1 5418 181 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 2 2022 54 EPIGENETIC CHANGES ASSOCIATED WITH DISEASE PROGRESSION IN A MOUSE MODEL OF CHILDHOOD ALLERGIC ASTHMA. DEVELOPMENT OF ASTHMA IN CHILDHOOD IS LINKED TO VIRAL INFECTIONS OF THE LOWER RESPIRATORY TRACT IN EARLY LIFE, WITH SUBSEQUENT CHRONIC EXPOSURE TO ALLERGENS. PROGRESSION TO PERSISTENT ASTHMA IS ASSOCIATED WITH A TH2-BIASED IMMUNOLOGICAL RESPONSE AND STRUCTURAL REMODELLING OF THE AIRWAYS. THE UNDERLYING MECHANISMS ARE UNCLEAR, BUT COULD INVOLVE EPIGENETIC CHANGES. TO INVESTIGATE THIS, WE EMPLOYED A RECENTLY DEVELOPED MOUSE MODEL IN WHICH SELF-LIMITED NEONATAL INFECTION WITH A PNEUMOVIRUS, FOLLOWED BY SENSITISATION TO OVALBUMIN VIA THE RESPIRATORY TRACT AND LOW-LEVEL CHRONIC CHALLENGE WITH AEROSOLISED ANTIGEN, LEADS TO DEVELOPMENT OF AN ASTHMATIC PHENOTYPE. WE ASSESSED EXPRESSION OF MICRORNA BY CELLS IN THE PROXIMAL AIRWAYS, COMPARING CHANGES OVER THE PERIOD OF DISEASE PROGRESSION, AND USED TARGET PREDICTION DATABASES TO IDENTIFY GENES LIKELY TO BE UP- OR DOWNREGULATED AS A CONSEQUENCE OF ALTERED REGULATION OF MICRORNA. IN PARALLEL, WE ASSESSED DNA METHYLATION IN PULMONARY CD4(+) T CELLS. WE FOUND THAT A LIMITED NUMBER OF MICRORNAS EXHIBITED MARKED UP- OR DOWNREGULATION FOLLOWING EARLY-LIFE INFECTION AND SENSITISATION, FOR MANY OF WHICH THE LEVELS OF EXPRESSION WERE FURTHER CHANGED FOLLOWING CHRONIC CHALLENGE WITH THE SENSITIZING ANTIGEN. TARGETS OF THESE MICRORNAS INCLUDED GENES INVOLVED IN IMMUNE OR INFLAMMATORY RESPONSES (E.G. GATA3, KITL) AND IN TISSUE REMODELLING (E.G. IGF1, TGFBR1), AS WELL AS GENES FOR VARIOUS TRANSCRIPTION FACTORS AND SIGNALLING PROTEINS. IN PULMONARY CD4(+) T CELLS, THERE WAS SIGNIFICANT DEMETHYLATION AT PROMOTER SITES FOR INTERLEUKIN-4 AND INTERFERON-GAMMA, THE LATTER INCREASING FOLLOWING CHRONIC CHALLENGE. WE CONCLUDE THAT, IN THIS MODEL, PROGRESSION TO AN ASTHMATIC PHENOTYPE IS LINKED TO EPIGENETIC REGULATION OF GENES ASSOCIATED WITH INFLAMMATION AND STRUCTURAL REMODELLING, AND WITH T-CELL COMMITMENT TO A TH2 IMMUNOLOGICAL RESPONSE. EPIGENETIC CHANGES ASSOCIATED WITH THIS PATTERN OF GENE ACTIVATION MIGHT PLAY A ROLE IN THE DEVELOPMENT OF CHILDHOOD ASTHMA. 