1 4704 98 NITRATION OF DISTINCT TYROSINE RESIDUES CAUSES INACTIVATION OF HISTONE DEACETYLASE 2. HISTONE DEACETYLASES (HDACS) ARE KEY MOLECULES INVOLVED IN EPIGENETIC REGULATION OF GENE EXPRESSION. WE HAVE PREVIOUSLY DEMONSTRATED THAT OXIDATIVE STRESS CAUSED A REDUCTION IN HDAC2, RESULTING IN AMPLIFIED INFLAMMATION AND REDUCED CORTICOSTEROID RESPONSIVENESS. HERE WE SHOWED NITRATIVE/OXIDATIVE STRESS REDUCED HDAC2 EXPRESSION VIA NITRATION OF DISTINCT TYROSINE RESIDUES. PEROXYNITRITE, HYDROGEN PEROXIDE AND CIGARETTE SMOKE-CONDITIONED MEDIUM REDUCED HDAC2 EXPRESSION IN A549 EPITHELIAL CELLS IN VITRO. THIS REDUCTION WAS DUE TO INCREASED PROTEASOMAL DEGRADATION FOLLOWING UBIQUITINATION RATHER THAN REDUCTION OF MRNA EXPRESSION OR STABILITY. HDAC2 WAS NITRATED UNDER NITRATIVE/OXIDATIVE STRESS AND IN THE PERIPHERAL LUNG TISSUES OF SMOKERS AND PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE. MUTAGENESIS STUDIES REPLACING TYROSINE (Y) RESIDUES WITH ALANINE REVEALED THAT Y253 IS AT LEAST PARTLY RESPONSIBLE FOR THE PROTEASOMAL DEGRADATION OF HDAC2 UNDER NITRATIVE STRESS. THUS, NITRATION OF DISTINCT TYROSINE RESIDUES MODIFIES BOTH THE EXPRESSION AND ACTIVITY OF HDAC2, HAVING AN IMPACT ON EPIGENETIC REGULATION. 2009 2 6015 36 THE ARGININE METHYLTRANSFERASE PRMT7 PROMOTES EXTRAVASATION OF MONOCYTES RESULTING IN TISSUE INJURY IN COPD. EXTRAVASATION OF MONOCYTES INTO TISSUE AND TO THE SITE OF INJURY IS A FUNDAMENTAL IMMUNOLOGICAL PROCESS, WHICH REQUIRES RAPID RESPONSES VIA POST TRANSLATIONAL MODIFICATIONS (PTM) OF PROTEINS. PROTEIN ARGININE METHYLTRANSFERASE 7 (PRMT7) IS AN EPIGENETIC FACTOR THAT HAS THE CAPACITY TO MONO-METHYLATE HISTONES ON ARGININE RESIDUES. HERE WE SHOW THAT IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) PATIENTS, PRMT7 EXPRESSION IS ELEVATED IN THE LUNG TISSUE AND LOCALIZED TO THE MACROPHAGES. IN MOUSE MODELS OF COPD, LUNG FIBROSIS AND SKIN INJURY, REDUCED EXPRESSION OF PRMT7 ASSOCIATES WITH DECREASED RECRUITMENT OF MONOCYTES TO THE SITE OF INJURY AND HENCE LESS SEVERE SYMPTOMS. MECHANISTICALLY, ACTIVATION OF NF-KAPPAB/RELA IN MONOCYTES INDUCES PRMT7 TRANSCRIPTION AND CONSEQUENTIAL MONO-METHYLATION OF HISTONES AT THE REGULATORY ELEMENTS OF RAP1A, WHICH LEADS TO INCREASED TRANSCRIPTION OF THIS GENE THAT IS RESPONSIBLE FOR ADHESION AND MIGRATION OF MONOCYTES. PERSISTENT MONOCYTE-DERIVED MACROPHAGE ACCUMULATION LEADS TO ALOX5 OVER-EXPRESSION AND ACCUMULATION OF ITS METABOLITE LTB4, WHICH TRIGGERS EXPRESSION OF ACSL4 A FERROPTOSIS PROMOTING GENE IN LUNG EPITHELIAL CELLS. CONCLUSIVELY, INHIBITION OF ARGININE MONO-METHYLATION MIGHT OFFER TARGETED INTERVENTION IN MONOCYTE-DRIVEN INFLAMMATORY CONDITIONS THAT LEAD TO EXTENSIVE TISSUE DAMAGE IF LEFT UNTREATED. 2022 3 1012 32 CIGARETTE SMOKE INDUCES DISTINCT HISTONE MODIFICATIONS IN LUNG CELLS: IMPLICATIONS FOR THE PATHOGENESIS OF COPD AND LUNG CANCER. CIGARETTE SMOKE (CS)-MEDIATED OXIDATIVE STRESS INDUCES SEVERAL SIGNALING CASCADES, INCLUDING KINASES, WHICH RESULTS IN CHROMATIN MODIFICATIONS (HISTONE ACETYLATION/DEACETYLATION AND HISTONE METHYLATION/DEMETHYLATION). WE HAVE PREVIOUSLY REPORTED THAT CS INDUCES CHROMATIN REMODELING IN PRO-INFLAMMATORY GENE PROMOTERS; HOWEVER, THE UNDERLYING SITE-SPECIFIC HISTONE MARKS FORMED IN HISTONES H3 AND H4 DURING CS EXPOSURE IN LUNGS IN VIVO AND IN LUNG CELLS IN VITRO, WHICH CAN EITHER DRIVE GENE EXPRESSION OR REPRESSION, ARE NOT KNOWN. WE HYPOTHESIZE THAT CS EXPOSURE IN MOUSE AND HUMAN BRONCHIAL EPITHELIAL CELLS (H292) CAN CAUSE SITE-SPECIFIC POSTTRANSLATIONAL