAMMATORY ACTIVATION. CONSISTENTLY, SILENCING OF HDAC3 EXPRESSION WITH SIRNA LARGELY RECAPITULATED THE EFFECTS OF HDAC3/6I ON MRNA LEVELS OF INFLAMMATORY MEDIATORS IN P. GINGIVALIS-INFECTED GFS. IN CONTRAST, P. GINGIVALIS INTERNALIZATION AND INTRACELLULAR SURVIVAL IN GFS REMAINED UNAFFECTED BY HDACI. ACTIVATION OF MITOGEN-ACTIVATED PROTEIN KINASES AND NFKAPPAB SIGNALING WAS UNAFFECTED BY GLOBAL OR HDAC3/6-SELECTIVE HDACI, AND NEW PROTEIN SYNTHESIS WAS NOT REQUIRED FOR GENE SUPPRESSION BY HDACI. FINALLY, PAN-HDACI AND HDAC3/6I SUPPRESSED P. GINGIVALIS-INDUCED EXPRESSION OF IL1B, CCL2, CCL5, CXCL10, MMP1, AND MMP3 IN GFS FROM PATIENTS WITH PERIODONTITIS. OUR RESULTS IDENTIFY HDAC3 AS AN IMPORTANT REGULATOR OF INFLAMMATORY GENE EXPRESSION IN GFS AND SUGGEST THAT THERAPEUTIC TARGETING OF HDAC ACTIVITY, IN PARTICULAR HDAC3, MAY BE CLINICALLY BENEFICIAL IN SUPPRESSING INFLAMMATION IN PERIODONTAL DISEASE. 2020 9 692 32 BRD4 PROMOTES HEPATIC STELLATE CELLS ACTIVATION AND HEPATIC FIBROSIS VIA MEDIATING P300/H3K27AC/PLK1 AXIS. HEPATIC FIBROSIS (HF) IS A REVERSIBLE WOUND-HEALING RESPONSE CHARACTERIZED BY EXCESSIVE EXTRACELLULAR MATRIX (ECM) DEPOSITION AND SECONDARY TO PERSISTENT CHRONIC INJURY. BROMODOMAIN PROTEIN 4 (BRD4) COMMONLY FUNCTIONS AS A "READER" TO REGULATE EPIGENETIC MODIFICATIONS INVOLVED IN VARIOUS BIOLOGICAL AND PATHOLOGICAL EVENTS, BUT THE MECHANISM OF HF REMAINS UNCLEAR. IN THIS STUDY, WE ESTABLISHED A CCL(4)-INDUCED HF MODEL AND SPONTANEOUS RECOVERY MODEL IN MICE AND FOUND ABERRANT BRD4 EXPRESSION, WHICH WAS CONSISTENT WITH THE RESULTS IN HUMAN HEPATIC STELLATE CELLS (HSCS)- LX2 CELLS IN VITRO. SUBSEQUENTLY, WE FOUND THAT DISTRICTION AND INHIBITION OF BRD4 RESTRAINED TGFBETA-INDUCED TRANS-DIFFERENTIATION OF LX2 CELLS INTO ACTIVATED, PROLIFERATIVE MYOFIBROBLASTS AND ACCELERATED APOPTOSIS, AND BRD4 OVEREXPRESSION BLOCKED MDI-INDUCED LX2 CELLS INACTIVATION AND PROMOTED THE PROLIFERATION AND INHIBITED APOPTOSIS OF INACTIVATED CELLS. ADDITIONALLY, ADENO-ASSOCIATED VIRUS SEROTYPE 8-LOADED SHORT HAIRPIN RNA-MEDIATED BRD4 KNOCKDOWN IN MICE SIGNIFICANTLY ATTENUATED CCL(4)-INDUCED FIBROTIC RESPONSES INCLUDING HSCS ACTIVATION AND COLLAGEN DEPOSITION. MECHANISTICALLY, BRD4 DEFICIENCY INHIBITED PLK1 EXPRESSION IN ACTIVATED LX2 CELLS, AND CHIP AND CO-IP ASSAYS REVEALED THAT BRD4 REGULATION OF PLK1 WAS DEPENDENT ON P300-MEDIATED ACETYLATION MODIFICATION FOR H3K27 ON THE PLK1 PROMOTER. IN CONCLUSION, BRD4 DEFICIENCY IN THE LIVER ALLEVIATES CCL(4)-INDUCED HF IN MICE, AND BRD4 PARTICIPATES IN THE ACTIVATION AND REVERSAL OF HSCS THROUGH POSITIVELY REGULATING THE P300/H3K27AC/PLK1 AXIS, PROVIDING A POTENTIAL INSIGHT FOR HF THERAPY. 