1  3079 182 GENOME-WIDE METHYLATION AND EXPRESSION ANALYSES REVEAL THE EPIGENETIC LANDSCAPE OF IMMUNE-RELATED DISEASES FOR TOBACCO SMOKING. BACKGROUND: SMOKING IS A MAJOR CAUSAL RISK FACTOR FOR LUNG CANCER, CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), CARDIOVASCULAR DISEASE (CVD), AND IS THE MAIN PREVENTABLE CAUSE OF DEATHS IN THE WORLD. THE COMPONENTS OF CIGARETTE SMOKE ARE INVOLVED IN IMMUNE AND INFLAMMATORY PROCESSES, WHICH MAY INCREASE THE PREVALENCE OF CIGARETTE SMOKE-RELATED DISEASES. HOWEVER, THE UNDERLYING MOLECULAR MECHANISMS LINKING SMOKING AND DISEASES HAVE NOT BEEN WELL EXPLORED. THIS STUDY WAS AIMED TO DEPICT A GLOBAL MAP OF DNA METHYLATION AND GENE EXPRESSION CHANGES INDUCED BY TOBACCO SMOKING AND TO EXPLORE THE MOLECULAR MECHANISMS BETWEEN SMOKING AND HUMAN DISEASES THROUGH WHOLE-GENOME BISULFITE SEQUENCING (WGBS) AND RNA-SEQUENCING (RNA-SEQ). RESULTS: WE PERFORMED WGBS ON 72 SAMPLES (36 SMOKERS AND 36 NONSMOKERS) AND RNA-SEQ ON 75 SAMPLES (38 SMOKERS AND 37 NONSMOKERS), AND CYTOKINE IMMUNOASSAY ON PLASMA FROM 22 MALES (9 SMOKERS AND 13 NONSMOKERS) WHO WERE RECRUITED FROM THE CITY OF JINCHENG IN CHINA. BY COMPARING THE DATA OF THE TWO GROUPS, WE DISCOVERED A GENOME-WIDE METHYLATION LANDSCAPE OF DIFFERENTIALLY METHYLATED REGIONS (DMRS) ASSOCIATED WITH SMOKING. FUNCTIONAL ENRICHMENT ANALYSES REVEALED THAT BOTH SMOKING-RELATED HYPER-DMR GENES (DMGS) AND HYPO-DMGS WERE RELATED TO SYNAPSE-RELATED PATHWAYS, WHEREAS THE HYPO-DMGS WERE SPECIFICALLY RELATED TO CANCER AND ADDICTION. THE DIFFERENTIALLY EXPRESSED GENES (DEGS) REVEALED BY RNA-SEQ ANALYSIS WERE SIGNIFICANTLY ENRICHED IN THE "IMMUNOSUPPRESSION" PATHWAY. CORRELATION ANALYSIS OF DMRS WITH THEIR CORRESPONDING GENE EXPRESSION SHOWED THAT GENES AFFECTED BY TOBACCO SMOKING WERE MOSTLY RELATED TO IMMUNE SYSTEM DISEASES. FINALLY, BY COMPARING CYTOKINE CONCENTRATIONS BETWEEN SMOKERS AND NONSMOKERS, WE FOUND THAT VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) WAS SIGNIFICANTLY UPREGULATED IN SMOKERS. CONCLUSIONS: IN SUM, WE FOUND THAT SMOKING-INDUCED DMRS HAVE DIFFERENT DISTRIBUTION PATTERNS IN HYPERMETHYLATED AND HYPOMETHYLATED AREAS BETWEEN SMOKERS AND NONSMOKERS. WE FURTHER IDENTIFIED AND VERIFIED SMOKING-RELATED DMGS AND DEGS THROUGH MULTI-OMICS INTEGRATION ANALYSIS OF DNA METHYLOME AND TRANSCRIPTOME DATA. THESE FINDINGS PROVIDE US A COMPREHENSIVE GENOMIC MAP OF THE MOLECULAR CHANGES INDUCED BY SMOKING WHICH WOULD ENHANCE OUR UNDERSTANDING OF THE HARMS OF SMOKING AND ITS RELATIONSHIP WITH DISEASES.	2021	

2  3423  49 HUMAN PRIMARY AIRWAY EPITHELIAL CELLS ISOLATED FROM ACTIVE SMOKERS HAVE EPIGENETICALLY IMPAIRED ANTIVIRAL RESPONSES. BACKGROUND: CIGARETTE SMOKING (CS) IS THE MAIN RISK FACTOR FOR THE DEVELOPMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND MOST COPD EXACERBATIONS ARE CAUSED BY RESPIRATORY INFECTIONS INCLUDING INFLUENZA. INFLUENZA INFECTIONS ARE MORE SEVERE IN SMOKERS. THE MECHANISM OF THE INCREASED RISK AND SEVERITY OF INFECTIONS IN SMOKERS IS LIKELY MULTIFACTORIAL, BUT CERTAINLY INCLUDES CHANGES IN IMMUNOLOGIC HOST DEFENSES. METHODS: WE INVESTIGATED RETINOIC ACID-INDUCIBLE PROTEIN I (RIG-I) AND INTERFERON (IFN) INDUCTION BY INFLUENZA A VIRUS (IAV) IN HUMAN BRONCHIAL EPITHELIAL CELLS (HBEC) ISOLATED FROM SMOKERS OR NONSMOKERS. SUBCULTURED HBEC CELLS WERE INFECTED WITH A/PUERTO RICO/8/1934 (PR8) IAV AT AN MOI OF 1. AFTER 24 H OF INFECTION, CELLS AND SUPERNATANTS WERE COLLECTED FOR QRT-PCR, IMMUNOBLOT OR ELISA TO DETERMINE