1 756 122 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 2 1251 25 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 3 1012 38 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 1326 23 DEPLETION OF NUCLEAR HISTONE H2A VARIANTS IS ASSOCIATED WITH CHRONIC DNA DAMAGE SIGNALING UPON DRUG-EVOKED SENESCENCE OF HUMAN SOMATIC CELLS. CELLULAR SENESCENCE IS ASSOCIATED WITH GLOBAL CHROMATIN CHANGES, ALTERED GENE EXPRESSION, AND ACTIVATION OF CHRONIC DNA DAMAGE SIGNALING. THESE EVENTS ULTIMATELY LEAD TO MORPHOLOGICAL AND PHYSIOLOGICAL TRANSFORMATIONS IN PRIMARY CELLS. IN THIS STUDY, WE SHOW THAT CHRONIC DNA DAMAGE SIGNALS CAUSED BY GENOTOXIC STRESS IMPACT THE EXPRESSION OF HISTONES H2A FAMILY MEMBERS AND LEAD TO THEIR DEPLETION IN THE NUCLEI OF SENESCENT HUMAN FIBROBLASTS. OUR DATA REINFORCE THE HYPOTHESIS THAT PROGRESSIVE CHROMATIN DESTABILIZATION MAY LEAD TO THE LOSS OF EPIGENETIC INFORMATION AND IMPAIRED CELLULAR FUNCTION ASSOCIATED WITH CHRONIC DNA DAMAGE UPON DRUG-EVOKED SENESCENCE. WE PROPOSE THAT CHANGES IN THE HISTONE BIOSYNTHESIS AND CHROMATIN ASSEMBLY MAY DIRECTLY CONTRIBUTE TO CELLULAR AGING. IN ADDITION, WE ALSO OUTLINE THE METHOD THAT ALLOWS FOR QUANTITATIVE AND UNBIASED MEASUREMENT OF THESE CHANGES. 2012 5 172 28 ABSENCE OF HDAC3 BY MATRIX STIFFNESS PROMOTES CHROMATIN REMODELING AND FIBROBLAST ACTIVATION IN IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC AND FATAL DISEASE CHARACTERIZED BY PROGRESSIVE AND IRREVERSIBLE LUNG SCARRING ASSOCIATED WITH PERSISTENT ACTIVATION OF FIBROBLASTS. EPIGENETICS COULD INTEGRATE DIVERSE MICROENVIRONMENTAL SIGNALS, SUCH AS STIFFNESS, TO DIRECT PERSISTENT FIBROBLAST ACTIVATION. HISTONE MODIFICATIONS BY DEACETYLASES (HDAC) MAY PLAY AN ESSENTIAL ROLE IN THE GENE EXPRESSION CHANGES INVOLVED IN THE PATHOLOGICAL REMODELING OF THE LUNG. PARTICULARLY, HDAC3 IS CRUCIAL FOR MAINTAINING CHROMATIN AND REGULATING GENE EXPRESSION, BUT LITTLE IS KNOWN ABOUT ITS ROLE IN IPF. IN THE STUDY, CONTROL AND IPF-DERIVED FIBROBLASTS WERE USED TO DETERMINE THE INFLUENCE OF HDAC3 ON CHROMATIN REMODELING AND GENE EXPRESSION ASSOCIATED WITH IPF SIGNATURE. ADDITIONALLY, THE CELLS WERE GROWN ON HYDROGELS TO MIMIC THE STIFFNESS OF A FIBROTIC LUNG. OUR RESULTS SHOWED A DECREASED HDAC3 IN THE NUCLEUS OF IPF FIBROBLASTS, WHICH CORRELATES WITH CHANGES IN NUCLEUS SIZE AND HETEROCHROMATIN LOSS. THE INHIBITION OF HDAC3 WITH A PHARMACOLOGICAL INHIBITOR CAUSES HYPERACETYLATION OF H3K9 AND PROVOKES AN INCREASED EXPRESSION OF COL1A1, ACTA2, AND P21. COMPARABLE RESULTS WERE FOUND IN HYDROGELS, WHERE MATRIX STIFFNESS PROMOTES THE LOSS OF NUCLEAR HDAC3 AND INCREASES THE PROFIBROTIC SIGNATURE. FINALLY, LATRUNCULIN B WAS USED TO CONFIRM THAT CHANGES BY STIFFNESS DEPEND ON THE MECHANOTRANSDUCTION SIGNALS. TOGETHER, THESE RESULTS SUGGEST THAT HDAC3 COULD BE A LINK BETWEEN EPIGENETIC MECHANISMS AND THE FIBROTIC MICROENVIRONMENT. 