HISTONE MODIFICATIONS (PTMS) THAT MAY PLAY AN IMPORTANT ROLE IN THE PATHOGENESIS OF CS-INDUCED CHRONIC LUNG DISEASES. WE USED A BOTTOM-UP MASS SPECTROMETRY APPROACH TO IDENTIFY SOME POTENTIALLY NOVEL HISTONE MARKS, INCLUDING ACETYLATION, MONOMETHYLATION, AND DIMETHYLATION, IN SPECIFIC LYSINE AND ARGININE RESIDUES OF HISTONES H3 AND H4 IN MOUSE LUNGS AND H292 CELLS. WE FOUND THAT CS-INDUCED DISTINCT POSTTRANSLATIONAL HISTONE MODIFICATION PATTERNS IN HISTONE H3 AND HISTONE H4 IN LUNG CELLS, WHICH MAY BE CONSIDERED AS USABLE BIOMARKERS FOR CS-INDUCED CHRONIC LUNG DISEASES. THESE IDENTIFIED HISTONE MARKS (HISTONE H3 AND HISTONE H4) MAY PLAY AN IMPORTANT ROLE IN THE EPIGENETIC STATE DURING THE PATHOGENESIS OF SMOKING-INDUCED CHRONIC LUNG DISEASES, SUCH AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND LUNG CANCER. 2014 4 756 34 CARM1 REGULATES SENESCENCE DURING AIRWAY EPITHELIAL CELL INJURY IN COPD PATHOGENESIS. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A LIFE-THREATENING LUNG DISEASE. ALTHOUGH CIGARETTE SMOKE WAS CONSIDERED THE MAIN CAUSE OF DEVELOPMENT, THE HETEROGENEOUS NATURE OF THE DISEASE LEAVES IT UNCLEAR WHETHER OTHER FACTORS CONTRIBUTE TO THE PREDISPOSITION OR IMPAIRED REGENERATION RESPONSE OBSERVED. RECENTLY, EPIGENETIC MODIFICATION HAS EMERGED TO BE A KEY PLAYER IN THE PATHOGENESIS OF COPD. THE ADDITION OF METHYL GROUPS TO ARGININE RESIDUES IN BOTH HISTONE AND NONHISTONE PROTEINS BY PROTEIN ARGININE METHYLTRANSFERASES (PRMTS) IS AN IMPORTANT POSTTRANSLATIONAL EPIGENETIC MODIFICATION EVENT REGULATING CELLULAR PROLIFERATION, DIFFERENTIATION, APOPTOSIS, AND SENESCENCE. HERE, WE HYPOTHESIZE THAT COACTIVATOR-ASSOCIATED ARGININE METHYLTRANSFERASE-1 (CARM1) REGULATES AIRWAY EPITHELIAL CELL INJURY IN COPD PATHOGENESIS BY CONTROLLING CELLULAR SENESCENCE. USING THE NAPHTHALENE (NA)-INDUCED MOUSE MODEL OF AIRWAY EPITHELIAL DAMAGE, WE DEMONSTRATE THAT LOSS OF CC10-POSITIVE CLUB CELLS IS ACCOMPANIED BY A REDUCTION IN CARM1-EXPRESSING CELLS OF THE AIRWAY EPITHELIUM. FURTHERMORE, CARM1 HAPLOINSUFFFICENT MICE SHOWED PERTURBED CLUB CELL REGENERATION FOLLOWING NA TREATMENT. IN ADDITION, CARM1 REDUCTION LED TO DECREASED NUMBERS OF ANTISENESCENT SIRTUIN 1-EXPRESSING CELLS ACCOMPANIED BY HIGHER P21, P16, AND BETA-GALACTOSIDASE-POSITIVE SENESCENT CELLS IN THE MOUSE AIRWAY FOLLOWING NA TREATMENT. IMPORTANTLY, CARM1-SILENCED HUMAN BRONCHIAL EPITHELIAL CELLS SHOWED IMPAIRED WOUND HEALING AND HIGHER BETA-GALACTOSIDASE ACTIVITY. THESE RESULTS DEMONSTRATE THAT CARM1 CONTRIBUTES TO AIRWAY REPAIR AND REGENERATION BY REGULATING AIRWAY EPITHELIAL CELL SENESCENCE. 2019 5 4889 41 OXIDATIVE STRESS AND CHROMATIN REMODELING IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND SMOKING-RELATED DISEASES. SIGNIFICANCE: CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS PREDOMINANTLY A TOBACCO SMOKE-TRIGGERED DISEASE WITH FEATURES OF CHRONIC LOW-GRADE SYSTEMIC INFLAMMATION AND AGING (INFLAMMAGING) OF THE LUNG ASSOCIATED WITH STEROID RESISTANCE INDUCED BY CIGARETTE SMOKE (CS)-MEDIATED OXIDATIVE STRESS. OXIDATIVE STRESS INDUCES VARIOUS KINASE SIGNALING PATHWAYS LEADING TO CHROMATIN MODIFICATIONS (HISTONE ACETYLATION/DEACETYLATION AND HISTONE METHYLATION/DEMETHYLATION) IN INFLAMMATION, SENESCENCE, AND STEROID RESISTANCE. RECENT ADVANCES: HISTONE MONO-, DI-, OR TRI-METHYLATION AT LYSINE RESIDUES RESULT IN EITHER GENE ACTIVATION (H3K4, H3K36, AND H3K79) OR REPRESSION (H3K9, H3K27, AND H3K20). CROSS-TALK OCCURS BETWEEN VARIOUS EPIGENETIC MARKS ON HISTONES AND