RIG-I, TOLL-LIKE RECEPTOR3 (TLR3) AND IFN EXPRESSION LEVELS. RESULTS: IAV EXPOSURE INDUCED A VIGOROUS IFN-BETA, IFN-LAMBDA 1 AND IFN-LAMBDA 2/3 ANTIVIRAL RESPONSE IN HBEC FROM NONSMOKERS AND SIGNIFICANT INDUCTION OF RIG-I AND TLR3. IN CELLS FROM SMOKERS, VIRAL RIG-I AND TLR3 MRNA INDUCTION WAS REDUCED 87 AND 79 % COMPARED TO THE RESPONSE FROM NONSMOKERS. CS EXPOSURE HISTORY WAS ASSOCIATED WITH INHIBITION OF VIRAL INDUCTION OF THE IFN-BETA, IFN-LAMBDA1 AND IFN-LAMBDA 2/3 MRNA RESPONSE BY 85, 96 AND 95 %, RESPECTIVELY, FROM THAT SEEN IN HBEC FROM NONSMOKERS. THE DEMETHYLATING AGENT 5-AZA-2-DEOXYCYTIDINE REVERSED THE IMMUNOSUPPRESSIVE EFFECTS OF CS EXPOSURE IN HBEC SINCE VIRAL INDUCTION OF ALL THREE IFNS WAS RESTORED. IFN-BETA INDUCTION OF RIG-I AND TLR3 WAS ALSO SUPPRESSED IN THE CELLS FROM SMOKERS. CONCLUSION: OUR RESULTS SUGGEST THAT ACTIVE SMOKING REDUCES EXPRESSION OF ANTIVIRAL CYTOKINES IN PRIMARY HBEC CELLS. THIS EFFECT LIKELY OCCURS VIA DOWNREGULATION OF RIG-I AND TLR3 DUE TO SMOKE-INDUCED EPIGENETIC MODIFICATIONS. REDUCTION IN LUNG EPITHELIAL CELL RIG-I AND TLR3 RESPONSES MAY BE A MAJOR MECHANISM CONTRIBUTING TO THE INCREASED RISK AND SEVERITY OF VIRAL RESPIRATORY INFECTIONS IN SMOKERS AND TO VIRAL-MEDIATED ACUTE EXACERBATIONS OF COPD.	2016	
                                                                                                                                                                                                                                                                                           
3  5744  38 SMOKING-INDUCED EXPRESSION OF THE GPR15 GENE INDICATES ITS POTENTIAL ROLE IN CHRONIC INFLAMMATORY PATHOLOGIES. DESPITE THE DESCRIBED CLEAR EPIGENETIC EFFECTS OF SMOKING, THE EFFECT OF SMOKING ON GENOME-WIDE GENE EXPRESSION IN THE BLOOD IS OBSCURE. WE THEREFORE STUDIED THE SMOKING-INDUCED CHANGES IN THE GENE-EXPRESSION PROFILE OF THE PERIPHERAL BLOOD. RNA WAS EXTRACTED FROM THE WHOLE BLOOD OF 48 INDIVIDUALS WITH A DETAILED SMOKING HISTORY (24 NEVER-SMOKERS, 16 SMOKERS, AND 8 EX-SMOKERS). GENE-EXPRESSION PROFILES WERE EVALUATED WITH RNA SEQUENCING, AND RESULTS WERE ANALYZED SEPARATELY IN 24 MEN AND 24 WOMEN. IN THE MALE SMOKERS, 13 GENES WERE STATISTICALLY SIGNIFICANTLY (FALSE-DISCOVERY RATE <0.1) DIFFERENTIALLY EXPRESSED; IN FEMALE SMOKERS, 5 GENES. ALTHOUGH MOST OF THE DIFFERENTIALLY EXPRESSED GENES WERE DIFFERENT BETWEEN THE MALE AND FEMALE SMOKERS, THE G-PROTEIN-COUPLED RECEPTOR 15 GENE (GPR15) WAS DIFFERENTIALLY EXPRESSED IN BOTH MALE AND FEMALE SMOKERS COMPARED WITH NEVER-SMOKERS. ANALYSIS OF GPR15 METHYLATION IDENTIFIED SIGNIFICANTLY GREATER HYPOMETHYLATION IN SMOKERS COMPARED WITH THAT IN NEVER-SMOKERS. GPR15 IS THE CHEMOATTRACTANT RECEPTOR THAT REGULATES T-CELL MIGRATION AND IMMUNITY. UP-REGULATION OF GPR15 COULD EXPLAIN TO SOME EXTENT THE HEALTH HAZARDS OF SMOKING WITH REGARD TO CHRONIC INFLAMMATORY DISEASES.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
4  5517  40 RISK FACTOR ASSESSMENT OF RHEUMATOID ARTHRITIS IN NORTH KERALA. OBJECTIVE: RHEUMATOID ARTHRITIS (RA) IS A MULTIFACTORIAL DISEASE; IT LEADS TO DISABLING AND PAINFUL CHRONIC INFLAMMATORY ARTHRITIS. ITS ONSET MAY BE DELAYED OR EVEN PREVENTED BY MODIFYING THE RISK FACTORS INVOLVED. MANY GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS ARE IMPLICATED IN THE PATHOGENESIS OF RA. THE OBJECTIVES OF THIS CASE-CONTROL STUDY WERE TO ASSESS VARIOUS RISK FACTORS IN OUR POPULATION AND TO COMPARE THE SAME WITH