2023 6 1708 39 DYSFUNCTION OF ENDOTHELIAL PROGENITOR CELLS FROM SMOKERS AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE PATIENTS DUE TO INCREASED DNA DAMAGE AND SENESCENCE. CARDIOVASCULAR DISEASE (CVD) IS A MAJOR CAUSE OF DEATH IN SMOKERS, PARTICULARLY IN THOSE WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). CIRCULATING ENDOTHELIAL PROGENITOR CELLS (EPC) ARE REQUIRED FOR ENDOTHELIAL HOMEOSTASIS, AND THEIR DYSFUNCTION CONTRIBUTES TO CVD. TO INVESTIGATE EPC DYSFUNCTION IN SMOKERS, WE ISOLATED AND EXPANDED BLOOD OUTGROWTH ENDOTHELIAL CELLS (BOEC) FROM PERIPHERAL BLOOD SAMPLES FROM HEALTHY NONSMOKERS, HEALTHY SMOKERS, AND COPD PATIENTS. BOEC FROM SMOKERS AND COPD PATIENTS SHOWED INCREASED DNA DOUBLE-STRAND BREAKS AND SENESCENCE COMPARED TO NONSMOKERS. SENESCENCE NEGATIVELY CORRELATED WITH THE EXPRESSION AND ACTIVITY OF SIRTUIN-1 (SIRT1), A PROTEIN DEACETYLASE THAT PROTECTS AGAINST DNA DAMAGE AND CELLULAR SENESCENCE. INHIBITION OF DNA DAMAGE RESPONSE BY SILENCING OF ATAXIA TELANGIECTASIA MUTATED (ATM) KINASE RESULTED IN UPREGULATION OF SIRT1 EXPRESSION AND DECREASED SENESCENCE. TREATMENT OF BOEC FROM COPD PATIENTS WITH THE SIRT1 ACTIVATOR RESVERATROL OR AN ATM INHIBITOR (KU-55933) ALSO RESCUED THE SENESCENT PHENOTYPE. USING AN IN VIVO MOUSE MODEL OF ANGIOGENESIS, WE DEMONSTRATED THAT SENESCENT BOEC FROM COPD PATIENTS ARE DYSFUNCTIONAL, DISPLAYING IMPAIRED ANGIOGENIC ABILITY AND INCREASED APOPTOSIS COMPARED TO CELLS FROM HEALTHY NONSMOKERS. THEREFORE, THIS STUDY IDENTIFIES EPIGENETIC REGULATION OF DNA DAMAGE AND SENESCENCE AS PATHOGENETIC MECHANISMS LINKED TO ENDOTHELIAL PROGENITORS' DYSFUNCTION IN SMOKERS AND COPD PATIENTS. THESE DEFECTS MAY CONTRIBUTE TO VASCULAR DISEASE AND CARDIOVASCULAR EVENTS IN SMOKERS AND COULD THEREFORE CONSTITUTE THERAPEUTIC TARGETS FOR INTERVENTION. 2013 7 5418 40 REGULATION OF DNA METHYLATION SIGNATURES ON NF-KAPPAB AND STAT3 PATHWAY GENES AND TET ACTIVITY IN CIGARETTE SMOKE EXTRACT-CHALLENGED CELLS/COPD EXACERBATION MODEL IN VITRO. BACKGROUND: CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A GLOBAL HEALTH PROBLEM. CURRENTLY, THERE IS A LACK OF KNOWLEDGE ABOUT THE PATHOBIOLOGY OF THIS DISEASE AND AVAILABLE THERAPIES ARE INEFFECTIVE. CIGARETTE SMOKING IS THE LEADING CAUSE OF COPD; HOWEVER, NOT ALL SMOKERS DEVELOP COPD. EXACERBATIONS OF COPD CAUSED BY MICROBES ARE COMMON AND DETRIMENTAL. APPROXIMATELY 20-50% OF PATIENT EXACERBATIONS ARE CAUSED BY BACTERIAL COLONIZATION IN THE LOWER AIRWAYS. IT IS GENERALLY ACCEPTED THAT EPIGENETIC MECHANISMS, ESPECIALLY DNA METHYLATION, PLAY AN IMPORTANT ROLE DURING PROGRESSION OF COPD. THUS, WE HYPOTHESIZED THAT DNA METHYLATION PATTERNS VARY SIGNIFICANTLY FOLLOWING SMOKE EXPOSURE AND DURING EXACERBATIONS CAUSED BY BACTERIAL INFECTIONS. TO TEST OUR HYPOTHESIS, WE USED AN IN VITRO STUDY MODEL THAT MIMICS COPD EXACERBATIONS AND PERFORMED EXTENSIVE STUDIES TO UNDERSTAND THE ROLE OF CPG PROMOTER METHYLATION OF NF-KAPPAB AND STAT3-MEDIATED PATHWAY GENES. BOTH NF-KAPPAB AND STAT3 TRANSCRIPTION FACTORS PLAY CRITICAL ROLES IN ORCHESTRATING INFLAMMATORY RESPONSES DURING CIGARETTE SMOKE EXPOSURE. IN BRIEF, HUMAN LUNG ADENOCARCINOMA CELLS WITH TYPE II ALVEOLAR EPITHELIUM CHARACTERISTICS (A549) WERE CHALLENGED WITH CIGARETTE SMOKE EXTRACT (CSE) OR DMSO (CONTROL) FOLLOWED BY A 3-H CHALLENGE WITH BACTERIAL LIPOPOLYSACCHARIDE (LPS; FROM PSEUDOMONAS AERUGINOSA) PRIOR TO THE TERMINATION OF CSE EXPOSURE (COPD EXACERBATION GROUP). THE PRODUCTION OF CYTOKINES/CHEMOKINES, REGULATION OF TRANSCRIPTION