DNA METHYLATION. BOTH CS AND OXIDANTS ALTER HISTONE ACETYLATION/DEACETYLATION AND METHYLATION/DEMETHYLATION LEADING TO ENHANCED PROINFLAMMATORY GENE EXPRESSION. CHROMATIN MODIFICATIONS OCCUR IN LUNGS OF PATIENTS WITH COPD. HISTONE DEACETYLASE 2 (HDAC2) REDUCTION (LEVELS AND ACTIVITY) IS ASSOCIATED WITH STEROID RESISTANCE IN RESPONSE TO OXIDATIVE STRESS. CRITICAL ISSUES: HISTONE MODIFICATIONS ARE ASSOCIATED WITH DNA DAMAGE/REPAIR AND EPIGENOMIC INSTABILITY AS WELL AS PREMATURE LUNG AGING, WHICH HAVE IMPLICATIONS IN THE PATHOGENESIS OF COPD. HDAC2/SIRTUIN1 (SIRT1)-DEPENDENT CHROMATIN MODIFICATIONS ARE ASSOCIATED WITH DNA DAMAGE-INDUCED INFLAMMATION AND SENESCENCE IN RESPONSE TO CS-MEDIATED OXIDATIVE STRESS. FUTURE DIRECTIONS: UNDERSTANDING CS/OXIDATIVE STRESS-MEDIATED CHROMATIN MODIFICATIONS AND THE CROSS-TALK BETWEEN HISTONE ACETYLATION AND METHYLATION WILL DEMONSTRATE THE INVOLVEMENT OF EPIGENETIC REGULATION OF CHROMATIN REMODELING IN INFLAMMAGING. THIS WILL LEAD TO IDENTIFICATION OF NOVEL EPIGENETIC-BASED THERAPIES AGAINST COPD AND OTHER SMOKING-RELATED LUNG DISEASES. PHARMACOLOGICAL ACTIVATION OF HDAC2/SIRT1 OR REVERSAL OF THEIR OXIDATIVE POST-TRANSLATIONAL MODIFICATIONS MAY OFFER THERAPIES FOR TREATMENT OF COPD AND CS-RELATED DISEASES BASED ON EPIGENETIC HISTONE MODIFICATIONS. 2013 6 4493 37 MORAXELLA CATARRHALIS INDUCES INFLAMMATORY RESPONSE OF BRONCHIAL EPITHELIAL CELLS VIA MAPK AND NF-KAPPAB ACTIVATION AND HISTONE DEACETYLASE ACTIVITY REDUCTION. MORAXELLA CATARRHALIS IS A MAJOR CAUSE OF INFECTIOUS EXACERBATIONS OF CHRONIC OBSTRUCTIVE LUNG DISEASE (COPD) AND MAY ALSO CONTRIBUTE TO THE PATHOGENESIS OF COPD. LITTLE IS KNOWN ABOUT M. CATARRHALIS-BRONCHIAL EPITHELIUM INTERACTION. WE INVESTIGATED ACTIVATION OF M. CATARRHALIS INFECTED BRONCHIAL EPITHELIAL CELLS AND CHARACTERIZED THE SIGNAL TRANSDUCTION PATHWAYS. MOREOVER, WE TESTED THE HYPOTHESIS THAT THE M. CATARRHALIS-INDUCED CYTOKINE EXPRESSION IS REGULATED BY ACETYLATION OF HISTONE RESIDUES AND CONTROLLED BY HISTONE DEACETYLASE ACTIVITY (HDAC). WE DEMONSTRATED THAT M. CATARRHALIS INDUCED A STRONG TIME- AND DOSE-DEPENDENT INFLAMMATORY RESPONSE IN THE BRONCHIAL EPITHELIAL CELL LINE (BEAS-2B), CHARACTERIZED BY THE RELEASE OF IL-8 AND GM-CSF. FOR THIS CYTOKINE LIBERATION ACTIVATION OF THE ERK AND P38 MITOGEN-ACTIVATED PROTEIN (MAP) KINASES AND TRANSCRIPTION FACTOR NF-KAPPAB WAS REQUIRED. FURTHERMORE, M. CATARRHALIS-INFECTED BRONCHIAL EPITHELIAL CELLS SHOWED AN ENHANCED ACETYLATION OF HISTONE H3 AND H4 GLOBALLY AND AT THE PROMOTER OF THE IL8 GENE. PREVENTING HISTONE DEACETYLATION BY THE HISTONE DEACETYLASE INHIBITOR TRICHOSTATIN A AUGMENTED THE M. CATARRHALIS-INDUCED IL-8 RESPONSE. AFTER EXPOSURE TO M. CATARRHALIS, WE FOUND A DECREASE IN GLOBAL HISTONE DEACETYLASE EXPRESSION AND ACTIVITY. OUR FINDINGS SUGGEST THAT M. CATARRHALIS-INDUCED ACTIVATION OF IL8 GENE TRANSCRIPTION WAS CAUSED BY INTERFERENCE WITH EPIGENETIC MECHANISMS REGULATING IL8 GENE ACCESSIBILITY. OUR FINDINGS PROVIDE INSIGHT INTO IMPORTANT MOLECULAR AND CELLULAR MECHANISMS OF M. CATARRHALIS-INDUCED ACTIVATION OF HUMAN BRONCHIAL EPITHELIUM. 