2023 10 1906 37 ENHANCER OF ZESTE HOMOLOG 2-CATALYSED H3K27 TRIMETHYLATION PLAYS A KEY ROLE IN ACUTE-ON-CHRONIC LIVER FAILURE VIA TNF-MEDIATED PATHWAY. ACUTE-ON-CHRONIC LIVER FAILURE IS MAINLY DUE TO HOST IMMUNITY SELF-DESTRUCTION. THE HISTONE H3 LYSINE 27 (H3K27) TRIMETHYLATING ENZYME, ENHANCER OF ZESTE HOMOLOG 2 (EZH2) MEDIATES EPIGENETIC SILENCING OF GENE EXPRESSION AND REGULATES IMMUNITY, ALSO INVOLVES PATHOGENESIS OF SEVERAL LIVER DISEASES. THE CURRENT STUDY WAS TO DETERMINE THE ROLE OF METHYLTRANSFERASE EZH2 AND ITS CATALYSED H3K27 TRIMETHYLATION (H3K27ME3) IN LIVER FAILURE, AND TO FURTHER INVESTIGATE THE POTENTIAL TARGET FOR LIVER FAILURE TREATMENT. EZH2 AND ITS CATALYSED H3K27ME3 WERE DETERMINED IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC) FROM LIVER FAILURE PATIENTS AND KUPFFER CELLS FROM EXPERIMENTAL MICE. FURTHERMORE, GSK126 (AN INHIBITOR FOR EZH2 TRIMETHYLATION FUNCTION) WAS APPLIED IN LIVER FAILURE MICE IN VIVO, AND LIPOPOLYSACCHARIDE-STIMULATED MONONUCLEAR CELLS IN VITRO. EZH2 AND H3K27ME3 WERE SIGNIFICANTLY UPREGULATED IN HUMAN PBMC FROM LIVER FAILURE PATIENTS OR MURINE KUPFFER CELLS FROM THE LIVER FAILURE ANIMALS, RESPECTIVELY. GSK126 AMELIORATED DISEASE SEVERITY IN LIVER FAILURE MICE, WHICH MAYBE ATTRIBUTE TO DOWN-REGULATE CIRCULATING AND HEPATIC PROINFLAMMATORY CYTOKINES, ESPECIALLY TNF VIA REDUCING H3K27ME3. IN-DEPTH CHROMATIN IMMUNOPRECIPITATION ANALYSIS UNRAVELLED THAT DECREASED ENRICHMENT OF H3K27ME3 ON TNF PROMOTOR, RESULTING IN TNF ELEVATION IN KUPFFER CELLS FROM LIVER FAILURE MICE. NUCLEAR FACTOR KAPPA B (NF-KAPPAB) AND PROTEIN KINASE B (AKT) SIGNALLING PATHWAYS WERE ACTIVATED UPON LIPOPOLYSACCHARIDE STIMULATION, BUT ATTENUATED BY USING GSK126, ACCOMPANIED WITH DECREASED TNF IN VITRO. IN CONCLUSION, EZH2 AND H3K27ME3 CONTRIBUTED TO THE PATHOGENESIS OF LIVER FAILURE VIA TRIGGERING TNF AND OTHER INDISPENSABLE PROINFLAMMATORY CYTOKINES. EZH2 WAS TO MODIFY H3K27ME3 ENRICHMENT, AS WELL AS, ACTIVATION OF THE DOWNSTREAM NF-KAPPAB AND AKT SIGNALLING PATHWAYS. 2018 11 5479 28 RESVERATROL ATTENUATES CIGARETTE SMOKE EXTRACT INDUCED CELLULAR SENESCENCE IN HUMAN AIRWAY EPITHELIAL CELLS BY REGULATING THE MIR-34A/SIRT1/NF-KAPPAB PATHWAY. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS CHARACTERIZED BY ACCELERATED LUNG AGING. SMOKING IS THE CRITICAL RISK FACTOR FOR COPD. CELLULAR SENESCENCE OF AIRWAY EPITHELIAL CELLS IS THE CYTOLOGICAL BASIS OF ACCELERATED LUNG AGING IN COPD, AND THE REGULATION OF MICRORNAS (MIRNAS) IS THE CENTRAL EPIGENETIC MECHANISM OF CELLULAR SENESCENCE. RESVERATROL (RES) IS A POLYPHENOL WITH ANTI-AGING PROPERTIES. THIS STUDY INVESTIGATED WHETHER RES ATTENUATES CIGARETTE SMOKE EXTRACT (CSE)-INDUCED CELLULAR