2013 3 1551 56 DNA METHYLATION IS GLOBALLY DISRUPTED AND ASSOCIATED WITH EXPRESSION CHANGES IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE SMALL AIRWAYS. DNA METHYLATION IS AN EPIGENETIC MODIFICATION THAT IS HIGHLY DISRUPTED IN RESPONSE TO CIGARETTE SMOKE AND INVOLVED IN A WIDE SPECTRUM OF MALIGNANT AND NONMALIGNANT DISEASES, BUT SURPRISINGLY NOT PREVIOUSLY ASSESSED IN SMALL AIRWAYS OF PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). SMALL AIRWAYS ARE THE PRIMARY SITES OF AIRFLOW OBSTRUCTION IN COPD. WE SOUGHT TO DETERMINE WHETHER DNA METHYLATION PATTERNS ARE DISRUPTED IN SMALL AIRWAY EPITHELIA OF PATIENTS WITH COPD, AND EVALUATE WHETHER CHANGES IN GENE EXPRESSION ARE ASSOCIATED WITH THESE DISRUPTIONS. GENOME-WIDE METHYLATION AND GENE EXPRESSION ANALYSIS WERE PERFORMED ON SMALL AIRWAY EPITHELIAL DNA AND RNA OBTAINED FROM THE SAME PATIENT DURING BRONCHOSCOPY, USING ILLUMINA'S INFINIUM HM27 AND AFFYMETRIX'S GENECHIP HUMAN GENE 1.0 ST ARRAYS. TO CONTROL FOR KNOWN EFFECTS OF CIGARETTE SMOKING ON DNA METHYLATION, METHYLATION AND GENE EXPRESSION PROFILES WERE COMPARED BETWEEN FORMER SMOKERS WITH AND WITHOUT COPD MATCHED FOR AGE, PACK-YEARS, AND YEARS OF SMOKING CESSATION. OUR RESULTS INDICATE THAT ABERRANT DNA METHYLATION IS (1) A GENOME-WIDE PHENOMENON IN SMALL AIRWAYS OF PATIENTS WITH COPD, AND (2) ASSOCIATED WITH ALTERED EXPRESSION OF GENES AND PATHWAYS IMPORTANT TO COPD, SUCH AS THE NF-E2-RELATED FACTOR 2 OXIDATIVE RESPONSE PATHWAY. DNA METHYLATION IS LIKELY AN IMPORTANT MECHANISM CONTRIBUTING TO MODULATION OF GENES IMPORTANT TO COPD PATHOLOGY. BECAUSE THESE METHYLATION EVENTS MAY UNDERLIE DISEASE-SPECIFIC GENE EXPRESSION CHANGES, THEIR CHARACTERIZATION IS A CRITICAL FIRST STEP TOWARD THE DEVELOPMENT OF EPIGENETIC MARKERS AND AN OPPORTUNITY FOR DEVELOPING NOVEL EPIGENETIC THERAPEUTIC INTERVENTIONS FOR COPD. 2014 4 6839 44 [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 5 3308 38 HIGH-RESOLUTION TRANSCRIPTOMIC AND EPIGENETIC PROFILING IDENTIFIES NOVEL REGULATORS OF COPD. PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) ARE STILL WAITING FOR CURATIVE TREATMENTS. CONSIDERING ITS ENVIRONMENTAL CAUSE, WE HYPOTHESIZED THAT COPD WILL BE ASSOCIATED WITH ALTERED EPIGENETIC SIGNALING IN LUNG CELLS. WE GENERATED GENOME-WIDE DNA METHYLATION MAPS AT SINGLE CPG RESOLUTION OF PRIMARY HUMAN LUNG FIBROBLASTS (HLFS) ACROSS COPD STAGES. WE SHOW THAT THE EPIGENETIC LANDSCAPE IS CHANGED EARLY IN COPD, WITH DNA METHYLATION CHANGES OCCURRING PREDOMINANTLY IN REGULATORY REGIONS. RNA SEQUENCING OF MATCHED FIBROBLASTS DEMONSTRATED DYSREGULATION OF GENES INVOLVED IN PROLIFERATION, DNA REPAIR, AND EXTRACELLULAR MATRIX ORGANIZATION. DATA INTEGRATION IDENTIFIED 110 CANDIDATE REGULATORS OF DISEASE PHENOTYPES THAT WERE LINKED TO FIBROBLAST REPAIR PROCESSES USING PHENOTYPIC SCREENS. OUR STUDY PROVIDES HIGH-RESOLUTION MULTI-OMIC