AGE- AND SEX-MATCHED CONTROLS. METHODS: WE STUDIED 118 CASES WITH RA DIAGNOSED USING THE EULAR CRITERIA. IN TOTAL, 581 AGE- AND SEX-MATCHED CONTROLS WERE SELECTED. EACH INDIVIDUAL WAS ADMINISTERED A SEPARATE QUESTIONNAIRE REGARDING THEIR RISK FACTORS (KNOWN RISK FACTORS WERE STUDIED). THE IMPLICATED DIETARY FACTORS WERE INCORPORATED IN A FOOD FREQUENCY QUESTIONNAIRE (FFQ) AND ADMINISTERED TO BOTH CASES AND CONTROLS. COMPARISON WAS MADE BETWEEN THOSE WHO CONSUME AN ITEM AT A PARTICULAR FREQUENCY, WHO CONSUME LESS, AND WHO CONSUME NOTHING AT ALL. AMONG THOSE WHO CONSUME, EACH GROUP WAS RE-COMPARED. STATISTICAL ANALYSIS WAS CONDUCTED USING STATISTICAL PACKAGE FOR SOCIAL SCIENCES (IBM CORP.; ARMONK, NY, USA). RESULTS: THERE WAS SIGNIFICANT RELATIONSHIP FOR FAMILY HISTORY, PERIODONTITIS, HISTORY OF CHIKUNGUNYA, AND SUN EXPOSURE (P<0.05). ASSOCIATION WITH VARIOUS FOOD ITEMS WAS STUDIED USING THE FFQ, BUT THE RELATIONSHIP WAS INCONSISTENT, PROBABLY DUE TO CONSUMPTION OF MODIFIED DIET BY THE PERSONS WITH RA. ALSO, A MAJORITY OF CASES WERE FEMALES AND NONSMOKERS FOR ASSESSING AN ASSOCIATION WITH SMOKING HABITS. CONCLUSION: IN OUR POPULATION, PREVIOUS INFECTIONS (E.G., CHIKUNGUNYA AND POOR ORAL HYGIENE WITH PERIODONTITIS) WERE THE PROMINENTLY OBSERVED RISK FACTORS. ALSO, SMOKING WAS LESS COMMON AMONG WOMEN, AND PROBABLY CONTRIBUTED LESS, AS MAJORITY OF CASES WERE FEMALES. FOR DIETARY PATTERN ASSOCIATION, A PROSPECTIVE COHORT STUDY MAY BE NEEDED.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
5  3767  48 INTEGRATIVE EPIGENOMIC ANALYSIS IN DIFFERENTIATED HUMAN PRIMARY BRONCHIAL EPITHELIAL CELLS EXPOSED TO CIGARETTE SMOKE. CIGARETTE SMOKE (CS) IS ONE OF THE MAJOR RISK FACTORS FOR MANY PULMONARY DISEASES, INCLUDING CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND LUNG CANCER. THE FIRST LINE OF DEFENSE FOR CS EXPOSURE IS THE BRONCHIAL EPITHELIAL CELLS. ELUCIDATION OF THE EPIGENETIC CHANGES DURING CS EXPOSURE IS KEY TO GAINING A MECHANISTIC UNDERSTANDING INTO HOW MATURE AND DIFFERENTIATED BRONCHIAL EPITHELIAL CELLS RESPOND TO CS. THEREFORE, WE PERFORMED EPIGENOMIC PROFILING IN CONJUNCTION WITH TRANSCRIPTIONAL PROFILING IN WELL-DIFFERENTIATED HUMAN BRONCHIAL EPITHELIAL (HBE) CELLS CULTURED IN AIR-LIQUID INTERFACE (ALI) EXPOSED TO THE VAPOR PHASE OF CS. THE GENOME-WIDE ENRICHMENT OF HISTONE 3 LYSINE 27 ACETYLATION WAS DETECTED BY CHROMATIN IMMUNOPRECIPITATION FOLLOWED BY NEXT GENERATION SEQUENCING (CHIP-SEQ) IN HBE CELLS AND SUGGESTED THE PLAUSIBLE BINDING OF SPECIFIC TRANSCRIPTION FACTORS RELATED TO CS EXPOSURE. ADDITIONALLY, INTERROGATION OF CHIP-SEQ DATA WITH GENE EXPRESSION PROFILING OF HBE CELLS AFTER CS EXPOSURE FOR DIFFERENT DURATIONS (3 HOURS, 2 DAYS, 4 DAYS) SUGGESTED THAT EARLIER EPIGENETIC CHANGES (3 HOURS AFTER CS EXPOSURE) MAY BE ASSOCIATED WITH LATER GENE EXPRESSION CHANGES INDUCED BY CS EXPOSURE (4 DAYS). THE INTEGRATION OF EPIGENETICS AND GENE EXPRESSION DATA REVEALED SIGNALING PATHWAYS RELATED TO CS-INDUCED EPIGENETIC CHANGES IN HBE CELLS THAT MAY IDENTIFY NOVEL REGULATORY PATHWAYS RELATED TO CS-INDUCED COPD.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