SENESCENCE IN HUMAN AIRWAY EPITHELIAL CELLS (BEAS-2B) THROUGH THE MIR-34A/SIRT1/NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) PATHWAY. BEAS-2B CELLS WERE TREATED WITH RES, CSE AND TRANSFECTED WITH MIR-34A-5P MIMICS. CELLULAR SENESCENCE WAS EVALUATED BY SENESCENCE -RELATED BETA-GALACTOSIDASE (SA-BETA-GAL) STAINING AND EXPRESSION OF SENESCENCE-RELATED GENES (P16, P21, AND P53). THE EXPRESSIONS OF MIR-34A-5P, SIRT1, AND NF-KAPPAB P65 WERE EXAMINED USING QUANTITATIVE REAL TIME POLYMERASE CHAIN REACTION AND WESTERN BLOTTING. THE SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP) CYTOKINES (IL-1BETA, IL-6, IL-8, TNF-ALPHA) WERE ASSESSED BY ENZYME-LINKED IMMUNOSORBENT ASSAY. THE BINDING BETWEEN MIR-34A-5P AND SIRT1 WAS CONFIRMED BY DUAL-LUCIFERASE REPORTER ASSAY. THE RESULTS SHOWED THAT CSE DOSE-DEPENDENTLY DECREASED CELL VIABILITY AND ELEVATED CELLULAR SENESCENCE, CHARACTERIZED BY INCREASED SA-BETA-GAL STAINING AND SENESCENCE-RELATED GENE EXPRESSIONS (P16, P21, AND P53). FURTHER, CSE DOSE-DEPENDENTLY INCREASED THE EXPRESSION OF MIR-34A-5P AND SASP CYTOKINES (IL-1BETA, IL-6, IL-8, TNF-ALPHA) IN BEAS-2B CELLS. PRETREATMENT WITH RES INHIBITED CSE-INDUCED CELLULAR SENESCENCE AND SECRETION OF SASP CYTOKINES (IL-1BETA, IL-6, IL-8, TNF-ALPHA) IN A DOSE-DEPENDENT MANNER. MOREOVER, RES REVERSED THE CSE-INDUCED DOWN-REGULATION OF SIRT1 AND UP-REGULATION OF MIR-34A-5P AND NF-KAPPAB P65. SIRT1 IS A TARGET OF MIR-34A-5P. OVEREXPRESSION OF MIR-34A-5P VIA TRANSFECTION WITH MIR-34A-5P MIMIC IN BEAS-2B CELLS ATTENUATED THE INHIBITORY EFFECT OF RES ON CELLULAR SENESCENCE, ACCOMPANIED BY REVERSING THE EXPRESSION OF SIRT1 AND NF-KAPPAB P65. IN CONCLUSION, RES ATTENUATED CSE-INDUCED CELLULAR SENESCENCE IN BEAS-2B CELLS BY REGULATING THE MIR-34A/SIRT1/NF-KAPPAB PATHWAY, WHICH MAY PROVIDE A NEW APPROACH FOR COPD TREATMENT. 2022 12 5868 32 SUPPRESSIVE EFFECTS OF METFORMIN ON T-HELPER 1-RELATED CHEMOKINES EXPRESSION IN THE HUMAN MONOCYTIC LEUKEMIA CELL LINE THP-1. PURPOSE OF THE STUDY: TYPE 1 AND TYPE 2 DIABETES MELLITUS (DM) ARE CHRONIC T-CELL-MEDIATED INFLAMMATORY DISEASES. METFORMIN IS A WIDELY USED DRUG FOR TYPE 2 DM THAT REDUCES THE NEED FOR INSULIN IN TYPE 1 DM. HOWEVER, WHETHER METFORMIN HAS AN ANTI-INFLAMMATORY EFFECT FOR TREATING DM IS UNKNOWN. WE INVESTIGATED THE ANTI-INFLAMMATORY MECHANISM OF METFORMIN IN THE HUMAN MONOCYTIC LEUKEMIA CELL LINE THP-1. MATERIALS AND METHODS: THE HUMAN MONOCYTIC LEUKEMIA CELL LINE THP-1 WAS PRETREATED WITH METFORMIN AND STIMULATED WITH LIPOPOLYSACCHARIDE (LPS). THE PRODUCTION OF T-HELPER (TH)-1-RELATED CHEMOKINES INCLUDING INTERFERON-GAMMA-INDUCED PROTEIN-10 (IP-10) AND MONOCYTE CHEMOATTRACTANT PROTEIN-1 (MCP-1), TH2-RELATED CHEMOKINE MACROPHAGE-DERIVED CHEMOKINE, AND THE PROINFLAMMATORY CHEMOKINE TUMOR NECROSIS FACTOR-ALPHA WAS MEASURED USING ENZYME-LINKED IMMUNOSORBENT ASSAY. INTRACELLULAR SIGNALING PATHWAYS WERE INVESTIGATED USING WESTERN BLOT ANALYSIS AND CHROMATIN IMMUNOPRECIPITATION ASSAY. RESULTS: METFORMIN SUPPRESSED LPS-INDUCED IP-10 AND MCP-1 PRODUCTION AS WELL AS LPS-INDUCED PHOSPHORYLATION OF C-JUN N-TERMINAL KINASE (JNK), P38, EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK), AND NUCLEAR FACTOR-KAPPA B (NF-KAPPAB). MOREOVER, METFORMIN SUPPRESSED LPS-INDUCED ACETYLATION OF HISTONES H3 AND H4 AT THE IP-10 PROMOTER. CONCLUSIONS: METFORMIN SUPPRESSED THE PRODUCTION OF TH1-RELATED CHEMOKINES IP-10 AND MCP-1 IN THP-1 CELLS. SUPPRESSIVE EFFECTS OF METFORMIN ON IP-10 PRODUCTION MIGHT BE ATTRIBUTED AT LEAST PARTIALLY TO THE JNK, P38, ERK, AND NF-KAPPAB PATHWAYS AS WELL AS TO EPIGENETIC REGULATION THROUGH THE ACETYLATION OF HISTONES H3 AND H4. THESE RESULTS INDICATED THE THERAPEUTIC ANTI-INFLAMMATORY POTENTIAL OF METFORMIN. 2018 13 589 33 BET BROMODOMAIN INHIBITORS SUPPRESS INFLAMMATORY ACTIVATION OF GINGIVAL FIBROBLASTS AND EPITHELIAL CELLS FROM PERIODONTITIS PATIENTS. BET BROMODOMAIN PROTEINS ARE IMPORTANT EPIGENETIC REGULATORS OF GENE EXPRESSION THAT BIND ACETYLATED HISTONE TAILS AND REGULATE THE FORMATION OF ACETYLATION-DEPENDENT CHROMATIN COMPLEXES. BET INHIBITORS SUPPRESS INFLAMMATORY RESPONSES IN MULTIPLE CELL TYPES AND ANIMAL MODELS, AND PROTECT AGAINST BONE LOSS IN EXPERIMENTAL PERIODONTITIS IN MICE. HERE, WE ANALYZED THE ROLE OF BET PROTEINS IN INFLAMMATORY ACTIVATION OF GINGIVAL FIBROBLASTS (GFS) AND GINGIVAL EPITHELIAL CELLS (GECS). WE SHOW THAT THE BET INHIBITORS I-BET151 AND JQ1 SIGNIFICANTLY REDUCED EXPRESSION AND/OR PRODUCTION OF DISTINCT, BUT OVERLAPPING, PROFILES OF CYTOKINE-INDUCIBLE MEDIATORS OF INFLAMMATION AND BONE RESORPTION IN GFS FROM HEALTHY DONORS (IL6, IL8, IL1B, CCL2, CCL5, COX2, AND MMP3) AND THE GEC LINE TIGK (IL6, IL8, IL1B, CXCL10, MMP9) WITHOUT AFFECTING CELL VIABILITY. ACTIVATION OF MITOGEN-ACTIVATED PROTEIN KINASE AND NUCLEAR FACTOR-KAPPAB PATHWAYS WAS UNAFFECTED BY I-BET151, AS WAS THE HISTONE ACETYLATION STATUS, AND NEW PROTEIN SYNTHESIS WAS NOT REQUIRED FOR THE ANTI-INFLAMMATORY EFFECTS OF BET INHIBITION. I-BET151 AND JQ1 ALSO SUPPRESSED EXPRESSION OF INFLAMMATORY CYTOKINES, CHEMOKINES, AND OSTEOCLASTOGENIC MEDIATORS IN GFS AND TIGKS INFECTED WITH THE KEY PERIODONTAL PATHOGEN PORPHYROMONAS GINGIVALIS. NOTABLY, P. GINGIVALIS INTERNALIZATION AND INTRACELLULAR SURVIVAL IN GFS AND TIGKS REMAINED UNAFFECTED BY BET INHIBITORS. FINALLY, INHIBITION OF BET PROTEINS SIGNIFICANTLY REDUCED P. GINGIVALIS-INDUCED INFLAMMATORY MEDIATOR EXPRESSION IN GECS AND GFS FROM PATIENTS WITH PERIODONTITIS. OUR RESULTS DEMONSTRATE THAT BET INHIBITORS MAY BLOCK THE EXCESSIVE INFLAMMATORY MEDIATOR PRODUCTION BY RESIDENT CELLS OF THE GINGIVAL TISSUE AND IDENTIFY THE BET FAMILY OF EPIGENETIC READER PROTEINS AS A POTENTIAL THERAPEUTIC TARGET IN THE TREATMENT OF PERIODONTAL DISEASE. 