MAPS OF HLFS ACROSS COPD STAGES. WE REVEAL NOVEL TRANSCRIPTOMIC AND EPIGENETIC SIGNATURES ASSOCIATED WITH COPD ONSET AND PROGRESSION AND IDENTIFY NEW CANDIDATE REGULATORS INVOLVED IN THE PATHOGENESIS OF CHRONIC LUNG DISEASES. THE PRESENCE OF VARIOUS EPIGENETIC FACTORS AMONG THE CANDIDATES DEMONSTRATES THAT EPIGENETIC REGULATION IN COPD IS AN EXCITING RESEARCH FIELD THAT HOLDS PROMISE FOR NOVEL THERAPEUTIC AVENUES FOR PATIENTS. 2023 6 2161 34 EPIGENETIC MECHANISMS IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE. EPIGENETIC MODIFICATION MAY AFFECT THE EXPRESSION OF MULTIPLE INFLAMMATORY GENES IN LUNGS OF PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). MAJOR EPIGENETIC EVENTS INCLUDE DNA METHYLATION AND VARIOUS POST-TRANSLATIONAL MODIFICATIONS OF HISTONES, SUCH AS HISTONE METHYLATION, ACETYLATION, PHOSPHORYLATION, UBIQUITINATION, AND SUMOYLATION. ENZYMES WHICH REGULATE THESE EPIGENETIC MODIFICATIONS CAN BE ACTIVATED BY SMOKING. BOTH ENVIRONMENTAL AND GENETIC FACTORS PLAY SIGNIFICANT EFFECT IN DEVELOPMENT OF COPD WHICH HAVE BEEN REPORTED BY MOST REFERENCES; HOWEVER, LITTLE IS KNOWN ABOUT THE EPIGENETIC PATHWAYS INVOLVED IN THE DISEASE. UNDERSTANDING THE EPIGENETIC MECHANISMS CAN HELP US CLARIFY THE PATHOGENESIS OF COPD AND IDENTIFY NOVEL TARGETS FOR DEVELOPING NEW THERAPIES FOR PATIENTS WITH COPD. 2015 7 3543 44 IMMUNOLOGY, GENETICS AND MICROBIOTA IN THE COPD PATHOPHYSIOLOGY: POTENTIAL SCOPE FOR PATIENT STRATIFICATION. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS CHARACTERIZED BY SUSTAINED INFLAMMATION OF THE AIRWAYS, LEADING TO DESTRUCTION OF LUNG TISSUE AND DECLINING PULMONARY FUNCTION. ALTHOUGH SMOKING IS THE MOST OBVIOUS RISK FACTOR FOR COPD, ONLY ABOUT 20% OF SMOKERS DEVELOP COPD AND SMOKING CESSATION DOES NOT REVERSE PROGRESSION OF COPD, INDICATING THAT WHILE SMOKING IS AN IMPORTANT CAUSE OR INITIATING FACTOR, IT IS NOT THE ONLY DRIVER OF ONGOING CHRONIC INFLAMMATION AND DISEASE PROGRESSION IN COPD PATIENTS. WE HYPOTHESIZE THAT SMOKING-INDUCED CHANGES IN LUNG MICROBIOTA, EPITHELIAL INTEGRITY AND EPIGENETIC CONTROL OF GENE EXPRESSION RESULT IN AUTOANTIGEN INDUCTION AND PERTURBED IMMUNE REGULATION IN GENETICALLY VUNERABLE INDIVIDUALS. IN OUR VIEW, COPD PATIENTS MAY BE STRATIFIED ACCORDING TO THEIR IMMUNOLOGICAL AND INFLAMMATORY STATUS RELATED TO SPECIFIC CHANGES IN THE LUNG MICROBIOTA (INNATE AND ADAPTIVE IMMUNITY), PRESENCE OF AUTOANTIGENS (ADAPTIVE IMMUNITY: TH1-B-CELL AXIS) AND EPIGENETIC MODIFICATIONS (INFLAMMATION AND STRUCTURAL CHANGES). 