6   401  53 ANALYSIS OF ABERRANT METHYLATION ON PROMOTER SEQUENCES OF TUMOR SUPPRESSOR GENES AND TOTAL DNA IN SPUTUM SAMPLES: A PROMISING TOOL FOR EARLY DETECTION OF COPD AND LUNG CANCER IN SMOKERS. BACKGROUND: CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A DISORDER ASSOCIATED TO CIGARETTE SMOKE AND LUNG CANCER (LC). SINCE EPIGENETIC CHANGES IN ONCOGENES AND TUMOR SUPPRESSOR GENES (TSGS) ARE CLEARLY IMPORTANT IN THE DEVELOPMENT OF LC. IN THIS STUDY, WE HYPOTHESIZE THAT TOBACCO SMOKERS ARE SUSCEPTIBLE FOR METHYLATION IN THE PROMOTER REGION OF TSGS IN AIRWAY EPITHELIAL CELLS WHEN COMPARED WITH NON-SMOKER SUBJECTS. THE PURPOSE OF THIS STUDY WAS TO INVESTIGATE THE USEFULNESS OF DETECTION OF GENES PROMOTER METHYLATION IN SPUTUM SPECIMENS, AS A COMPLEMENTARY TOOL TO IDENTIFY LC BIOMARKERS AMONG SMOKERS WITH EARLY COPD. METHODS: WE DETERMINED THE AMOUNT OF DNA IN INDUCED SPUTUM FROM PATIENTS WITH COPD (N = 23), LC (N = 26), AS WELL AS IN HEALTHY SUBJECTS (CTR) (N = 33), USING A COMMERCIAL KIT FOR DNA PURIFICATION, FOLLOWED BY ABSORBANCE MEASUREMENT AT 260 NM. THE FREQUENCY OF CDKN2A, CDH1 AND MGMT PROMOTER METHYLATION IN THE SAME GROUPS WAS DETERMINED BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP). THE FISHER'S EXACT TEST WAS EMPLOYED TO COMPARE FREQUENCY OF RESULTS BETWEEN DIFFERENT GROUPS. RESULTS: DNA CONCENTRATION WAS 7.4 AND 5.8 TIMES HIGHER IN LC AND COPD COMPARED TO THE (CTR) (P < 0.0001), RESPECTIVELY. METHYLATION STATUS OF CDKN2A AND MGMT WAS SIGNIFICANTLY HIGHER IN COPD AND LC PATIENTS COMPARED WITH CTR GROUP (P < 0.0001). FREQUENCY OF CDH1 METHYLATION ONLY SHOWED A STATISTICALLY SIGNIFICANT DIFFERENCE BETWEEN LC PATIENTS AND CTR GROUP (P < 0.05). CONCLUSIONS: WE PROVIDE EVIDENCE THAT ABERRANT METHYLATION OF TSGS IN SAMPLES OF INDUCED SPUTUM IS A USEFUL TOOL FOR EARLY DIAGNOSTIC OF LUNG DISEASES (LC AND COPD) IN SMOKER SUBJECTS. VIRTUAL SLIDES: THE ABSTRACT MUST FINISH WITH THE FOLLOWING TEXT: VIRTUAL SLIDES THE VIRTUAL SLIDE(S) FOR THIS ARTICLE CAN BE FOUND HERE: HTTP://WWW.DIAGNOSTICPATHOLOGY.DIAGNOMX.EU/VS/1127865005664160.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                      
7  2643  47 EPIGENOMIC ASSOCIATION ANALYSIS IDENTIFIES SMOKING-RELATED DNA METHYLATION SITES IN AFRICAN AMERICANS. CIGARETTE SMOKING IS AN ENVIRONMENTAL RISK FACTOR FOR MANY CHRONIC DISEASES, AND DISEASE RISK CAN OFTEN BE MANAGED BY SMOKING CONTROL. SMOKING CAN INDUCE CELLULAR AND MOLECULAR CHANGES, INCLUDING EPIGENETIC MODIFICATION, BUT THE SHORT- AND LONG-TERM EPIGENETIC MODIFICATIONS CAUSED BY CIGARETTE SMOKING AT THE GENE LEVEL HAVE NOT BEEN WELL UNDERSTOOD. RECENT STUDIES HAVE IDENTIFIED SMOKING-RELATED DNA METHYLATION (DNAM) SITES IN CAUCASIANS. TO DETERMINE WHETHER THE SAME DNAM SITES ASSOCIATE WITH SMOKING IN AFRICAN AMERICANS, AND TO IDENTIFY NOVEL SMOKING-RELATED DNAM SITES, WE CONDUCTED A METHYLOME-WIDE ASSOCIATION STUDY OF CIGARETTE SMOKING USING A DISCOVERY SAMPLE OF 972 AFRICAN AMERICANS, AND A REPLICATION SAMPLE OF 239 AFRICAN AMERICANS WITH TWO ARRAY-BASED METHODS. AMONG 15 DNAM SITES SIGNIFICANTLY ASSOCIATED WITH SMOKING AFTER CORRECTION FOR MULTIPLE TESTING IN OUR DISCOVERY SAMPLE, 5 DNAM SITES ARE REPLICATED IN AN INDEPENDENT COHORT, AND 14 SITES IN THE REPLICATION SAMPLE HAVE EFFECTS IN THE SAME DIRECTION AS IN THE DISCOVERY SAMPLE. THE TOP TWO SMOKING-RELATED DNAM SITES IN F2RL3 (FACTOR II RECEPTOR-LIKE 3) AND GPR15 (G-PROTEIN-COUPLED RECEPTOR 15) OBSERVED IN AFRICAN AMERICANS ARE CONSISTENT WITH PREVIOUS FINDINGS IN CAUCASIANS. THE ASSOCIATIONS BETWEEN THE REPLICATED DNAM SITES AND SMOKING REMAIN SIGNIFICANT AFTER ADJUSTING FOR GENETIC BACKGROUND. DESPITE THE DISTINCT GENETIC BACKGROUND BETWEEN AFRICAN AMERICANS AND CAUCASIANS, THE DNAM FROM THE TWO ETHNIC GROUPS SHARES COMMON ASSOCIATIONS WITH CIGARETTE SMOKING, WHICH SUGGESTS A COMMON MOLECULAR MECHANISM OF EPIGENETIC MODIFICATION INFLUENCED BY ENVIRONMENTAL EXPOSURE.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