2006 7 2352 27 EPIGENETIC REGULATION OF NRF2/KEAP1 BY PHYTOCHEMICALS. EPIGENETICS HAS PROVIDED A NEW DIMENSION TO OUR UNDERSTANDING OF NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2/KELCH-LIKE ECH-ASSOCIATED PROTEIN 1 (HUMAN NRF2/KEAP1 AND MURINE NRF2/KEAP1) SIGNALING. UNLIKE THE GENETIC CHANGES AFFECTING DNA SEQUENCE, THE REVERSIBLE NATURE OF EPIGENETIC ALTERATIONS PROVIDES AN ATTRACTIVE AVENUE FOR CANCER INTERCEPTION. THUS, TARGETING EPIGENETIC MECHANISMS IN THE CORRESPONDING SIGNALING NETWORKS REPRESENTS AN ENTICING STRATEGY FOR THERAPEUTIC INTERVENTION WITH DIETARY PHYTOCHEMICALS ACTING AT TRANSCRIPTIONAL, POST-TRANSCRIPTIONAL, AND POST-TRANSLATIONAL LEVELS. THIS REGULATION INVOLVES THE INTERPLAY OF HISTONE MODIFICATIONS AND DNA METHYLATION STATES IN THE HUMAN NFE2L2/KEAP1 AND MURINE NFE2L2/KEAP1 GENES, ACETYLATION OF LYSINE RESIDUES IN NRF2 AND NRF2, INTERACTION WITH BROMODOMAIN AND EXTRATERMINAL DOMAIN (BET) ACETYL "READER" PROTEINS, AND NON-CODING RNAS SUCH AS MICRORNA (MIRNA) AND LONG NON-CODING RNA (LNCRNA). PHYTOCHEMICALS DOCUMENTED TO MODULATE NRF2 SIGNALING ACT BY REVERSING HYPERMETHYLATED STATES IN THE CPG ISLANDS OF NFE2L2 OR NFE2L2, VIA THE INHIBITION OF DNA METHYLTRANSFERASES (DNMTS) AND HISTONE DEACETYLASES (HDACS), THROUGH THE INDUCTION OF TEN-ELEVEN TRANSLOCATION (TET) ENZYMES, OR BY INDUCING MIRNA TO TARGET THE 3'-UTR OF THE CORRESPONDING MRNA TRANSCRIPTS. TO DATE, FEWER THAN TWENTY PHYTOCHEMICALS HAVE BEEN REPORTED AS NRF2 EPIGENETIC MODIFIERS, INCLUDING CURCUMIN, SULFORAPHANE, RESVERATROL, RESERPINE, AND URSOLIC ACID. THIS OPENS AVENUES FOR EXPLORING ADDITIONAL DIETARY PHYTOCHEMICALS THAT REGULATE THE HUMAN EPIGENOME, AND THE POTENTIAL FOR NOVEL STRATEGIES TO TARGET NRF2 SIGNALING WITH A VIEW TO BENEFICIAL INTERCEPTION OF CANCER AND OTHER CHRONIC DISEASES. 2020 8 1105 31 COMBINED INHIBITION OF HISTONE DEACETYLASES AND BET FAMILY PROTEINS AS EPIGENETIC THERAPY FOR NERVE INJURY-INDUCED NEUROPATHIC PAIN. CURRENT TREATMENTS FOR NEUROPATHIC PAIN HAVE OFTEN MODERATE EFFICACY AND PRESENT UNWANTED EFFECTS SHOWING THE NEED TO DEVELOP EFFECTIVE THERAPIES. ACCUMULATING EVIDENCE SUGGESTS THAT HISTONE ACETYLATION PLAYS ESSENTIAL ROLES IN CHRONIC PAIN AND THE ANALGESIC ACTIVITY OF HISTONE DEACETYLASES (HDACS) INHIBITORS IS DOCUMENTED. BROMODOMAIN AND EXTRA-TERMINAL DOMAIN (BET) PROTEINS ARE EPIGENETIC READERS THAT INTERACT WITH ACETYLATED LYSINE RESIDUES ON HISTONES, BUT LITTLE IS KNOWN ABOUT THEIR IMPLICATION IN NEUROPATHIC PAIN. THUS, THE CURRENT STUDY WAS AIMED TO INVESTIGATE THE EFFECT OF THE COMBINATION OF HDAC AND BET INHIBITORS IN THE SPARED NERVE INJURY (SNI) MODEL IN MICE. INTRANASAL ADMINISTRATION OF I-BET762 (BET INHIBITOR) OR SAHA (HDAC INHIBITOR) ATTENUATED THERMAL AND MECHANICAL HYPERSENSITIVITY AND THIS ANTIALLODYNIC ACTIVITY WAS IMPROVED BY CO-ADMINISTRATION OF BOTH DRUGS. SPINAL CORD SECTIONS OF SNI MICE SHOWED AN INCREASED EXPRESSION OF HDAC1 AND BRD4 PROTEINS AND COMBINATION PRODUCED A STRONGER REDUCTION COMPARED TO EACH EPIGENETIC AGENT ALONE. SAHA AND I-BET762, ADMINISTERED ALONE OR IN COMBINATION, COUNTERACTED THE SNI-INDUCED MICROGLIA ACTIVATION BY INHIBITING THE EXPRESSION OF IBA1, CD11B, INDUCIBLE NITRIC OXIDE SYNTHASE (INOS), THE ACTIVATION OF NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) AND SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION-1 (STAT1) WITH COMPARABLE EFFICACY. CONVERSELY, THE EPIGENETIC INHIBITORS SHOWED A MODEST EFFECT ON SPINAL PROINFLAMMATORY CYTOKINES CONTENT THAT WAS SIGNIFICANTLY POTENTIATED BY THEIR COMBINATION. PRESENT RESULTS INDICATE A KEY ROLE OF ACETYLATED HISTONES AND THEIR RECRUITMENT BY BET PROTEINS ON MICROGLIA-MEDIATED SPINAL NEUROINFLAMMATION. TARGETING NEUROPATHIC PAIN WITH THE COMBINATION OF HDAC AND BET INHIBITORS MAY REPRESENT A PROMISING NEW THERAPEUTIC OPTION. 