2015 8 2228 44 EPIGENETIC MODIFICATIONS OF HISTONES IN PERIODONTAL DISEASE. PERIODONTITIS IS A CHRONIC INFECTIOUS DISEASE DRIVEN BY DYSBIOSIS, AN IMBALANCE BETWEEN COMMENSAL BACTERIA AND THE HOST ORGANISM. PERIODONTITIS IS A LEADING CAUSE OF TOOTH LOSS IN ADULTS AND OCCURS IN ABOUT 50% OF THE US POPULATION. IN ADDITION TO THE CLINICAL CHALLENGES ASSOCIATED WITH TREATING PERIODONTITIS, THE PROGRESSION AND CHRONIC NATURE OF THIS DISEASE SERIOUSLY AFFECT HUMAN HEALTH. EMERGING EVIDENCE SUGGESTS THAT PERIODONTITIS IS ASSOCIATED WITH MECHANISMS BEYOND BACTERIA-INDUCED PROTEIN AND TISSUE DEGRADATION. HERE, WE HYPOTHESIZE THAT BACTERIA ARE ABLE TO INDUCE EPIGENETIC MODIFICATIONS IN ORAL EPITHELIAL CELLS MEDIATED BY HISTONE MODIFICATIONS. IN THIS STUDY, WE FOUND THAT DYSBIOSIS IN VIVO LED TO EPIGENETIC MODIFICATIONS, INCLUDING ACETYLATION OF HISTONES AND DOWNREGULATION OF DNA METHYLTRANSFERASE 1. IN ADDITION, IN VITRO EXPOSURE OF ORAL EPITHELIAL CELLS TO LIPOPOLYSACCHARIDES RESULTED IN HISTONE MODIFICATIONS, ACTIVATION OF TRANSCRIPTIONAL COACTIVATORS, SUCH AS P300/CBP, AND ACCUMULATION OF NUCLEAR FACTOR-KAPPAB (NF-KAPPAB). GIVEN THAT ORAL EPITHELIAL CELLS ARE THE FIRST LINE OF DEFENSE FOR THE PERIODONTIUM AGAINST BACTERIA, WE ALSO EVALUATED WHETHER ACTIVATION OF PATHOGEN RECOGNITION RECEPTORS INDUCED HISTONE MODIFICATIONS. WE FOUND THAT ACTIVATION OF THE TOLL-LIKE RECEPTORS 1, 2, AND 4 AND THE NUCLEOTIDE-BINDING OLIGOMERIZATION DOMAIN PROTEIN 1 INDUCED HISTONE ACETYLATION IN ORAL EPITHELIAL CELLS. OUR FINDINGS CORROBORATE THE EMERGING CONCEPT THAT EPIGENETIC MODIFICATIONS PLAY A ROLE IN THE DEVELOPMENT OF PERIODONTITIS. 2016 9 1245 42 CURRENT CONCEPTS ON THE ROLE OF INFLAMMATION IN COPD AND LUNG CANCER. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND LUNG CANCER ARE LEADING CAUSE OF DEATH, AND BOTH ARE ASSOCIATED WITH CIGARETTE SMOKE EXPOSURE. IT HAS BEEN SHOWN THAT 50-70% OF PATIENTS DIAGNOSED WITH LUNG CANCER SUFFER FROM COPD, AND REDUCED LUNG FUNCTION IS AN IMPORTANT EVENT IN LUNG CANCER SUGGESTING AN ASSOCIATION BETWEEN COPD AND LUNG CANCER. HOWEVER, A CAUSAL RELATIONSHIP BETWEEN COPD AND LUNG TUMORIGENESIS IS NOT YET FULLY UNDERSTOOD. RECENT STUDIES HAVE SUGGESTED A CENTRAL ROLE OF CHRONIC INFLAMMATION IN THE PATHOGENESIS OF BOTH THE DISEASES. FOR EXAMPLE, IMMUNE DYSFUNCTION, ABNORMAL ACTIVATION OF NF-KAPPAB, EPITHELIAL-TO-MESENCHYMAL TRANSITION, ALTERED ADHESION SIGNALING PATHWAYS, AND EXTRACELLULAR MATRIX DEGRADATION/ALTERED SIGNALING ARE THE KEY UNDERLYING MECHANISMS IN BOTH COPD AND LUNG CANCER. THESE