2019 14 1667 27 DOWNREGULATION OF PCAF BY MIR-181A/B PROVIDES FEEDBACK REGULATION TO TNF-ALPHA-INDUCED TRANSCRIPTION OF PROINFLAMMATORY GENES IN LIVER EPITHELIAL CELLS. ABERRANT CELLULAR RESPONSES TO PROINFLAMMATORY CYTOKINES, SUCH AS TNF-ALPHA, ARE PATHOGENIC FEATURES IN MOST CHRONIC INFLAMMATORY DISEASES. A VARIETY OF EXTRACELLULAR AND INTRACELLULAR FEEDBACK PATHWAYS HAS EVOLVED TO PREVENT AN INAPPROPRIATE CELLULAR REACTION TO THESE PROINFLAMMATORY CYTOKINES. IN THIS STUDY, WE REPORT THAT TNF-ALPHA TREATMENT OF HUMAN AND MOUSE CHOLANGIOCYTES AND HEPATOCYTES DOWNREGULATED EXPRESSION OF P300/CBP-ASSOCIATED FACTOR (PCAF), A COACTIVATOR AND AN ACETYLTRANSFERASE THAT PROMOTES HISTONE ACETYLATION AND GENE TRANSCRIPTION. OF THESE UPREGULATED MICRORNAS IN TNF-ALPHA-TREATED CELLS, MIR-181A/B (MIR-181A AND MIR-181B) SUPPRESSED TRANSLATION OF PCAF MRNA. FUNCTIONAL MANIPULATION OF MIR-181A/B CAUSED RECIPROCAL ALTERATIONS IN PCAF PROTEIN EXPRESSION IN CULTURED CHOLANGIOCYTES AND HEPATOCYTES. INHIBITION OF MIR-181A/B FUNCTION WITH ANTI-MIRS BLOCKED TNF-ALPHA-INDUCED SUPPRESSION OF PCAF EXPRESSION. PROMOTER RECRUITMENT OF PCAF WAS SHOWN TO BE ASSOCIATED WITH TNF-ALPHA-INDUCED TRANSCRIPTION OF INFLAMMATORY GENES. INTRIGUINGLY, PRETREATMENT OF CELLS WITH TNF-ALPHA INHIBITED TRANSCRIPTION OF INFLAMMATORY GENES IN RESPONSE TO SUBSEQUENT TNF-ALPHA STIMULATION. OVEREXPRESSION OF PCAF OR INHIBITION OF MIR-181A/B FUNCTION WITH ANTI-MIRS ATTENUATED THE INHIBITORY EFFECTS OF TNF-ALPHA PRETREATMENT ON EPITHELIAL INFLAMMATORY RESPONSE TO SUBSEQUENT TNF-ALPHA STIMULATION. DOWNREGULATION OF PCAF AND THE INHIBITORY EFFECTS OF TNF-ALPHA PRETREATMENT ON LIVER EPITHELIAL INFLAMMATORY RESPONSE WERE FURTHER CONFIRMED IN A MOUSE MODEL OF TNF-ALPHA I.P. INJECTION. THESE DATA SUGGEST THAT PCAF IS A TARGET FOR MIR-181A/B, AND DOWNREGULATION OF PCAF BY TNF-ALPHA PROVIDES NEGATIVE FEEDBACK REGULATION TO INFLAMMATORY REACTIONS IN LIVER EPITHELIAL CELLS, A PROCESS THAT MAY BE RELEVANT TO THE EPIGENETIC FINE-TUNING OF EPITHELIAL INFLAMMATORY PROCESSES IN GENERAL. 