2021 9 482 30 ARSENITE BINDS TO THE ZINC FINGER MOTIF OF TIP60 HISTONE ACETYLTRANSFERASE AND INDUCES ITS DEGRADATION VIA THE 26S PROTEASOME. ARSENIC IS A UBIQUITOUS ENVIRONMENTAL CONTAMINANT WITH WIDESPREAD PUBLIC HEALTH CONCERN. EPIDEMIOLOGICAL STUDIES HAVE REVEALED THAT CHRONIC HUMAN EXPOSURE TO ARSENIC IN DRINKING WATER IS ASSOCIATED WITH THE PREVALENCE OF SKIN, LUNG, AND BLADDER CANCERS. ABERRANT HISTONE MODIFICATIONS (E.G., METHYLATION, ACETYLATION, AND UBIQUITINATION) WERE PREVIOUSLY FOUND TO BE ACCOMPANIED BY ARSENIC EXPOSURE; THUS, PERTURBATION OF EPIGENETIC PATHWAYS IS THOUGHT TO CONTRIBUTE TO ARSENIC CARCINOGENESIS. ARSENITE IS KNOWN TO INTERACT WITH ZINC FINGER MOTIFS OF PROTEINS, AND ZINC FINGER MOTIF IS PRESENT IN AND INDISPENSABLE FOR THE ENZYMATIC ACTIVITIES OF CRUCIAL HISTONE-MODIFYING ENZYMES ESPECIALLY THE MYST FAMILY OF HISTONE ACETYLTRANSFERASES (E.G., TIP60). HENCE, WE REASONED THAT TRIVALENT ARSENIC MAY TARGET THE ZINC FINGER MOTIF OF THESE ENZYMES, DISTURB THEIR ENZYMATIC ACTIVITIES, AND ALTER HISTONE ACETYLATION. HEREIN, WE FOUND THAT AS(3+) COULD BIND DIRECTLY TO THE ZINC-FINGER MOTIF OF TIP60 IN VITRO AND IN CELLS. IN ADDITION, EXPOSURE TO AS(3+) COULD LEAD TO A DOSE-DEPENDENT DECREASE IN TIP60 PROTEIN LEVEL VIA THE UBIQUITIN-PROTEASOME PATHWAY. THUS, THE RESULTS FROM THE PRESENT STUDY REVEALED, FOR THE FIRST TIME, THAT ARSENITE MAY TARGET CYSTEINE RESIDUES IN THE ZINC-FINGER MOTIF OF THE TIP60 HISTONE ACETYLTRANSFERASE, THEREBY ALTERING THE H4K16AC HISTONE EPIGENETIC MARK. OUR RESULTS ALSO SHED SOME NEW LIGHT ON THE MECHANISMS UNDERLYING THE ARSENIC-INDUCED EPIGENOTOXICITY AND CARCINOGENESIS IN HUMANS. 2017 10 6176 24 THE HISTONE H3 LYSINE-27 DEMETHYLASE JMJD3 LINKS INFLAMMATION TO INHIBITION OF POLYCOMB-MEDIATED GENE SILENCING. EPIGENETIC CHROMATIN MARKS RESTRICT THE ABILITY OF DIFFERENTIATED CELLS TO CHANGE GENE EXPRESSION PROGRAMS IN RESPONSE TO ENVIRONMENTAL CUES AND TO TRANSDIFFERENTIATE. POLYCOMB GROUP (PCG) PROTEINS MEDIATE GENE SILENCING AND REPRESS TRANSDIFFERENTIATION IN A MANNER DEPENDENT ON HISTONE H3 LYSINE 27 TRIMETHYLATION (H3K27ME3). HOWEVER, MACROPHAGES MIGRATED INTO INFLAMED TISSUES CAN TRANSDIFFERENTIATE, BUT IT IS UNKNOWN WHETHER INFLAMMATION ALTERS PCG-DEPENDENT SILENCING. HERE WE SHOW THAT THE JMJC-DOMAIN PROTEIN JMJD3 IS A H3K27ME DEMETHYLASE EXPRESSED IN MACROPHAGES IN RESPONSE TO BACTERIAL PRODUCTS AND INFLAMMATORY CYTOKINES. JMJD3 BINDS PCG TARGET GENES AND REGULATES THEIR H3K27ME3 LEVELS AND TRANSCRIPTIONAL ACTIVITY. THE DISCOVERY OF AN INDUCIBLE ENZYME THAT ERASES A HISTONE MARK CONTROLLING DIFFERENTIATION AND CELL IDENTITY PROVIDES A LINK BETWEEN INFLAMMATION AND REPROGRAMMING OF THE EPIGENOME, WHICH COULD BE THE BASIS FOR MACROPHAGE PLASTICITY AND MIGHT EXPLAIN THE DIFFERENTIATION ABNORMALITIES IN CHRONIC INFLAMMATION. 2007 11 6321 21 THE ROLE AND MECHANISM OF LYSINE METHYLTRANSFERASE AND ARGININE METHYLTRANSFERASE IN KIDNEY DISEASES. METHYLATION CAN OCCUR IN BOTH HISTONES AND NON-HISTONES. KEY LYSINE AND ARGININE METHYLTRANSFERASES UNDER INVESTIGATION FOR RENAL DISEASE TREATMENT INCLUDE ENHANCER OF ZESTE HOMOLOG 2 (EZH2), G9A, DISRUPTOR OF TELOMERIC SILENCING 1-LIKE PROTEIN (DOT1L), AND PROTEIN ARGININE METHYLTRANSFERASES (PRMT) 1 AND 5. RECENT STUDIES HAVE SHOWN THAT METHYLTRANSFERASES EXPRESSION AND ACTIVITY ARE ALSO INCREASED IN SEVERAL ANIMAL MODELS OF KIDNEY INJURY, SUCH AS ACUTE KIDNEY INJURY(AKI), OBSTRUCTIVE NEPHROPATHY, DIABETIC NEPHROPATHY AND LUPUS NEPHRITIS. THE INHIBITION OF MOST METHYLTRANSFERASES CAN ATTENUATE KIDNEY INJURY, WHILE THE ROLE OF METHYLTRANSFERASE IN DIFFERENT ANIMAL MODELS REMAINS CONTROVERSIAL. IN THIS ARTICLE, WE SUMMARIZE THE ROLE AND MECHANISM OF LYSINE METHYLTRANSFERASE AND ARGININE METHYLTRANSFERASE IN VARIOUS KIDNEY DISEASES AND HIGHLIGHT METHYLTRANSFERASE AS A POTENTIAL THERAPEUTIC TARGET FOR KIDNEY DISEASES. 