PARAMETERS ALONG WITH OTHER PROCESSES, SUCH AS CHROMATIN MODIFICATIONS/EPIGENETIC CHANGES, ANGIOGENESIS, AND AUTOPHAGY/APOPTOSIS ARE ALTERED BY CIGARETTE SMOKE, ARE CRUCIAL IN THE DEVELOPMENT OF COPD AND LUNG CANCER. UNDERSTANDING THE CELLULAR AND MOLECULAR MECHANISMS UNDERLYING THESE PROCESSES WILL PROVIDE NOVEL AVENUES FOR HALTING THE CHRONIC INFLAMMATION IN COPD AND DEVISING THERAPEUTIC STRATEGIES AGAINST LUNG CANCER. 2009 10 4028 39 LUNG TUMORS, COPD AND IMMUNE RESPONSE: IS EPIGENETICS THE BOTTOM LINE? NSCLC IS A HETEROGENEOUS DISORDER CONSISTING OF DISTINCT MOLECULAR SUBTYPES WHICH CAN BE TREATED BY USING SPECIFIC DRUGS TARGETED TO DISTINCT GENETIC LESIONS. IT IS WELL KNOWN THAT NSCLS INCIDENCE IS HIGHER IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) PATIENTS BECAUSE THEY SHARE A COMMON RISK FACTOR (CIGARETTE SMOKING) AND IT IS BELIEVED THAT THE TYPICAL INFLAMMATORY MICROENVIRONMENT OBSERVED IN COPD MAY INFLUENCE THE MOLECULAR MECHANISMS RESPONSIBLE OF CARCINOGENESIS. IN THE LAST YEARS, THE ROLE OF EPIGENETIC PROCESSES IN CELL BIOLOGY AND TISSUE PATHOLOGY HAS BEEN EXTENSIVELY STUDIED BOTH IN COPD AND NSCLC. THE RECENT PAPER BY WAUTERS ET AL. SHOWED A SPECIFIC PATTERN OF DRIVER MUTATIONS AND MOLECULAR FEATURES IN NSCLC RAISING IN THE CONTEXT OF COPD. ALL THESE FINDINGS HAVE SHOWN FOR THE FIRST TIME THAT LUNG TUMORS FOUND IN COPD PATIENTS DIFFER FROM THOSE OBSERVED IN PATIENT WITHOUT COPD DUE TO THE PRESENCE OF A SPECIFIC TUMOR MICROENVIRONMENT WHICH IS CHARACTERIZED BY REDUCED CD4+ TREG CELLS. ON THIS BASIS, THE PRESENT WORK AIMS AT DISCUSSING AND ANALYZING THE CONTEXT-SPECIFIC MECHANISMS OF CLONAL SELECTION AND EVOLUTION MAINLY FOCUSING ON THE EPIGENETIC ALTERATIONS AND AT POINTING OUT THE POTENTIAL THERAPEUTIC IMPLICATIONS. 2016 11 5324 49 PULMONARY MICRORNA PROFILING: IMPLICATIONS IN UPPER LOBE PREDOMINANT LUNG DISEASE. BACKGROUND: NUMEROUS PULMONARY DISEASES MANIFEST WITH UPPER LOBE PREDOMINANCE INCLUDING CYSTIC FIBROSIS, SMOKING-RELATED CHRONIC OBSTRUCTIVE PULMONARY DISEASE, AND TUBERCULOSIS. ZONAL HYPOXIA, CHARACTERISTIC OF THESE PULMONARY MALADIES, AND OXYGEN STRESS IN GENERAL IS KNOWN TO EXERT PROFOUND EFFECTS ON VARIOUS IMPORTANT ASPECTS OF CELL BIOLOGY. LUNG MACROPHAGES ARE MAJOR PARTICIPANTS IN THE PULMONARY INNATE IMMUNE RESPONSE AND REGIONAL DIFFERENCES IN MACROPHAGE RESPONSIVENESS TO HYPOXIA MAY CONTRIBUTE IN THE DEVELOPMENT OF LUNG DISEASE. MICRORNAS ARE UBIQUITOUS REGULATORS OF HUMAN BIOLOGY AND EMERGING EVIDENCE INDICATES ALTERED MICRORNA EXPRESSION MODULATES