FACTORS, AND DNA METHYLATION OF SPECIFIC GENES WERE THEN ASSESSED. WE ALSO STUDIED CHANGES IN THE EXPRESSION AND ACTIVITY OF TEN-ELEVEN TRANSLOCASES (TETS), THE ENZYMES RESPONSIBLE FOR DNA DEMETHYLATION, AND ASSESSED THEIR ROLE IN REGULATING DNA METHYLATION IN THE CSE-CHALLENGED GROUP. RESULTS: THERE WAS A SIGNIFICANT INCREASE IN THE RELEASE OF CYTOKINES/CHEMOKINES (IL-8, MCP-1, IL-6 AND CCL5) IN THE COPD EXACERBATION GROUP AS COMPARED TO THE CONTROL GROUP. HYPOMETHYLATION OF NF-KAPPAB-MEDIATED PATHWAY GENES CORRELATED WITH THEIR INDUCTION IN OUR COPD EXACERBATION STUDY MODEL. FURTHER, WE OBSERVED AN IMPORTANT ROLE OF TET1/2 IN REGULATING THE DNA METHYLATION OF NF-KAPPAB, STAT3, IKK, AND NIK GENES AND CYTOKINE/CHEMOKINE PRODUCTION BY A549 CELLS DURING CSE CHALLENGE. CONCLUSIONS: STUDIES TO FURTHER DEFINE THE ROLE OF TETS IN CSE-MEDIATED EPIGENETIC REGULATION MAY LEAD TO THE DEVELOPMENT OF BETTER AND MORE EFFECTIVE THERAPEUTIC INTERVENTION STRATEGIES FOR COPD. 2020 8 3193 34 HDAC INHIBITION REGULATES OXIDATIVE STRESS IN CD4(+)THELPER CELLS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND NON-SMALL CELL LUNG CANCER PATIENTS VIA MITOCHONDRIAL TRANSCRIPTION FACTOR A (MTTFA) MODULATING NF-KAPPAB/HIF1ALPHA AXIS. HISTONE DEACETYLASES (HDACS) PLAY A CRUCIAL ROLE IN THE EPIGENETIC REGULATION OF GENE EXPRESSION BY REMODELLING CHROMATIN. ISOENZYMES OF THE HDAC FAMILY EXHIBIT ABERRANT REGULATION IN A WIDE VARIETY OF CANCERS AS WELL AS SEVERAL INFLAMMATORY LUNG DISORDERS LIKE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). INHIBITION OF HDACS IS A POTENTIAL THERAPEUTIC STRATEGY THAT COULD BE USED TO REVERSE EPIGENETIC MODIFICATION. TRICHOSTATIN A (TSA), A POWERFUL HISTONE DEACETYLASE (HDAC) INHIBITOR, HAS ANTI-CANCER EFFECTS IN NUMEROUS CANCER TYPES. HOWEVER, IT IS NOT YET APPARENT HOW HDAC INHIBITORS AFFECT HUMAN NON-SMALL CELL LUNG CANCER CELLS (NSCLC) AND COPD. THIS STUDY AIMS TO INVESTIGATE TSA'S ROLE IN RESTORING MITOCHONDRIAL DYSFUNCTION AND ITS EFFECT ON HYPOXIA AND INFLAMMATION IN CD4(+)T CELLS OBTAINED FROM PATIENTS WITH COPD AND LUNG CANCER. AS A RESULT OF TREATMENT WITH TSA, THERE IS A REDUCTION IN THE EXPRESSION OF INFLAMMATORY CYTOKINES AND A DECREASED ENRICHMENT OF TRANSCRIPTIONAL FACTORS ASSOCIATED WITH INFLAMMATION AT VEGFA GENE LOCI. WE HAVE SEEN A SUBSTANTIAL DECREASE IN THE EXPRESSION OF NF-KAPPAB AND HIF1ALPHA, WHICH ARE THE CRITICAL MEDIATORS OF INFLAMMATION AND HYPOXIA, RESPECTIVELY. FOLLOWING TSA TREATMENT, MTTFA EXPRESSION WAS INCREASED, FACILITATING PATIENTS WITH COPD AND NSCLC IN THE RECOVERY OF THEIR DYSFUNCTIONAL MITOCHONDRIA. FURTHERMORE, WE HAVE DISCOVERED THAT TSA TREATMENT IN PATIENTS WITH COPD AND NSCLC MAY LEAD TO IMMUNOPROTECTIVE NESS BY INDUCING TH1NESS. OUR FINDING GIVES A NEW INSIGHT INTO THE EXISTING BODY OF KNOWLEDGE REGARDING TSA-BASED THERAPEUTIC METHODS AND HIGHLIGHTS THE NECESSITY OF EPIGENETIC THERAPY FOR THESE DEVASTATING LUNG DISORDERS. 