8   972  53 CHRONIC OBSTRUCTIVE PULMONARY DISEASE IS ASSOCIATED WITH EPIGENOME-WIDE DIFFERENTIAL METHYLATION IN BAL LUNG CELLS. DNA METHYLATION PATTERNS IN CHRONIC PULMONARY OBSTRUCTIVE DISEASE (COPD) MIGHT OFFER NEW INSIGHTS INTO DISEASE PATHOGENESIS. TO ASSESS METHYLATION PROFILES IN THE MAIN COPD TARGET ORGAN, WE PERFORMED AN EPIGENOME-WIDE ASSOCIATION STUDY ON BAL CELLS. BRONCHOSCOPIES WERE PERFORMED IN 18 SUBJECTS WITH COPD AND 15 CONTROL SUBJECTS (EX- AND CURRENT SMOKERS). DNA METHYLATION WAS MEASURED USING THE ILLUMINA METHYLATIONEPIC BEADCHIP KIT, COVERING MORE THAN 850,000 CPGS. DIFFERENTIALLY METHYLATED POSITIONS (DMPS) WERE EXAMINED FOR 1) ENRICHMENT IN PATHWAYS AND FUNCTIONAL GENE RELATIONSHIPS USING THE KYOTO ENCYCLOPEDIA OF GENES AND GENOMES AND GENE ONTOLOGY, 2) ACCELERATED AGING USING HORVATH'S EPIGENETIC CLOCK, 3) CORRELATION WITH GENE EXPRESSION, AND 4) COLOCALIZATION WITH GENETIC VARIATION. WE FOUND 1,155 BONFERRONI-SIGNIFICANT (P < 6.74 X 10(-8)) DMPS ASSOCIATED WITH COPD, MANY WITH LARGE EFFECT SIZES. FUNCTIONAL ANALYSIS IDENTIFIED BIOLOGICALLY PLAUSIBLE PATHWAYS AND GENE RELATIONSHIPS, INCLUDING ENRICHMENT FOR TRANSCRIPTION FACTOR ACTIVITY. STRONG CORRELATION WAS FOUND BETWEEN DNA METHYLATION AND CHRONOLOGICAL AGE BUT NOT BETWEEN COPD AND ACCELERATED AGING. FOR 79 UNIQUE DMPS, DNA METHYLATION CORRELATED SIGNIFICANTLY WITH GENE EXPRESSION IN BAL CELLS. THIRTY-NINE PERCENT OF DMPS WERE COLOCALIZED WITH COPD-ASSOCIATED SNPS. TO THE BEST OF OUR KNOWLEDGE, THIS IS THE FIRST EPIGENOME-WIDE ASSOCIATION STUDY OF COPD ON BAL CELLS, AND OUR ANALYSES REVEALED MANY DIFFERENTIAL METHYLATION SITES. INTEGRATION WITH MRNA DATA SHOWED A STRONG FUNCTIONAL READOUT FOR RELEVANT GENES, IDENTIFYING SITES WHERE DNA METHYLATION MIGHT DIRECTLY AFFECT EXPRESSION. ALMOST HALF OF DMPS WERE COLOCATED WITH SNPS IDENTIFIED IN PREVIOUS GENOME-WIDE ASSOCIATION STUDIES OF COPD, SUGGESTING JOINT GENETIC AND EPIGENETIC PATHWAYS RELATED TO DISEASE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
9  2910  51 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
10  3497  56 IDENTIFICATION OF NOVEL EPIGENETIC ABNORMALITIES AS SPUTUM BIOMARKERS FOR LUNG CANCER RISK AMONG SMOKERS AND COPD PATIENTS. OBJECTIVES: SMOKING IS A COMMON RISK FACTOR FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND LUNG CANCER. ALTHOUGH COPD PATIENTS HAVE HIGHER RISK OF LUNG CANCER COMPARED TO NON-COPD SMOKERS, THE MOLECULAR LINKS BETWEEN THESE DISEASES ARE NOT WELL-DEFINED. THIS STUDY AIMS TO IDENTIFY GENES THAT ARE DOWNREGULATED BY CIGARETTE SMOKE AND COMMONLY REPRESSED IN COPD AND LUNG CANCER. MATERIALS AND METHODS: PRIMARY HUMAN AIRWAY EPITHELIAL CELLS (HAEC) WERE EXPOSED TO CIGARETTE-SMOKE-EXTRACT (CSE) FOR 10-WEEKS AND SIGNIFICANTLY SUPPRESSED GENES WERE IDENTIFIED BY TRANSCRIPTOME ARRAY. EPIGENETIC ABNORMALITIES OF THESE GENES IN LUNG ADENOCARCINOMA (LUAD) FROM PATIENTS WITH OR WITHOUT COPD WERE DETERMINED USING GENOME-WIDE AND GENE-SPECIFIC ASSAYS AND BY IN VITRO TREATMENT OF CELL LINES WITH TRICHOSTATIN-A OR 5-AZA-2-DEOXYCYTIDINE. RESULTS: THE TEN MOST COMMONLY DOWNREGULATED GENES FOLLOWING CHRONIC CSE EXPOSURE OF HAEC AND SHOW PROMOTER HYPERMETHYLATION IN LUAD WERE SELECTED. AMONG THESE, EXPRESSION OF CCNA1, SNCA, AND ZNF549 WAS SIGNIFICANTLY REDUCED IN LUNG TISSUES FROM COPD COMPARED WITH NON-COPD