2012 15 5227 28 PRMT6 MEDIATES INFLAMMATION VIA ACTIVATION OF THE NF-KAPPAB/P65 PATHWAY ON A CIGARETTE SMOKE EXTRACT-INDUCED MURINE EMPHYSEMA MODEL. INTRODUCTION: SMOKE-DRIVEN LUNG INFLAMMATION IS CONSIDERED TO BE THE MAJOR PATHOPHYSIOLOGY MECHANISM OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)/EMPHYSEMA. PROTEIN ARGININE METHYLTRANSFERASE 6 (PRMT6) IS A KEY EPIGENETIC ENZYME, WHICH IS RELATED TO PROTECTING THE TRI-METHYLATION OF H3K4 (H3K4ME3). WE HYPOTHESIZED THAT PTMT6 PROTECTS LUNG INFLAMMATION THROUGH THE NUCLEAR FACTOR KAPPA B (NF-KAPPAB) PATHWAY. METHODS: MICE WERE INJECTED WITH CIGARETTE SMOKE EXTRACT (CSE) OR PBS TO ESTABLISH A MICE MODEL, INTRATRACHEALLY INSTILLED WITH OVEREXPRESSED PRMT6 OR NEGATIVE CONTROL VECTOR. MORPHOMETRY OF LUNG SLIDES AND LUNG FUNCTION WERE MEASURED. WE DETERMINED THE PROTEIN EXPRESSION OF PRMT6 AND ITS RELATED HISTONE TARGETS, THE ACTIVATION OF NF-KAPPAB PATHWAY, THE LEVEL OF TUMOR NECROSIS FACTOR ALPHA (TNFALPHA) AND INTERLEUKIN-1BETA (IL-1BETA). RESULTS: AFTER PRMT6 OVEREXPRESSION, THE MORPHOMETRY INDEXES AND LUNG FUNCTION WERE IMPROVED. ALSO, THE EXPRESSION OF H3K4ME3 WAS DECREASED. OVEREXPRESSED PRMT6 COULD SUPPRESS CSE-INDUCED NF-KAPPAB ACTIVATION AND PRO-INFLAMMATION GENES EXPRESSION. CONCLUSIONS: THE OVEREXPRESSED PRMT6 COULD SERVE AS AN INFLAMMATION INHIBITOR, POTENTIALLY THROUGH BLOCKING THE NF-KAPPAB/P65 PATHWAY IN THE MURINE EMPHYSEMA MODEL. 2020 16 2784 25 EZH2 PROMOTES EXTRACELLULAR MATRIX DEGRADATION VIA NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) AND P38 SIGNALING PATHWAYS IN PULPITIS. PULPITIS IS A COMPLICATED CHRONIC INFLAMMATORY PROCESS WHICH CAN BE IN A DYNAMIC BALANCE BETWEEN DAMAGE AND REPAIR. THE EXTRACELLULAR MATRIX PLAYS AN IMPORTANT REGULATORY ROLE IN WOUND HEALING AND TISSUE REPAIR. THE AIM OF THIS STUDY WAS TO EXPLORE THE ROLE OF THE EPIGENETIC MARK, ENHANCER OF ZESTE HOMOLOG 2 (EZH2) ON THE DEGRADATION OF EXTRACELLULAR MATRIX DURING PULPITIS. QUANTITATIVE POLYMERASE CHAIN REACTION WAS USED TO ASSESS THE EXPRESSION OF MATRIX METALLOPROTEINASES (MMPS) AND TYPE I COLLAGEN IN HUMAN DENTAL PULP CELLS (HDPCS) UPON EZH2 AND EI1 (EZH2 INHIBITOR) STIMULATION. THE MECHANISM OF EZH2 AFFECTING EXTRACELLULAR MATRIX WAS EXPLORED THROUGH QUANTITATIVE POLYMERASE CHAIN REACTION AND WESTERN BLOT. A RAT MODEL OF DENTAL PULP INFLAMMATION WAS ESTABLISHED, AND THE EXPRESSION OF TYPE I COLLAGEN IN DENTAL PULP UNDER EZH2 STIMULATION WAS DETECTED BY IMMUNOHISTOCHEMICAL STAINING. EZH2 UPREGULATED THE EXPRESSION OF MMP-1, MMP-3, MMP-8, AND MMP-10 AND DECREASED THE PRODUCTION OF TYPE I COLLAGEN IN HDPCS, WHILE EI1 HAD THE OPPOSITE EFFECT. EZH2 ACTIVATED THE NUCLEAR FACTOR-KAPPA B (NF-KAPPAB) AND P38 SIGNALING PATHWAYS IN HDPCS, THE INHIBITION OF WHICH REVERSED THE INDUCTION OF MMPS AND THE SUPPRESSION OF TYPE I COLLAGEN. EZH2 CAN DOWNREGULATE THE TYPE I COLLAGEN LEVELS IN AN EXPERIMENTAL MODEL OF DENTAL PULPITIS IN RATS. EZH2 PROMOTES EXTRACELLULAR MATRIX DEGRADATION VIA NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) AND P38 SIGNALING PATHWAYS IN PULPITIS. EZH2 CAN DECREASE THE TYPE I COLLAGEN LEVELS IN VIVO AND IN VITRO. 