2023 9 4889 31 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 10 5560 38 ROLE OF HISTONE DEACETYLASE 2 IN EPIGENETICS AND CELLULAR SENESCENCE: IMPLICATIONS IN LUNG INFLAMMAGING AND COPD. HISTONE DEACETYLASE 2 (HDAC2) IS A CLASS I HISTONE DEACETYLASE THAT REGULATES VARIOUS CELLULAR PROCESSES, SUCH AS CELL CYCLE, SENESCENCE, PROLIFERATION, DIFFERENTIATION, DEVELOPMENT, APOPTOSIS, AND GLUCOCORTICOID FUNCTION IN INHIBITING INFLAMMATORY RESPONSE. HDAC2 HAS BEEN SHOWN TO PROTECT AGAINST DNA DAMAGE RESPONSE AND CELLULAR SENESCENCE/PREMATURE AGING VIA AN EPIGENETIC MECHANISM IN RESPONSE TO OXIDATIVE STRESS. THESE PHENOMENA ARE OBSERVED IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). HDAC2 IS POSTTRANSLATIONALLY MODIFIED BY OXIDATIVE/CARBONYL STRESS IMPOSED BY CIGARETTE SMOKE AND OXIDANTS, LEADING TO ITS REDUCTION VIA AN UBIQUITINATION-PROTEASOME DEPENDENT DEGRADATION IN LUNGS OF PATIENTS WITH COPD. IN THIS PERSPECTIVE, WE HAVE DISCUSSED THE ROLE OF HDAC2 POSTTRANSLATIONAL MODIFICATIONS AND ITS ROLE IN REGULATION OF INFLAMMATION, HISTONE/DNA EPIGENETIC MODIFICATIONS, DNA DAMAGE RESPONSE, AND CELLULAR SENESCENCE, PARTICULARLY IN INFLAMMAGING, AND DURING THE DEVELOPMENT OF COPD. WE HAVE ALSO DISCUSSED THE POTENTIAL DIRECTIONS FOR FUTURE TRANSLATIONAL RESEARCH AVENUES IN MODULATING LUNG INFLAMMAGING AND CELLULAR SENESCENCE BASED ON EPIGENETIC CHROMATIN MODIFICATIONS IN DISEASES ASSOCIATED WITH INCREASED OXIDATIVE STRESS. 2012 11 468 33 ARGININE METHYLTRANSFERASES MEDIATE AN EPIGENETIC OVARIAN RESPONSE TO ENDOMETRIOSIS. ENDOMETRIOSIS IS ASSOCIATED WITH INFERTILITY AND DEBILITATING CHRONIC PAIN. ABNORMAL EPIGENETIC MODIFICATIONS IN THE HUMAN ENDOMETRIUM HAVE RECENTLY BEEN IMPLICATED IN THE PATHOGENESIS OF THIS CONDITION. HOWEVER, WHETHER AN ALTERED EPIGENETIC LANDSCAPE CONTRIBUTES TO PATHOLOGICAL CHANGES IN THE OVARY IS UNKNOWN. USING AN ESTABLISHED BABOON ENDOMETRIOSIS MODEL, EARLY-, AND LATE-STAGE EPIGENETIC CHANGES IN THE OVARY WERE INVESTIGATED. TRANSCRIPT PROFILING OF KEY CHROMATIN-MODIFYING ENZYMES USING PATHWAY-FOCUSED PCR ARRAYS ON OVARIAN TISSUE FROM HEALTHY CONTROL ANIMALS AND AT 3 AND 15 MONTHS OF ENDOMETRIOSIS REVEALED DRAMATIC CHANGES IN GENE EXPRESSION IN A DISEASE DURATION-DEPENDENT MANNER. INGENUITY PATHWAY ANALYSIS INDICATED THAT TRANSCRIPTS FOR CHROMATIN-REMODELING ENZYMES ASSOCIATED WITH REPRODUCTIVE SYSTEM DISEASE AND CANCER DEVELOPMENT WERE ABNORMALLY REGULATED, MOST PROMINENTLY THE ARGININE METHYLTRANSFERASES CARM1, PRMT2, AND PRMT8. DOWNREGULATION OF CARM1 PROTEIN EXPRESSION WAS ALSO DETECTED IN THE OVARY, FULLY-GROWN OOCYTES AND EUTOPIC ENDOMETRIUM FOLLOWING 15 MONTHS OF ENDOMETRIOSIS. SODIUM BISULFITE SEQUENCING REVEALED DNA HYPERMETHYLATION WITHIN THE PRMT8 PROMOTER, SUGGESTING THAT DEREGULATED CPG METHYLATION MAY PLAY A ROLE IN TRANSCRIPTIONAL REPRESSION OF THIS GENE. THESE RESULTS DEMONSTRATE THAT ENDOMETRIOSIS IS ASSOCIATED WITH CHANGES OF EPIGENETIC PROFILES IN THE PRIMATE OVARY AND SUGGEST THAT ARGININE METHYLTRANSFERASES PLAY A PROMINENT ROLE IN MEDIATING THE OVARIAN RESPONSE TO ENDOMETRIOSIS. OWING TO THE CRITICAL ROLE OF CARM1 IN NUCLEAR RECEPTOR-MEDIATED TRANSCRIPTION AND MAINTENANCE OF PLURIPOTENCY IN THE CLEAVAGE STAGE EMBRYO, OUR RESULTS SUGGEST THAT EPIGENETIC ALTERATIONS IN THE OVARY MAY HAVE FUNCTIONAL CONSEQUENCES FOR OOCYTE QUALITY AND THE ETIOLOGY OF INFERTILITY ASSOCIATED WITH ENDOMETRIOSIS. 