RESPIRATORY DISEASE PROCESSES. THE OBJECTIVE OF THIS STUDY IS TO GAIN INSIGHT INTO THE EPIGENETIC AND CELLULAR MECHANISMS INFLUENCING REGIONAL DIFFERENCES IN LUNG DISEASE BY INVESTIGATING EFFECT OF HYPOXIA ON REGIONAL MICRORNA EXPRESSION IN THE LUNG. ALL STUDIES WERE PERFORMED USING PRIMARY ALVEOLAR MACROPHAGES (N = 10) OR BRONCHOALVEOLAR LAVAGE FLUID (N = 16) ISOLATED FROM HUMAN SUBJECTS. MICRORNA WAS ASSAYED VIA THE NANOSTRING NCOUNTER MICRORNA ASSAY. RESULTS: DIVERGENT MOLECULAR PATTERNS OF MICRORNA EXPRESSION WERE OBSERVED IN ALTERNATE LUNG LOBES, SPECIFICALLY NOTED WAS DISPARATE EXPRESSION OF MIR-93 AND MIR-4454 IN ALVEOLAR MACROPHAGES ALONG WITH ALTERED EXPRESSION OF MIR-451A AND MIR-663A IN BRONCHOALVEOLAR LAVAGE FLUID. GENE ONTOLOGY WAS USED TO IDENTIFY POTENTIAL DOWNSTREAM TARGETS OF DIVERGENT MICRORNAS. TARGETS INCLUDE CYTOKINES AND MATRIX METALLOPROTEINASES, MOLECULES THAT COULD HAVE A SIGNIFICANT IMPACT ON PULMONARY INFLAMMATION AND FIBROSIS. CONCLUSIONS: OUR FINDINGS SHOW VARIANT REGIONAL MICRORNA EXPRESSION ASSOCIATED WITH HYPOXIA IN ALVEOLAR MACROPHAGES AND BAL FLUID IN THE LUNG-UPPER VS LOWER LOBE. FUTURE STUDIES SHOULD ADDRESS WHETHER THESE SPECIFIC MICRORNAS MAY ACT INTRACELLULARLY, IN A PARACRINE/ENDOCRINE MANNER TO DIRECT THE INNATE IMMUNE RESPONSE OR MAY ULTIMATELY BE INVOLVED IN PULMONARY HOST-TO-PATHOGEN TRANS-KINGDOM CROSS-TALK. 2017 12 1708 42 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 13 2212 42 EPIGENETIC MODIFICATIONS AND THERAPY IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD): AN UPDATE REVIEW. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) THAT IS ONE OF THE MOST PREVALENT CHRONIC ADULT DISEASES AND THE THIRD LEADING CAUSE OF FATALITY UNTIL 2020. ELASTASE/ANTI-ELASTASE HYPOTHESIS, CHRONIC INFLAMMATION, APOPTOSIS, OXIDANT-ANTIOXIDANT BALANCE AND INFECTIVE REPAIR CAUSE PATHOGENESIS OF COPD ARE AMONG THE FACTORS AT PLAY. EPIGENETIC CHANGES ARE POST-TRANSLATIONAL MODIFICATIONS IN HISTONE PROTEINS AND DNA SUCH AS METHYLATION AND ACETYLATION AS WELL AS DYSREGULATION OF MIRNAS EXPRESSION. IN THIS UPDATE REVIEW, WE HAVE EXAMINED RECENT STUDIES ON THE UPREGULATION OR DOWNREGULATION OF METHYLATION IN DIFFERENT GENES ASSOCIATED WITH COPD. DYSREGULATION OF HDAC ACTIVITY WHICH IS CAUSED BY SOME FACTORS AND MIRNAS PLAYS A KEY ROLE IN THE SUPPRESSION AND REDUCTION OF COPD DEVELOPMENT. ALSO, SOME THERAPEUTIC APPROACHES ARE PROPOSED AGAINST COPD BY TARGETING HDAC2 AND MIRNAS, WHICH HAVE THERAPEUTIC EFFECTS. 