2022 12 1251 31 CURRENT PERSPECTIVES ON ROLE OF CHROMATIN MODIFICATIONS AND DEACETYLASES IN LUNG INFLAMMATION IN COPD. CHROMATIN MODIFICATIONS AND EPIGENETIC REGULATION ARE CRITICAL FOR SUSTAINED AND ABNORMAL INFLAMMATORY RESPONSE SEEN IN LUNGS OF PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) BECAUSE THE ACTIVITIES OF ENZYMES THAT REGULATE THESE EPIGENETIC MODIFICATIONS ARE ALTERED IN RESPONSE TO CIGARETTE SMOKE. CIGARETTE SMOKE INDUCES CHROMATIN MODIFICATIONS AND EPIGENETIC CHANGES BY CAUSING POST-TRANSLATIONAL MODIFICATIONS OF HISTONE ACETYLTRANSFERASES, AND HISTONE/NON-HISTONE DEACETYLASES (HDACS), SUCH AS HDAC2 AND SIRTUIN 1 (SIRT1), WHICH LEADS TO CHROMATIN REMODELING. IN THIS REVIEW, WE DISCUSSED THE CURRENT KNOWLEDGE ON CIGARETTE SMOKE/OXIDANTS-INDUCED POST-TRANSLATIONAL MODIFICATIONS OF DEACETYLASES (HDAC2 AND SIRT1), DISRUPTION OF HDAC2/SIRT1-RELA/P65 COREPRESSOR COMPLEX ASSOCIATED WITH ACETYLATION OF RELA/P65, AND CHROMATIN MODIFICATIONS (HISTONE H3 PHOSPHO-ACETYLATION) LEADING TO SUSTAINED PRO-INFLAMMATORY GENE TRANSCRIPTION. KNOWLEDGE ON MOLECULAR MECHANISMS OF EPIGENETIC CHANGES IN ABNORMAL LUNG INFLAMMATION WILL HELP IN UNDERSTANDING THE PATHOPHYSIOLOGY OF COPD WHICH MAY LEAD TO THE DEVELOPMENT OF NOVEL EPIGENETIC THERAPIES IN THE NEAR FUTURE. 2009 13 3360 28 HISTONE H4K20 TRIMETHYLATION IS DECREASED IN MURINE MODELS OF HEART DISEASE. HEART DISEASE IS THE LEADING CAUSE OF DEATH IN THE DEVELOPED WORLD, AND ITS COMORBIDITIES SUCH AS HYPERTENSION, DIABETES, AND HEART FAILURE ARE ACCOMPANIED BY MAJOR TRANSCRIPTOMIC CHANGES IN THE HEART. DURING CARDIAC DYSFUNCTION, WHICH LEADS TO HEART FAILURE, THERE ARE GLOBAL EPIGENETIC ALTERATIONS TO CHROMATIN THAT OCCUR CONCOMITANTLY WITH MORPHOLOGICAL CHANGES IN THE HEART IN RESPONSE TO ACUTE AND CHRONIC STRESS. THESE EPIGENETIC ALTERATIONS INCLUDE THE REVERSIBLE METHYLATION OF LYSINE RESIDUES ON HISTONE PROTEINS. LYSINE METHYLATIONS ON HISTONES H3K4 AND H3K9 WERE AMONG THE FIRST METHYLATED LYSINE RESIDUES IDENTIFIED AND HAVE BEEN LINKED TO GENE ACTIVATION AND SILENCING, RESPECTIVELY. HOWEVER, MUCH LESS IS KNOWN REGARDING OTHER METHYLATED HISTONE RESIDUES, INCLUDING HISTONE H4K20. TRIMETHYLATION OF HISTONE H4K20 HAS BEEN SHOWN TO REPRESS GENE EXPRESSION; HOWEVER, THIS MODIFICATION HAS NEVER BEEN EXAMINED IN THE HEART. HERE, WE UTILIZED IMMUNOBLOTTING AND MASS SPECTROMETRY TO QUANTIFY HISTONE H4K20 TRIMETHYLATION IN THREE MODELS OF CARDIAC DYSFUNCTION. OUR RESULTS SHOW THAT LYSINE METHYLATION AT THIS SITE IS DIFFERENTIALLY REGULATED IN THE CARDIOMYOCYTE, LEADING TO INCREASED H4K20 TRIMETHYLATION DURING ACUTE HYPERTROPHIC STRESS IN CELL MODELS AND DECREASED H4K20 TRIMETHYLATION DURING SUSTAINED ISCHEMIC INJURY AND CARDIAC DYSFUNCTION IN ANIMAL MODELS. IN ADDITION, WE EXAMINED PUBLICLY AVAILABLE DATA SETS TO ANALYZE ENZYMES THAT REGULATE H4K20 METHYLATION AND IDENTIFIED TWO DEMETHYLASES (KDM7B AND KDM7C) AND TWO METHYLTRANSFERASES (KMT5A AND SMYD5) THAT WERE ALL DIFFERENTIALLY EXPRESSED IN HEART FAILURE PATIENTS. THIS IS THE FIRST STUDY TO EXAMINE HISTONE H4K20 TRIMETHYLATION IN THE HEART AND TO DETERMINE HOW THIS POST-TRANSLATIONAL MODIFICATION IS DIFFERENTIALLY REGULATED IN MULTIPLE MODELS OF CARDIAC DISEASE. 