2015 12 5422 40 REGULATION OF LUNG EPITHELIAL CELL SENESCENCE IN SMOKING-INDUCED COPD/EMPHYSEMA BY MICROR-125A-5P VIA SP1 MEDIATION OF SIRT1/HIF-1A. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AFFECTS THE HEALTH OF MORE THAN 300 MILLION PEOPLE WORLDWIDE; AT PRESENT, THERE IS NO EFFECTIVE DRUG TO TREAT COPD. SMOKING IS THE MOST IMPORTANT RISK FACTOR, BUT THE MOLECULAR MECHANISM BY WHICH SMOKING CAUSES THE DISEASE IS UNCLEAR. THE SENESCENCE OF LUNG EPITHELIAL CELLS IS RELATED TO DEVELOPMENT OF COPD. REGULATION OF MIRNAS IS THE MAIN EPIGENETIC MECHANISM RELATED TO AGING. BETA-GALACTOSE STAINING SHOWED THAT THE LUNG TISSUES OF SMOKERS HAVE A HIGHER DEGREE OF CELLULAR SENESCENCE, AND THE EXPRESSION OF MIR-125A-5P IS HIGH. THIS EFFECT IS OBVIOUS FOR SMOKERS WITH COPD/EMPHYSEMA, AND THERE IS A NEGATIVE CORRELATION BETWEEN MIR-125A-5P LEVELS AND VALUES FOR FORCED EXPIRATORY VOLUME IN ONE SECOND (FEV1)/FORCED VITAL CAPACITY (FVC). AFTER BALB/C MICE WERE CHRONICALLY EXPOSED TO VARIOUS CONCENTRATIONS OF CIGARETTE SMOKE (CS), PLETHYSMOGRAPHY SHOWED THAT LUNG FUNCTION WAS IMPAIRED, LUNG TISSUE SENESCENCE WAS INCREASED, AND THE SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP) IN BRONCHOALVEOLAR LAVAGE FLUID WAS INCREASED. FOR MOUSE LUNG EPITHELIAL (MLE)-12 CELLS TREATED WITH CIGARETTE SMOKE EXTRACT (CSE), SP1 AND SIRT1 LEVELS WERE LOW, HIF-1ALPHA ACETYLATION LEVELS WERE HIGH, AND CELL SENESCENCE AND SECRETION OF SASP FACTORS WERE ELEVATED. DOWN-REGULATION OF MIR-125A-5P OR UP-REGULATION OF SP1 REVERSED THESE EFFECTS. IN ADDITION, COMPARED WITH MICE EXPOSED TO CS, KNOCKDOWN OF MIR-125A-5P REDUCED LUNG EPITHELIAL CELL SENESCENCE AND COPD/EMPHYSEMA. THEREFORE, IN SMOKING-INDUCED COPD, ELEVATED MIR-125A-5P PARTICIPATES IN THE SENESCENCE OF LUNG EPITHELIAL CELLS THROUGH SP1/SIRT1/HIF-1ALPHA. THESE FINDINGS PROVIDE EVIDENCE RELATED TO THE PATHOGENESIS OF COPD/EMPHYSEMA CAUSED BY CHRONIC SMOKING. 2022 13 164 28 ABNORMAL HISTONE METHYLATION IS RESPONSIBLE FOR INCREASED VASCULAR ENDOTHELIAL GROWTH FACTOR 165A SECRETION FROM AIRWAY SMOOTH MUSCLE CELLS IN ASTHMA. VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF), A KEY ANGIOGENIC MOLECULE, IS ABERRANTLY EXPRESSED IN SEVERAL DISEASES INCLUDING ASTHMA WHERE IT CONTRIBUTES TO BRONCHIAL VASCULAR REMODELING AND CHRONIC INFLAMMATION. ASTHMATIC HUMAN AIRWAY SMOOTH MUSCLE CELLS HYPERSECRETE VEGF, BUT THE MECHANISM IS UNCLEAR. IN THIS STUDY, WE DEFINED THE MECHANISM IN HUMAN AIRWAY SMOOTH MUSCLE CELLS FROM NONASTHMATIC AND ASTHMATIC PATIENTS. WE FOUND THAT ASTHMATIC CELLS LACKED A REPRESSION COMPLEX AT THE VEGF PROMOTER, WHICH WAS PRESENT IN NONASTHMATIC CELLS. RECRUITMENT OF G9A, TRIMETHYLATION OF HISTONE H3 AT LYSINE 9 (H3K9ME3), AND A RESULTANT DECREASE IN RNA POLYMERASE II AT THE VEGF PROMOTER WAS CRITICAL TO REPRESSION OF VEGF SECRETION IN NONASTHMATIC CELLS. AT THE ASTHMATIC PROMOTER, H3K9ME3 WAS ABSENT BECAUSE OF FAILED RECRUITMENT OF G9A; RNA POLYMERASE II BINDING, IN ASSOCIATION WITH TATA-BINDING PROTEIN-ASSOCIATED FACTOR 1, WAS INCREASED; H3K4ME3 WAS PRESENT; AND SP1 BINDING WAS EXAGGERATED AND SUSTAINED. IN CONTRAST, DNA METHYLATION AND HISTONE ACETYLATION WERE SIMILAR IN ASTHMATIC AND NONASTHMATIC CELLS. THIS IS THE FIRST STUDY, TO OUR KNOWLEDGE, TO SHOW THAT AIRWAY CELLS IN ASTHMA HAVE ALTERED EPIGENETIC REGULATION OF REMODELING GENE(S). HISTONE METHYLATION AT GENES SUCH AS VEGF MAY BE AN IMPORTANT NEW THERAPEUTIC TARGET. 