CASES WHILE EXPRESSION OF CCNA1 AND SNCA WAS FURTHER DOWNREGULATED IN TUMORS WITH COPD. THE PROMOTER REGIONS OF ALL THREE GENES WERE HYPERMETHYLATED IN LUAD BUT NOT NORMAL OR COPD LUNGS. THE REDUCED EXPRESSION AND ABERRANT PROMOTER HYPERMETHYLATION OF THESE GENES IN LUAD WERE INDEPENDENTLY VALIDATED USING DATA FROM THE CANCER GENOME ATLAS PROJECT. IMPORTANTLY, SNCA AND ZNF549 METHYLATION DETECTED IN SPUTUM DNA FROM LUAD (52% AND 38%) CASES WERE MORE PREVALENT COMPARED TO CANCER-FREE SMOKERS (26% AND 15%), RESPECTIVELY (P < 0.02). CONCLUSIONS: OUR DATA SHOW THAT SUPPRESSION OF CCNA1, SNCA, AND ZNF549 IN LUNG CANCER AND COPD OCCURS WITH OR WITHOUT PROMOTER HYPERMETHYLATION, RESPECTIVELY. DETECTING METHYLATION OF THESE AND PREVIOUSLY IDENTIFIED GENES IN SPUTUM OF CANCER-FREE SMOKERS MAY SERVE AS NON-INVASIVE BIOMARKERS FOR EARLY DETECTION OF LUNG CANCER AMONG HIGH RISK SMOKERS INCLUDING COPD PATIENTS.	2020	
                                                                                                                                                                                                                                                                                                                                                     
11  5743  45 SMOKING SUPPRESSES THE THERAPEUTIC POTENTIAL OF ADIPOSE STEM CELLS IN CROHN'S DISEASE PATIENTS THROUGH EPIGENETIC CHANGES. PATIENTS WITH CROHN'S DISEASE (CD) WHO SMOKE ARE KNOWN TO HAVE A WORSE PROGNOSIS THAN NEVER-SMOKERS AND A HIGHER RISK FOR POST-SURGICAL RECURRENCE, WHEREAS PATIENTS WHO QUIT SMOKING AFTER SURGERY HAVE SIGNIFICANTLY LOWER POST-OPERATIVE RECURRENCE. THE HYPOTHESIS WAS THAT SMOKING INDUCES EPIGENETIC CHANGES THAT IMPAIR THE CAPACITY OF ADIPOSE STEM CELLS (ASCS) TO SUPPRESS THE IMMUNE SYSTEM. IT WAS ALSO QUESTIONED WHETHER THIS IMPAIRMENT REMAINS IN EX-SMOKERS WITH CD. ASCS WERE ISOLATED FROM NON-SMOKERS, SMOKERS AND EX-SMOKERS WITH CD AND THEIR INTERACTIONS WITH IMMUNE CELLS WERE STUDIED. THE ASCS FROM BOTH SMOKERS AND EX-SMOKERS PROMOTED MACROPHAGE POLARIZATION TO AN M1 PRO-INFLAMMATORY PHENOTYPE, WERE NOT ABLE TO INHIBIT T- AND B-CELL PROLIFERATION IN VITRO AND ENHANCED THE GENE AND PROTEIN EXPRESSION OF INFLAMMATORY MARKERS INCLUDING INTERLEUKIN-1B. GENOME-WIDE EPIGENETIC ANALYSIS USING TWO DIFFERENT BIOINFORMATIC APPROACHES REVEALED SIGNIFICANT CHANGES IN THE METHYLATION PATTERNS OF GENES THAT ARE CRITICAL FOR WOUND HEALING, IMMUNE AND METABOLIC RESPONSE AND P53-MEDIATED DNA DAMAGE RESPONSE IN ASCS FROM SMOKERS AND EX-SMOKERS WITH CD. IN CONCLUSION, CIGARETTE SMOKING INDUCES A PRO-INFLAMMATORY EPIGENETIC SIGNATURE IN ASCS THAT LIKELY COMPROMISES THEIR THERAPEUTIC POTENTIAL.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
12   304  47 AIRWAY AGING AND METHYLATION DISRUPTIONS IN HIV-ASSOCIATED CHRONIC OBSTRUCTIVE PULMONARY DISEASE. RATIONALE: AGE-RELATED DISEASES LIKE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) OCCUR AT HIGHER RATES IN PEOPLE LIVING WITH HUMAN IMMUNODEFICIENCY VIRUS (PLWH) THAN IN UNINFECTED POPULATIONS. OBJECTIVES: TO IDENTIFY WHETHER ACCELERATED AGING CAN BE OBSERVED IN THE AIRWAYS OF PLWH WITH COPD, MANIFEST BY A UNIQUE DNA METHYLATION SIGNATURE. METHODS: BRONCHIAL EPITHELIAL BRUSHINGS FROM PLWH WITH AND WITHOUT COPD AND HIV-UNINFECTED ADULTS WITH AND WITHOUT COPD (N = 76) WERE PROFILED FOR DNA METHYLATION AND GENE EXPRESSION. WE EVALUATED GLOBAL ALU AND LINE-1 METHYLATION AND CALCULATED THE EPIGENETIC AGE USING THE