2022 14 697 29 BROMODOMAIN AND EXTRATERMINAL PROTEINS AS NOVEL EPIGENETIC TARGETS FOR RENAL DISEASES. EPIGENETIC MECHANISMS, ESPECIALLY DNA METHYLATION AND HISTONE MODIFICATIONS, ARE DYNAMIC PROCESSES THAT REGULATE THE GENE EXPRESSION TRANSCRIPTIONAL PROGRAM IN NORMAL AND DISEASED STATES. THE BROMODOMAIN AND EXTRATERMINAL (BET) PROTEIN FAMILY (BRD2, BRD3, BRD4, AND BRDT) ARE EPIGENETIC READERS THAT, VIA BROMODOMAINS, REGULATE GENE TRANSCRIPTION BY BINDING TO ACETYLATED LYSINE RESIDUES ON HISTONES AND MASTER TRANSCRIPTIONAL FACTORS. EXPERIMENTAL DATA HAVE DEMONSTRATED THE INVOLVEMENT OF SOME BET PROTEINS IN MANY PATHOLOGICAL CONDITIONS, INCLUDING TUMOR DEVELOPMENT, INFECTIONS, AUTOIMMUNITY, AND INFLAMMATION. SELECTIVE BROMODOMAIN INHIBITORS ARE EPIGENETIC DRUGS THAT BLOCK THE INTERACTION BETWEEN BET PROTEINS AND ACETYLATED PROTEINS, THUS EXERTING BENEFICIAL EFFECTS. RECENT DATA HAVE DESCRIBED THE BENEFICIAL EFFECT OF BET INHIBITION ON EXPERIMENTAL RENAL DISEASES. EMERGING EVIDENCE UNDERSCORES THE IMPORTANCE OF ENVIRONMENTAL MODIFICATIONS IN THE ORIGIN OF PATHOLOGICAL FEATURES IN CHRONIC KIDNEY DISEASES (CKD). SEVERAL CELLULAR PROCESSES SUCH AS OXIDATION, METABOLIC DISORDERS, CYTOKINES, INFLAMMATION, OR ACCUMULATED UREMIC TOXINS MAY INDUCE EPIGENETIC MODIFICATIONS THAT REGULATE KEY PROCESSES INVOLVED IN RENAL DAMAGE AND IN OTHER PATHOLOGICAL CONDITIONS OBSERVED IN CKD PATIENTS. HERE, WE REVIEW HOW TARGETING BROMODOMAINS IN BET PROTEINS MAY REGULATE ESSENTIAL PROCESSES INVOLVED IN RENAL DISEASES AND IN ASSOCIATED COMPLICATIONS FOUND IN CKD PATIENTS, SUCH AS CARDIOVASCULAR DAMAGE, HIGHLIGHTING THE POTENTIAL OF EPIGENETIC THERAPEUTIC STRATEGIES AGAINST BET PROTEINS FOR CKD TREATMENT AND ASSOCIATED RISKS. 2019 15 2910 37 GENE EXPRESSION PROFILING OF EPIGENETIC CHROMATIN MODIFICATION ENZYMES AND HISTONE MARKS BY CIGARETTE SMOKE: IMPLICATIONS FOR COPD AND LUNG CANCER. CHROMATIN-MODIFYING ENZYMES MEDIATE DNA METHYLATION AND HISTONE MODIFICATIONS ON RECRUITMENT TO SPECIFIC TARGET GENE LOCI IN RESPONSE TO VARIOUS STIMULI. THE KEY ENZYMES THAT REGULATE CHROMATIN ACCESSIBILITY FOR MAINTENANCE OF MODIFICATIONS IN DNA AND HISTONES, AND FOR MODULATION OF GENE EXPRESSION PATTERNS IN RESPONSE TO CIGARETTE SMOKE (CS), ARE NOT KNOWN. WE HYPOTHESIZE THAT CS EXPOSURE ALTERS THE GENE EXPRESSION PATTERNS OF CHROMATIN-MODIFYING ENZYMES, WHICH THEN AFFECTS MULTIPLE DOWNSTREAM PATHWAYS INVOLVED IN THE RESPONSE TO CS. WE HAVE, THEREFORE, ANALYZED CHROMATIN-MODIFYING ENZYME PROFILES AND VALIDATED BY QUANTITATIVE REAL-TIME PCR (QPCR). WE ALSO PERFORMED IMMUNOBLOT ANALYSIS OF TARGETED HISTONE MARKS IN C57BL/6J MICE EXPOSED TO ACUTE AND SUBCHRONIC CS, AND OF LUNGS FROM NONSMOKERS, SMOKERS, AND PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). WE FOUND A SIGNIFICANT INCREASE IN EXPRESSION OF SEVERAL CHROMATIN MODIFICATION ENZYMES, INCLUDING DNA METHYLTRANSFERASES, HISTONE ACETYLTRANSFERASES, HISTONE METHYLTRANSFERASES, AND SET DOMAIN PROTEINS, HISTONE KINASES, AND UBIQUITINASES. OUR QPCR VALIDATION DATA REVEALED A SIGNIFICANT DOWNREGULATION OF DNMT1, DNMT3A, DNMT3B, HDAC2, HDAC4, HAT1, PRMT1, AND AURKB WE IDENTIFIED TARGETED CHROMATIN HISTONE MARKS (H3K56AC AND H4K12AC), WHICH ARE INDUCED BY CS. THUS CS-INDUCED GENOTOXIC STRESS DIFFERENTIALLY AFFECTS THE EXPRESSION OF EPIGENETIC MODULATORS THAT REGULATE TRANSCRIPTION OF TARGET GENES VIA DNA METHYLATION AND SITE-SPECIFIC HISTONE MODIFICATIONS. THIS MAY HAVE IMPLICATIONS IN DEVISING EPIGENETIC-BASED THERAPIES FOR COPD AND LUNG CANCER. 