2012 14 6839 28 [LUNG CANCER AND ITS EPIGENETICS ASSOCIATION WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE]. LUNG CANCER AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) ARE THE LEADING CAUSES OF MORBIDITY AND MORTALITY WORLDWIDE. DEVELOPMENT OF LUNG CANCER INVOLVES BOTH GENETIC AND ENVIRONMENT FACTORS. IN ADDITION TO GENETIC ALTERATIONS, EPIGENETIC MECHANISM IS CLOSELY INVOLVED IN PATHOGENESIS OF LUNG CANCER. CHARACTERIZED BY AN ABNORMAL PERSISTENT INFLAMMATORY RESPONSE TO NOXIOUS ENVIRONMENTAL STIMULATION, COPD HAS SHOWN TO INCREASE THE SUSCEPTIBILITY FOR LUNG TUMORIGENESIS IN PREVIOUS RESEARCH. CURRENT RESEARCH ON EPIGENETICS OF LUNG CANCER AND COPD HAS FOCUSED ON ABERRANT DNA METHYLATION, HISTONE ACETYLATION AND NON-CODING RNAS REGULATION. THE ABERRANT DNA METHYLATION ASSOCIATED WITH LUNG CANCER AND COPD HAS INCLUDED OVEREXPRESSION OF DNA METHYLTRANSFERASE, GLOBAL DNA HYPOMETHYLATION AND DNA HYPERMETHYLATION IN PROMOTER REGIONS, WHILE HISTONE ACETYLATION AND HISTONE METHYLATION ARE THE MAJOR CHANGES FOR HISTONE MODIFICATION, IN WHICH HISTONE ACETYLTRANSFERASES, HISTONE DEACETYLASES, HISTONE METHYLTRANSFERASES AND HISTONE DEMETHYLASES PLAY THE MOST IMPORTANT ROLES. RNA INTERFERENCE AND MICRORNAS ARE BOTH HOT TOPICS OF RESEARCH ON NON-CODING RNAS REGULATION. UNDERSTANDING OF CONCURRENT EPIGENETIC ALTERATIONS IN THE PATHOGENESIS OF LUNG CANCER AND COPD MAY FACILITATE IDENTIFICATION OF SPECIFIC THERAPEUTIC TARGETS AND DEVELOPMENT OF EFFECTIVE TREATMENT. 2013 15 2926 25 GENERATION OF AN EPIGENETIC SIGNATURE BY CHRONIC HYPOXIA IN PROSTATE CELLS. INCREASING LEVELS OF TISSUE HYPOXIA HAVE BEEN REPORTED AS A NATURAL FEATURE OF THE AGING PROSTATE GLAND AND MAY BE A RISK FACTOR FOR THE DEVELOPMENT OF PROSTATE CANCER. IN THIS STUDY, WE HAVE USED PWR-1E BENIGN PROSTATE EPITHELIAL CELLS AND AN EQUIVALENTLY AGED HYPOXIA-ADAPTED PWR-1E SUB-LINE TO IDENTIFY PHENOTYPIC AND EPIGENETIC CONSEQUENCES OF CHRONIC HYPOXIA IN PROSTATE CELLS. WE HAVE IDENTIFIED A SIGNIFICANTLY ALTERED CELLULAR PHENOTYPE IN RESPONSE TO CHRONIC HYPOXIA AS CHARACTERIZED BY INCREASED RECEPTOR-MEDIATED APOPTOTIC RESISTANCE, THE INDUCTION OF CELLULAR SENESCENCE, INCREASED INVASION AND THE INCREASED SECRETION OF IL-1 BETA, IL6, IL8 AND TNFALPHA CYTOKINES. IN ASSOCIATION WITH THESE PHENOTYPIC CHANGES AND THE ABSENCE OF HIF-1 ALPHA PROTEIN EXPRESSION, WE HAVE DEMONSTRATED SIGNIFICANT INCREASES IN GLOBAL LEVELS OF DNA METHYLATION AND H3K9 HISTONE ACETYLATION IN THESE CELLS, CONCOMITANT WITH THE INCREASED EXPRESSION OF DNA METHYLTRANSFERASE DMNT3B AND GENE-SPECIFIC CHANGES IN DNA METHYLATION AT KEY IMPRINTING LOCI. IN CONCLUSION, WE HAVE DEMONSTRATED A GENOME-WIDE ADJUSTMENT OF DNA METHYLATION AND HISTONE ACETYLATION UNDER CHRONIC HYPOXIC CONDITIONS IN THE PROSTATE. THESE EPIGENETIC SIGNATURES MAY REPRESENT AN ADDITIONAL MECHANISM TO PROMOTE AND MAINTAIN A HYPOXIC-ADAPTED CELLULAR PHENOTYPE WITH A POTENTIAL ROLE IN TUMOUR DEVELOPMENT. 