HORVATH CLOCK AND THE METHYLATION TELOMERE LENGTH ESTIMATOR. TO IDENTIFY GENOME-WIDE DIFFERENTIAL DNA METHYLATION AND GENE EXPRESSION ASSOCIATED WITH HIV AND COPD, ROBUST LINEAR MODELS WERE USED FOLLOWED BY AN EXPRESSION QUANTITATIVE TRAIT METHYLATION (EQTM) ANALYSIS. MEASUREMENTS AND MAIN RESULTS: EPIGENETIC AGE ACCELERATION AND SHORTER METHYLATION ESTIMATES OF TELOMERE LENGTH WERE FOUND IN PLWH WITH COPD COMPARED WITH PLWH WITHOUT COPD AND UNINFECTED PATIENTS WITH AND WITHOUT COPD. GLOBAL HYPOMETHYLATION WAS IDENTIFIED IN PLWH. WE IDENTIFIED 7,970 CYTOSINE BASES LOCATED NEXT TO A GUANINE BASE (CPG SITES), 293 GENES, AND 9 EXPRESSION QUANTITATIVE TRAIT METHYLATION-GENE PAIRS ASSOCIATED WITH THE INTERACTION BETWEEN HIV AND COPD. ACTIN BINDING LIM PROTEIN FAMILY MEMBER 3 (ABLIM3) WAS ONE OF THE NOVEL CANDIDATE GENES FOR HIV-ASSOCIATED COPD HIGHLIGHTED BY OUR ANALYSIS. CONCLUSIONS: METHYLATION AGE ACCELERATION IS OBSERVED IN THE AIRWAY EPITHELIUM OF PLWH WITH COPD, A PROCESS THAT MAY BE RESPONSIBLE FOR THE HEIGHTENED RISK OF COPD IN THIS POPULATION. THEIR DISTINCT METHYLATION PROFILE, DIFFERING FROM THAT OBSERVED IN PATIENTS WITH COPD ALONE, SUGGESTS A UNIQUE PATHOGENESIS TO HIV-ASSOCIATED COPD. THE ASSOCIATIONS WARRANT FURTHER INVESTIGATION TO ESTABLISH CAUSALITY.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
13  1589  64 DNA METHYLATION PROFILING IN A CIGARETTE SMOKE-EXPOSED MOUSE MODEL OF AIRWAY INFLAMMATION. PURPOSE: DNA METHYLATION, A MAJOR EPIGENETIC MODIFICATION, HAS BEEN DOCUMENTED TO PLAY AN IMPORTANT ROLE IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). IN THIS STUDY, WE AIMED TO PROFILE THE DNA METHYLATION PATTERNS IN A MOUSE MODEL OF AIRWAY INFLAMMATION INDUCED BY CIGARETTE SMOKE (CS), A FOREMOST RISK FACTOR OF COPD. MATERIAL AND METHODS: TO ESTABLISH A MODEL OF AIRWAY INFLAMMATION, WILD-TYPE MICE WERE EXPOSED TO MAINSTREAM CS OR ROOM AIR FOR 2 HOURS TWICE DAILY, 6 DAYS PER WEEK FOR CONSECUTIVE 4 WEEKS. LUNG TISSUES OF THE MICE WERE COLLECTED FOR GENOME-WIDE DNA METHYLATION ANALYSIS BY LIQUID HYBRIDIZATION CAPTURE-BASED BISULFITE SEQUENCING, WHICH WERE USED FOR INTERSECTION ANALYSIS WITH GENE EXPRESSION BY CDNA MICROARRAY TO IDENTIFY CANDIDATE METHYLATED GENES. THEN, FUNCTIONAL ENRICHMENT ANALYSES WITH PROTEIN-PROTEIN INTERACTION (PPI) NETWORK REGARDING THESE GENES WERE CONDUCTED TO EXPLORE THE POTENTIAL MECHANISMS. RESULTS: AFTER 4-WEEK CS EXPOSURE, THE LEVEL OF DNA METHYLATION ACCOMPANIED BY A SUBACUTE AIRWAY INFLAMMATION WAS MARKEDLY ENHANCED, AND 2002 DIFFERENTIALLY METHYLATED GENES (DMGS) WERE ANNOTATED, INCLUDING 565 DMGS CONTAINED METHYLATIONS IN GENE PROMOTERS, WHICH WERE USED FOR INTERSECTION WITH THE DIFFERENTIALLY EXPRESSED GENES. THEN, 135 CANDIDATE METHYLATED GENES WERE FURTHER SELECTED BY THE INTERSECTION, AMONG WHICH 58 GENES WITH FUNCTIONAL METHYLATED MODIFICATION WERE FINALLY IDENTIFIED. FURTHER ANALYSES REVEALED CANDIDATE METHYLATED GENES WERE SIGNIFICANTLY ENRICHED IN A COMPLICATED NETWORK OF SIGNALS AND PROCESSES, INCLUDING INTERLEUKINS, TOLL-LIKE RECEPTORS, T-CELLS DIFFERENTIATION, OXIDATIVE STRESS, MAST CELLS ACTIVATION, STEM CELLS PROLIFERATION, ETC., AS WELL AS THE 58 FUNCTIONAL METHYLATED GENES WERE PARTIALLY LOCATED AT KEY POSITIONS IN PPI NETWORK, ESPECIALLY CXCL1, DDX58 AND JAK3. CONCLUSION: THIS STUDY SUGGESTS CS EXPOSURE SIGNIFICANTLY ENHANCES DNA METHYLATED LEVEL, AND THE POTENTIAL FUNCTIONAL METHYLATED GENES ARE CLOSELY RELATED TO COMPLICATED INFLAMMATORY-IMMUNE RESPONSES, WHICH MAY PROVIDE SOME NEW EXPERIMENTAL EVIDENCE IN UNDERSTANDING THE EPIGENETIC MECHANISMS OF CS-INDUCED AIRWAY INFLAMMATION IN COPD.	2022	
                                                                                                                                                                                                                         