2020 14 2493 51 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 15 2170 39 EPIGENETIC MECHANISMS IN RESPIRATORY MUSCLE DYSFUNCTION OF PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE. EPIGENETIC EVENTS ARE DIFFERENTIALLY EXPRESSED IN THE LUNGS AND AIRWAYS OF PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). MOREOVER, EPIGENETIC MECHANISMS ARE INVOLVED IN THE SKELETAL (PERIPHERAL) MUSCLE DYSFUNCTION OF COPD PATIENTS. WHETHER EPIGENETIC EVENTS MAY ALSO REGULATE RESPIRATORY MUSCLE DYSFUNCTION IN COPD REMAINS UNKNOWN. WE HYPOTHESIZED THAT EPIGENETIC MECHANISMS WOULD BE DIFFERENTIALLY EXPRESSED IN THE MAIN INSPIRATORY MUSCLE (DIAPHRAGM) OF PATIENTS WITH COPD OF A WIDE RANGE OF DISEASE SEVERITY COMPARED TO HEALTHY CONTROLS. IN DIAPHRAGM MUSCLE SPECIMENS (THORACOTOMY DUE TO LUNG LOCALIZED NEOPLASMS) OF SEDENTARY PATIENTS WITH MILD-TO-MODERATE AND SEVERE COPD, WITH PRESERVED BODY COMPOSITION, AND SEDENTARY HEALTHY CONTROLS, EXPRESSION OF MUSCLE-ENRICHED MICRORNAS, HISTONE ACETYLTRANSFERASES (HATS) AND DEACETYLASES (HDACS), TOTAL DNA METHYLATION AND PROTEIN ACETYLATION, SMALL UBIQUITIN-RELATED MODIFIER (SUMO) LIGASES, MUSCLE-SPECIFIC TRANSCRIPTION FACTORS, AND MUSCLE STRUCTURE WERE EXPLORED. ALL SUBJECTS WERE ALSO CLINICALLY EVALUATED: LUNG AND MUSCLE FUNCTIONS AND EXERCISE CAPACITY. COMPARED TO HEALTHY CONTROLS, PATIENTS EXHIBITED MODERATE AIRFLOW LIMITATION AND DIFFUSION CAPACITY, AND REDUCED EXERCISE TOLERANCE AND TRANSDIAPHRAGMATIC STRENGTH. MOREOVER, IN THE DIAPHRAGM OF THE COPD PATIENTS, MUSCLE-SPECIFIC MICRORNA EXPRESSION WAS DOWNREGULATED, WHILE HDAC4 AND MYOCYTE ENHANCER FACTOR (MEF)2C PROTEIN LEVELS WERE HIGHER, AND DNA METHYLATION LEVELS, MUSCLE FIBER TYPES AND SIZES DID NOT DIFFER BETWEEN PATIENTS AND CONTROLS. IN THE MAIN RESPIRATORY MUSCLE OF COPD PATIENTS WITH A WIDE RANGE OF DISEASE SEVERITY AND NORMAL BODY COMPOSITION, MUSCLE-SPECIFIC MICRORNAS WERE DOWNREGULATED, WHILE HDAC4 AND MEF2C LEVELS WERE UPREGULATED. IT IS LIKELY THAT THESE EPIGENETIC EVENTS ACT AS BIOLOGICAL ADAPTIVE MECHANISMS TO BETTER OVERCOME THE CONTINUOUS INSPIRATORY LOADS OF THE RESPIRATORY SYSTEM IN COPD. THESE FINDINGS MAY OFFER NOVEL THERAPEUTIC STRATEGIES TO SPECIFICALLY TARGET RESPIRATORY MUSCLE DYSFUNCTION IN PATIENTS WITH COPD. 2014 16 2926 36 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 17 3193 51 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 18 4228 31 METHYLATION OF INFLAMMATORY CELLS IN LUNG DISEASES. THIS CHAPTER OVERVIEWS ROLES OF DNA METHYLATION IN INFLAMMATORY CELL BIOLOGY WITH THE FOCUSES ON LYMPHOCYTES AND