2009 16 5889 27 SYSTEMS APPROACHES TO MODELING CHRONIC MUCOSAL INFLAMMATION. THE RESPIRATORY MUCOSA IS A MAJOR COORDINATOR OF THE INFLAMMATORY RESPONSE IN CHRONIC AIRWAY DISEASES, INCLUDING ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). SIGNALS PRODUCED BY THE CHRONIC INFLAMMATORY PROCESS INDUCE EPITHELIAL MESENCHYMAL TRANSITION (EMT) THAT DRAMATICALLY ALTERS THE EPITHELIAL CELL PHENOTYPE. THE EFFECTS OF EMT ON EPIGENETIC REPROGRAMMING AND THE ACTIVATION OF TRANSCRIPTIONAL NETWORKS ARE KNOWN, ITS EFFECTS ON THE INNATE INFLAMMATORY RESPONSE ARE UNDEREXPLORED. WE USED A MULTIPLEX GENE EXPRESSION PROFILING PLATFORM TO INVESTIGATE THE PERTURBATIONS OF THE INNATE PATHWAYS INDUCED BY TGF BETA IN A PRIMARY AIRWAY EPITHELIAL CELL MODEL OF EMT. EMT HAD DRAMATIC EFFECTS ON THE INDUCTION OF THE INNATE PATHWAY AND THE COUPLING INTERVAL OF THE CANONICAL AND NONCANONICAL NF- KAPPA B PATHWAYS. SIMULATION EXPERIMENTS DEMONSTRATE THAT RAPID, COORDINATED CAP-INDEPENDENT TRANSLATION OF TRAF-1 AND NF- KAPPA B2 IS REQUIRED TO REDUCE THE NONCANONICAL PATHWAY COUPLING INTERVAL. EXPERIMENTS USING AMANTADINE CONFIRMED THE PREDICTION THAT TRAF-1 AND NF- KAPPA B2/P100 PRODUCTION IS MEDIATED BY AN IRES-DEPENDENT MECHANISM. THESE DATA INDICATE THAT THE EPIGENETIC CHANGES PRODUCED BY EMT INDUCE DYNAMIC STATE CHANGES OF THE INNATE SIGNALING PATHWAY. FURTHER APPLICATIONS OF SYSTEMS APPROACHES WILL PROVIDE UNDERSTANDING OF THIS COMPLEX PHENOTYPE THROUGH DETERMINISTIC MODELING AND MULTIDIMENSIONAL (GENOMIC AND PROTEOMIC) PROFILING. 2013 17 3527 32 IL-6 ENHANCES THE NUCLEAR TRANSLOCATION OF DNA CYTOSINE-5-METHYLTRANSFERASE 1 (DNMT1) VIA PHOSPHORYLATION OF THE NUCLEAR LOCALIZATION SEQUENCE BY THE AKT KINASE. THE EPIGENETIC PROGRAMMING OF GENOMIC DNA IS ACCOMPLISHED, IN PART, BY SEVERAL DNA CYTOSINE-5-METHYLTRANSFERASES THAT ACT BY COVALENTLY MODIFYING CYTOSINES WITH THE ADDITION OF A METHYL GROUP. THIS COVALENT MODIFICATION IS MAINTAINED BY THE DNA CYTOSINE-5-METHYLTRANSFERASE-1 ENZYME (DNMT1), WHICH IS CAPABLE OF ACTING IN CONCERT WITH OTHER SIMILAR ENZYMES TO SILENCE IMPORTANT TUMOR SUPPRESSOR GENES. IL-6 IS A MULTIFUNCTIONAL MEDIATOR OF INFLAMMATION, ACTING THROUGH SEVERAL MAJOR SIGNALING CASCADES, INCLUDING THE PHOSPHATIDYLINOSITOL-3-KINASE PATHWAY (PI-3-K), WHICH ACTIVATES PROTEIN KINASE B (AKT/PKB) DOWNSTREAM. HERE, WE SHOW THAT THE SUBCELLULAR LOCALIZATION OF DNMT1 CAN BE ALTERED BY THE ADDITION OF IL-6, INCREASING THE RATE OF NUCLEAR TRANSLOCATION OF THE ENZYME FROM THE CYTOSOLIC COMPARTMENT. THE MECHANISM OF NUCLEAR TRANSLOCATION OF DNMT1 IS GREATLY ENHANCED BY PHOSPHORYLATION OF THE DNMT1 NUCLEAR LOCALIZATION SIGNAL (NLS) BY PKB/AKT KINASE. MUTAGENIC ALTERATION OF THE TWO AKT TARGET AMINO ACIDS WITHIN THE NLS RESULTS IN A MAJOR LOSS OF DNMT1 NUCLEAR TRANSLOCATION, WHILE THE CREATION OF A "PHOSPHO-MIMIC" AMINO ACID (MUTATION TO ACIDIC RESIDUES) RESTORES THIS COMPARTMENTATION ABILITY. THESE OBSERVATIONS SUGGEST AN INTERESTING HYPOTHESIS REGARDING HOW MEDIATORS OF CHRONIC INFLAMMATION MAY DISTURB THE DELICATE BALANCE OF CELLULAR COMPARTMENTALIZATION OF IMPORTANT PROTEINS, AND REVEALS A POTENTIAL MECHANISM FOR THE INDUCTION OR ENHANCEMENT OF TUMOR GROWTH VIA ALTERATION OF THE COMPONENTS INVOLVED IN THE EPIGENETIC PROGRAMMING OF A CELL. 2007 