2016 16 2370 21 EPIGENETIC REGULATION OF THE ALTERNATIVELY ACTIVATED MACROPHAGE PHENOTYPE. ALTERNATIVELY ACTIVATED (M2) MACROPHAGES PLAY CRITICAL ROLES IN DIVERSE CHRONIC DISEASES, INCLUDING PARASITE INFECTIONS, CANCER, AND ALLERGIC RESPONSES. HOWEVER, LITTLE IS KNOWN ABOUT THE ACQUISITION AND MAINTENANCE OF THEIR PHENOTYPE. WE REPORT THAT M2-MACROPHAGE MARKER GENES ARE EPIGENETICALLY REGULATED BY RECIPROCAL CHANGES IN HISTONE H3 LYSINE-4 (H3K4) AND HISTONE H3 LYSINE-27 (H3K27) METHYLATION; AND THE LATTER METHYLATION MARKS ARE REMOVED BY THE H3K27 DEMETHYLASE JUMONJI DOMAIN CONTAINING 3 (JMJD3). WE FOUND THAT CONTINUOUS INTERLEUKIN-4 (IL-4) TREATMENT LEADS TO DECREASED H3K27 METHYLATION, AT THE PROMOTER OF M2 MARKER GENES, AND A CONCOMITANT INCREASE IN JMJD3 EXPRESSION. FURTHERMORE, WE DEMONSTRATE THAT IL-4-DEPENDENT JMJD3 EXPRESSION IS MEDIATED BY STAT6, A MAJOR TRANSCRIPTION FACTOR OF IL-4-MEDIATED SIGNALING. AFTER IL-4 STIMULATION, ACTIVATED STAT6 IS INCREASED AND BINDS TO CONSENSUS SITES AT THE JMJD3 PROMOTER. INCREASED JMJD3 CONTRIBUTES TO THE DECREASE OF H3K27 DIMETHYLATION AND TRIMETHYLATION (H3K27ME2/3) MARKS AS WELL AS THE TRANSCRIPTIONAL ACTIVATION OF SPECIFIC M2 MARKER GENES. THE DECREASE IN H3K27ME2/3 AND INCREASE IN JMJD3 RECRUITMENT WERE CONFIRMED BY IN VIVO STUDIES USING A SCHISTOSOMA MANSONI EGG-CHALLENGED MOUSE MODEL, A WELL-STUDIED SYSTEM KNOWN TO SUPPORT AN M2 PHENOTYPE. COLLECTIVELY, THESE DATA INDICATE THAT CHROMATIN REMODELING IS MECHANISTICALLY IMPORTANT IN THE ACQUISITION OF THE M2-MACROPHAGE PHENOTYPE. 2009 17 689 36 BRD4 AS A THERAPEUTIC TARGET IN PULMONARY DISEASES. BROMODOMAIN AND EXTRA-TERMINAL DOMAIN (BET) PROTEINS ARE EPIGENETIC MODULATORS THAT REGULATE GENE TRANSCRIPTION THROUGH INTERACTING WITH ACETYLATED LYSINE RESIDUES OF HISTONE PROTEINS. BET PROTEINS HAVE MULTIPLE ROLES IN REGULATING KEY CELLULAR FUNCTIONS SUCH AS CELL PROLIFERATION, DIFFERENTIATION, INFLAMMATION, OXIDATIVE AND REDOX BALANCE, AND IMMUNE RESPONSES. AS A RESULT, BET PROTEINS HAVE BEEN FOUND TO BE ACTIVELY INVOLVED IN A BROAD RANGE OF HUMAN LUNG DISEASES INCLUDING ACUTE LUNG INFLAMMATION, ASTHMA, PULMONARY ARTERIAL HYPERTENSION, PULMONARY FIBROSIS, AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). DUE TO THE IDENTIFICATION OF SPECIFIC SMALL MOLECULAR INHIBITORS OF BET PROTEINS, TARGETING BET IN THESE LUNG DISEASES HAS BECOME AN AREA OF INCREASING INTEREST. EMERGING EVIDENCE HAS DEMONSTRATED THE BENEFICIAL EFFECTS OF BET INHIBITORS IN PRECLINICAL MODELS OF VARIOUS HUMAN LUNG DISEASES. THIS IS, IN GENERAL, LARGELY RELATED TO THE ABILITY OF BET PROTEINS TO BIND TO PROMOTERS OF GENES THAT ARE CRITICAL FOR INFLAMMATION, DIFFERENTIATION, AND BEYOND. BY MODULATING THESE CRITICAL GENES, BET PROTEINS ARE INTEGRATED INTO THE PATHOGENESIS OF DISEASE PROGRESSION. THE INTRINSIC HISTONE ACETYLTRANSFERASE ACTIVITY OF BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) IS OF PARTICULAR INTEREST, SEEMS TO ACT INDEPENDENTLY OF ITS BROMODOMAIN BINDING ACTIVITY, AND HAS IMPLICATION IN SOME CONTEXTS. IN THIS REVIEW, WE PROVIDE A BRIEF OVERVIEW OF THE RESEARCH ON BET PROTEINS WITH A FOCUS ON BRD4 IN SEVERAL MAJOR HUMAN LUNG DISEASES, THE UNDERLYING MOLECULAR MECHANISMS, AS WELL AS FINDINGS OF TARGETING BET PROTEINS USING PHARMACEUTICAL INHIBITORS IN DIFFERENT LUNG DISEASES PRECLINICALLY. 2023 18 699 25 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 19 3527 23 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 20 589 27 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