2021 17 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 18 3175 32 H2AX PHOSPHORYLATION REGULATED BY P38 IS INVOLVED IN BIM EXPRESSION AND APOPTOSIS IN CHRONIC MYELOGENOUS LEUKEMIA CELLS INDUCED BY IMATINIB. INCREASING EVIDENCE SUGGESTS THAT HISTONE H2AX PLAYS A CRITICAL ROLE IN REGULATION OF TUMOR CELL APOPTOSIS AND ACTS AS A NOVEL HUMAN TUMOR SUPPRESSOR PROTEIN. HOWEVER, THE ACTION OF H2AX IN CHRONIC MYELOGENOUS LEUKEMIA (CML) CELLS IS UNKNOWN. THE DETAILED MECHANISM AND EPIGENETIC REGULATION BY H2AX REMAIN ELUSIVE IN CANCER CELLS. HERE, WE REPORT THAT H2AX WAS INVOLVED IN APOPTOSIS OF CML CELLS. OVEREXPRESSION OF H2AX INCREASED APOPTOTIC SENSITIVITY OF CML CELLS (K562) INDUCED BY IMATINIB. HOWEVER, OVEREXPRESSION OF SER139-MUTATED H2AX (BLOCKING PHOSPHORYLATION) DECREASED SENSITIVITY OF K562 CELLS TO APOPTOSIS. SIMILARLY, KNOCKDOWN OF H2AX MADE K562 CELLS RESISTANT TO APOPTOTIC INDUCTION. THESE RESULTS REVEALED THAT THE FUNCTION OF H2AX INVOLVED IN APOPTOSIS IS STRICTLY RELATED TO ITS PHOSPHORYLATION (SER139). OUR DATA FURTHER INDICATED THAT IMATINIB MAY STIMULATE MITOGEN-ACTIVATED PROTEIN KINASE (MAPK) FAMILY MEMBER P38, AND H2AX PHOSPHORYLATION FOLLOWED A SIMILAR TIME COURSE, SUGGESTING A PARALLEL RESPONSE. H2AX PHOSPHORYLATION CAN BE BLOCKED BY P38 SIRNA OR ITS INHIBITOR. THESE DATA DEMONSTRATED THAT H2AX PHOSPHORYLATION WAS REGULATED BY P38 MAPK PATHWAY IN K562 CELLS. HOWEVER, THE P38 MAPK DOWNSTREAM, MITOGEN- AND STRESS-ACTIVATED PROTEIN KINASE-1 AND -2, WHICH PHOSPHORYLATED HISTONE H3, WERE NOT REQUIRED FOR H2AX PHOSPHORYLATION DURING APOPTOSIS. FINALLY, WE PROVIDED EPIGENETIC EVIDENCE THAT H2AX PHOSPHORYLATION REGULATED APOPTOSIS-RELATED GENE BIM EXPRESSION. BLOCKING OF H2AX PHOSPHORYLATION INHIBITED BIM GENE EXPRESSION. TAKEN TOGETHER, THESE DATA DEMONSTRATED THAT H2AX PHOSPHORYLATION REGULATED BY P38 IS INVOLVED IN BIM EXPRESSION AND APOPTOSIS IN CML CELLS INDUCED BY IMATINIB. 2014 19 4162 32 MECP2 REGULATES PTCH1 EXPRESSION THROUGH DNA METHYLATION IN RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC AUTOIMMUNE INFLAMMATORY DISEASE, IN WHICH PATHOGENESIS IS NOT CLEAR. MANY RESEARCH DEMONSTRATED THAT FIBROBLAST-LIKE SYNOVIOCYTES (FLSS) PLAY A KEY ROLE IN RA PATHOGENESIS, JOIN IN THE CARTILAGE INJURY AND HYPERPLASIA OF THE SYNOVIUM, AND CONTRIBUTE TO THE RELEASE OF INFLAMMATORY CYTOKINES. WE USED ADJUVANT ARTHRITIS (AA) RATS AS RA ANIMAL MODELS. THE METHYL-CPG-BINDING PROTEIN 2 (MECP2) ENABLES THE SUPPRESSED