18 2493 36 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 19 3351 27 HISTONE DEMETHYLASE JARID1B REGULATES PROLIFERATION AND MIGRATION OF PULMONARY ARTERIAL SMOOTH MUSCLE CELLS IN MICE WITH CHRONIC HYPOXIA-INDUCED PULMONARY HYPERTENSION VIA NUCLEAR FACTOR-KAPPA B (NFKB). CHRONIC HYPOXIA-INDUCED PULMONARY HYPERTENSION (PH) IS A DISORDER THAT IS CHARACTERIZED BY INCREASED PULMONARY ARTERIAL PRESSURE RESULTING FROM LUNG DISEASES OR SHORTAGE OF OXYGEN IN THE BODY. EXCESS PROLIFERATION OF PULMONARY VASCULAR CELLS SUCH AS PULMONARY ARTERY ENDOTHELIAL CELLS (PAECS) AND PULMONARY ARTERY SMOOTH MUSCLE CELLS (PASMCS) PLAYS A CRITICAL ROLE IN THE PATHOGENESIS OF PH. RECENT EVIDENCE INDICATES THAT, IN ADDITION TO GENETIC PREDISPOSITION AND ENVIRONMENTAL FACTORS, EPIGENETIC MECHANISMS PLAY A PIVOTAL ROLE IN ETIOLOGY OF PH. IN THIS STUDY, WE INVESTIGATED THE POSSIBLE ROLE PLAYED BY JUMONJI AT-RICH INTERACTIVE DOMAIN 1B (JARID1B), A HISTONE DEMETHYLASE, IN REGULATING THE PROLIFERATION OF VASCULAR SMOOTH MUSCLE CELLS IN CHRONIC HYPOXIA-INDUCED PH CONDITION. QUANTITATIVE POLYMERASE CHAIN REACTION ANALYSIS OF SAMPLES FROM RATS WITH PH SHOWED AN ELEVATED EXPRESSION OF JARID1B IN THEIR PASMCS, POSITIVELY CORRELATING WITH INCREASED NUCLEAR FACTOR-KAPPA B (NFKB) EXPRESSION. FURTHER FUNCTIONAL STUDIES IN VITRO INDICATED THAT OVEREXPRESSION OF JARID1B INCREASED THE PROLIFERATION AND MIGRATION OF PASMCS, WHICH WERE INHIBITED BY DEPLETION OF NFKB. GENOMEWIDE TRANSCRIPTIONAL ANALYSIS REVEALED THAT THE JARID1B REGULATED NFKB SIGNALING PATHWAY BY DIRECTLY BINDING TO ITS PROMOTER. WE HAVE ALSO SHOWN THAT JARID1B INDIRECTLY REGULATES THE EXPRESSION OF VASCULAR ENDOTHELIAL GROWTH FACTOR VIA NFKB SIGNALING AND HENCE MAY ALSO PLAY A CRUCIAL ROLE IN CONTROLLING PAECS, LEADING TO CHANGES IN VASCULAR ARCHITECTURE IN PH. OUR FINDINGS COULD LEAD TO FURTHER STUDIES ON THE ROLE OF JARID1B IN PH ETIOLOGY AND THEREFORE COULD LEAD TO A POTENTIAL THERAPEUTIC TARGET FOR CHRONIC HYPOXIA INDUCED PULMONARY HYPERTENSION. 2018 20 3322 25 HISTONE ACETYLTRANSFERASE P300 INDUCES DE NOVO SUPER-ENHANCERS TO DRIVE CELLULAR SENESCENCE. ACCUMULATION OF SENESCENT CELLS DURING AGING CONTRIBUTES TO CHRONIC INFLAMMATION AND AGE-RELATED DISEASES. WHILE SENESCENCE IS ASSOCIATED WITH PROFOUND ALTERATIONS OF THE EPIGENOME, A SYSTEMATIC VIEW OF EPIGENETIC FACTORS IN REGULATING SENESCENCE IS LACKING. HERE, WE CURATED A LIBRARY OF SHORT HAIRPIN RNAS FOR TARGETED SILENCING OF ALL KNOWN EPIGENETIC PROTEINS AND PERFORMED A HIGH-THROUGHPUT SCREEN TO IDENTIFY KEY CANDIDATES WHOSE DOWNREGULATION CAN DELAY REPLICATIVE SENESCENCE OF PRIMARY HUMAN CELLS. THIS SCREEN IDENTIFIED MULTIPLE NEW PLAYERS INCLUDING THE HISTONE ACETYLTRANSFERASE P300 THAT WAS FOUND TO BE A PRIMARY DRIVER OF THE SENESCENT PHENOTYPE. P300, BUT NOT THE PARALOGOUS CBP, INDUCES A DYNAMIC HYPER-ACETYLATED CHROMATIN STATE AND PROMOTES THE FORMATION OF ACTIVE ENHANCER ELEMENTS IN THE NON-CODING GENOME, LEADING TO A SENESCENCE-SPECIFIC GENE EXPRESSION PROGRAM. OUR WORK ILLUSTRATES A CAUSAL ROLE OF HISTONE ACETYLTRANSFERASES AND ACETYLATION IN SENESCENCE AND SUGGESTS P300 AS A POTENTIAL THERAPEUTIC TARGET FOR SENESCENCE AND AGE-RELATED DISEASES. 2019