MACROPHAGES/MONOCYTES IN LUNG DISEASES, ALTHOUGH THE MOLECULAR MECHANISMS BY WHICH TARGET GENES ARE METHYLATED AND REGULATED IN LUNG DISEASES REMAIN UNCLEAR. MOST OF EPIGENETIC STUDIES ON DNA METHYLATION OF TARGET GENES IN LUNG DISEASES MAINLY DEMONSTRATED THE CORRELATION OF DNA METHYLATION OF TARGET GENES WITH THE LEVELS OF OTHER CORRESPONDING FACTORS, WITH THE SPECIFICITY OF CLINICAL PHENOMES, AND WITH THE SEVERITY OF LUNG DISEASES. THERE IS AN URGENT NEED TO IDENTIFY AND VALIDATE THE SPECIFICITY AND REGULATORY MECHANISMS OF INFLAMMATORY CELL EPIGENETICS IN DEPTH. THE EPIGENETIC HETEROGENEITY AMONG DIFFERENT SUBSETS OF T CELLS AND AMONG PROMOTERS OR NON-PROMOTERS OF TARGET GENES SHOULD BE FURTHERMORE CLARIFIED IN ACUTE OR CHRONIC LUNG DISEASES AND CANCERS. THE HYPER/HYPO-METHYLATION AND MODIFICATIONS OF CHROMOSOL AND EXTRACHROMOSOMAL DNA MAY RESULT IN ALTERNATIONS IN PROTEINS WITHIN INFLAMMATORY CELLS, WHICH CAN BE IDENTIFIED AS DISEASE-SPECIFIC BIOMARKERS AND THERAPEUTIC TARGETS. 2020 19 6533 39 TRANSCRIPTIONAL REGULATION OF INFLAMMATORY GENES ASSOCIATED WITH SEVERE ASTHMA. THE 10% OF PATIENTS WITH THE MOST SEVERE ASTHMA ARE RESPONSIBLE FOR A LARGE PART OF HEALTHCARE EXPENDITURE AND MORBIDITY. UNDERSTANDING THE PROCESSES INVOLVED IS KEY IF NEW THERAPEUTIC APPROACHES ARE TO BE DEVELOPED. EVIDENCE IS ACCUMULATING THAT CHRONIC DISEASES SUCH AS ASTHMA ARE ASSOCIATED WITH TEMPORAL AND SPATIAL ALTERATIONS IN THE PATTERN OF INFLAMMATORY GENE EXPRESSION WITHIN THE AIRWAYS. EXPRESSION OF THESE GENES CAN BE REGULATED BY TRANSCRIPTIONAL, POSTTRANSCRIPTIONAL, TRANSLATIONAL AND EPIGENETIC MECHANISMS. IT IS WELL ESTABLISHED THAT BINDING OF ACTIVATED TRANSCRIPTION FACTORS TO SPECIFIC INDUCIBLE GENE PROMOTER SITES IS TIGHTLY CONTROLLED BY CHROMATIN STATE AS A RESULT OF HISTONE MODIFICATIONS, PARTICULARLY THE BALANCE BETWEEN HISTONE ACETYLATION AND DEACETYLATION [1]. THE INTERACTION BETWEEN TRANSCRIPTION FACTORS AND THE PROMOTER IS KEY TO THE DIVERSIFICATION OF GENE EXPRESSION IN A TIME DEPENDENT MANNER LEADING TO ALTERED GENE EXPRESSION PROFILES. ALTERATIONS OF THE ACCESSIBILITY OF TRANSCRIPTION FACTORS TO THE DNA CAN HAVE RESIDING EFFECTS UPON GENE TRANSCRIPTION. THIS REVIEW WILL FOCUS ON THE REGULATION OF SEVERAL GROUPS OF KEY GENES WHICH ARE INVOLVED IN CHRONIC AIRWAY INFLAMMATION AND REMODELLING IN ASTHMA DRAWING MAINLY FROM OUR EXPERIENCE OF STUDYING THESE PROCESSES IN AIRWAY SMOOTH MUSCLE CELLS. AN OVERVIEW IS SHOWN IN FIGURE 1. 2011 20 5422 43 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