CHROMATIN STRUCTURE TO BE SELECTIVELY DETECTED IN AA FLSS. OVEREXPRESSION OF THIS PROTEIN LEADS TO AN INCREASE OF INTEGRAL METHYLATION LEVELS. SOME RESEARCH HAS CONFIRMED THE HEDGEHOG (HH) SIGNALING PATHWAY PLAYS AN IMPORTANT ROLE IN RA PATHOGENESIS; FURTHERMORE, PATCHED 1 (PTCH1) IS A NEGATIVE FRACTION OF HH SIGNALING PATHWAY. WE USED 5-AZA-2'-DEOXYCYTIDINE (5-AZADC) AS DNA METHYLATION INHIBITOR. IN OUR RESEARCH, WE FOUND MECP2 REDUCED PTCH1 EXPRESSION IN AA FLSS; 5-AZADC OBSTRUCTED THE LOSS OF PTCH1 EXPRESSION. 5-AZADC, TREATMENT OF AA FLSS, ALSO BLOCKS THE RELEASE OF INFLAMMATORY CYTOKINES. IN ORDER TO PROBE THE POTENTIAL MOLECULAR MECHANISM, WE ASSUMED THE EPIGENETIC PARTICIPATION IN THE REGULATION OF PTCH1. RESULTS DEMONSTRATED THAT PTCH1 HYPERMETHYLATION IS RELATED TO THE PERSISTENT FLS ACTIVATION AND INFLAMMATION IN AA RATS. KNOCKDOWN OF MECP2 USING SMALL-INTERFERING RNA TECHNIQUE ADDED PTCH1 EXPRESSION IN AA FLSS. OUR RESULTS INDICATE THAT DNA METHYLATION MAY OFFER MOLECULE MECHANISMS, AND THE REDUCED PTCH1 METHYLATION LEVEL COULD REGULATE INFLAMMATION THROUGH KNOCKDOWN OF MECP2. GRAPHICAL ABSTRACT PTCH1 IS AN INHIBITORY PROTEIN OF THE HEDGEHOG SIGNALING PATHWAY. INCREASED EXPRESSION OF PTCH1 CAN INHIBIT THE EXPRESSION OF GLI1 AND SHH, THEREBY INHIBITING THE ACTIVATION OF HEDGEHOG SIGNALING PATHWAY. INACTIVATED HEDGEHOG SIGNALING PATHWAY INHIBITS THE SECRETION OF IL-6 AND TNF-ALPHA. MECP2 MEDIATES HYPERMETHYLATION OF PTCH1 GENE AND DECREASES THE EXPRESSION OF PTCH1 PROTEIN, THUS ACTIVATING HEDGEHOG SIGNALING PATHWAY AND INCREASING SECRETION OF IL-6 AND TNF-ALPHA. 2017 20 6687 23 VALIDATION OF THE EPIGENETIC READER BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) AS A THERAPEUTIC TARGET FOR TREATMENT OF AIRWAY REMODELING. STRUCTURAL REMODELING IS CENTRAL TO THE INITIATION AND PROGRESSION OF MANY CHRONIC LUNG DISEASES, REPRESENTING AN IMPORTANT UNMET NEED. WE EXAMINE THE EVIDENCE SUPPORTING BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) AS A VALIDATED BIOLOGICAL TARGET FOR TREATMENT OF AIRWAY REMODELING. IN EPITHELIAL CELLS AND FIBROBLASTS, BRD4 SERVES AS A SCAFFOLD FOR CHROMATIN REMODELING COMPLEXES IN ACTIVE SUPER-ENHANCERS. IN RESPONSE TO INFLAMMATORY STIMULI, BRD4 IS REPOSITIONED TO INNATE AND MESENCHYMAL GENES ACTIVATING THEIR PRODUCTION. PROOF-OF-CONCEPT STUDIES SHOW PROMISING BENEFIT OF SELECTIVE BRD4 INHIBITORS IN DISRUPTING EPITHELIAL MESENCHYMAL TRANSITION AND MYOFIBROBLAST TRANSITION IN DIVERSE MODELS OF LUNG INJURY. RECENT IDENTIFICATION OF BIOMARKERS OF BRD4 PROVIDES A BASIS FOR FURTHER DRUG DEVELOPMENT FOR APPLICATION IN VIRAL-INDUCED AIRWAY INFLAMMATION, COPD AND INTERSTITIAL LUNG DISEASES. 2020