14  1264  49 CYP2E1 EPIGENETIC REGULATION IN CHRONIC, LOW-LEVEL TOLUENE EXPOSURE: RELATIONSHIP WITH OXIDATIVE STRESS AND SMOKING HABIT. BACKGROUND: CYP2E1 IS A VERSATILE PHASE I DRUG-METABOLIZING ENZYME RESPONSIBLE FOR THE BIOTRANSFORMATION OF MOST VOLATILE ORGANIC COMPOUNDS, INCLUDING TOLUENE. HUMAN TOLUENE EXPOSURE INCREASES CYP2E1 MRNA AND MODIFIES ITS ACTIVITY IN LEUCOCYTES; HOWEVER, EPIGENETIC IMPLICATIONS OF THIS INTERACTION HAVE NOT BEEN INVESTIGATED. GOAL: TO DETERMINE PROMOTER METHYLATION OF CYP2E1 AND OTHER GENES KNOWN TO BE AFFECTED BY TOLUENE EXPOSURE. METHODS: WE OBTAINED VENOUS BLOOD FROM 24 TANNERY WORKERS EXPOSED TO TOLUENE (MEAN LEVELS: 10.86+/-7MG/M(3)) AND 24 ADMINISTRATIVE WORKERS (REFERENCE GROUP, MEAN LEVELS 0.21+/-0.02MG/M(3)) ALL OF THEM FROM THE CITY OF LEON, GUANAJUATO, MEXICO. AFTER DNA EXTRACTION AND BISULFITE TREATMENT, WE PERFORMED PCR-PYROSEQUENCING IN ORDER TO MEASURE METHYLATION LEVELS AT PROMOTER REGION OF 13 GENES. RESULTS: IN EXPOSED GROUP WE FOUND SIGNIFICANT CORRELATIONS BETWEEN TOLUENE AIRBORNE LEVELS AND CYP2E1 PROMOTER METHYLATION (R=-.36, P<0.05), AS WELL AS FOR IL6 PROMOTER METHYLATION LEVELS (R=.44, P<0.05). MOREOVER, CYP2E1 PROMOTER METHYLATION LEVELS WHERE HIGHER IN TOLUENE-EXPOSED SMOKERS COMPARED TO NONSMOKERS (P=0.009). WE ALSO OBSERVED SIGNIFICANT CORRELATIONS FOR CYP2E1 PROMOTER METHYLATION WITH GSTP1 AND SOD1 PROMOTER METHYLATION LEVELS (R=-.37, P<0.05 AND R=-.34, P<0.05 RESPECTIVELY). CONCLUSION: THESE RESULTS HIGHLIGHT THE IMPORTANCE OF CONSIDERING CYP2E1 EPIGENETIC MODIFICATIONS, AS WELL AS ITS INTERACTIONS WITH OTHER GENES, AS KEY FACTORS FOR UNRAVELING THE SUB CELLULAR MECHANISMS OF TOXICITY EXERTED BY OXIDATIVE STRESS, WHICH CAN INITIATE DISEASE PROCESS IN CHRONIC, LOW-LEVEL TOLUENE EXPOSURE. PEOPLE CO-EXPOSED TO TOLUENE AND TOBACCO SMOKE ARE IN HIGHER RISK DUE TO A POSSIBLE CYP2E1 REPRESSION.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
15  3460  34 HYPOMETHYLATION OF THE IL8 PROMOTER IN NASAL EPITHELIAL CELLS OF PATIENTS WITH CHRONIC RHINOSINUSITIS WITH NASAL POLYPS. BACKGROUND: IL-8 IS AN IMPORTANT CHEMOKINE IMPLICATED IN THE PATHOGENESIS OF CHRONIC RHINOSINUSITIS (CRS), BUT LITTLE IS KNOWN ABOUT EPIGENETIC REGULATION OF IL8 IN THE PATHOGENESIS OF CRS. OBJECTIVE: WE SOUGHT TO INVESTIGATE THE RELATIONSHIP BETWEEN THE DNA METHYLATION LEVEL IN THE IL8 PROXIMAL PROMOTER AND CRS IN HAN CHINESE SUBJECTS. METHODS: PATIENTS WITH CHRONIC RHINOSINUSITIS WITH NASAL POLYPS (CRSWNP; N = 187), PATIENTS WITH CHRONIC RHINOSINUSITIS WITHOUT NASAL POLYPS (CRSSNP; N = 89), AND CONTROL SUBJECTS (N = 57) WERE ENROLLED IN 2 INDEPENDENT COHORTS. PURIFIED HUMAN NASAL EPITHELIAL CELLS FROM EACH PARTICIPANT WERE ASSESSED FOR PERCENTAGE DNA METHYLATION OF CPG SITES IN THE IL8 PROXIMAL PROMOTER BY USING BISULFITE PYROSEQUENCING AND FOR FUNCTIONAL ASPECTS OF METHYLATION STATUS BY USING IN VITRO ASSAYS. RESULTS: DNA METHYLATION OF CPG SITES 1, 2, AND 3, RESPECTIVELY, IN THE IL8 PROXIMAL PROMOTER WAS SIGNIFICANTLY DECREASED IN HUMAN NASAL EPITHELIAL CELLS OF PATIENTS WITH CRSWNP COMPARED WITH THAT IN PATIENTS WITH CRSSNP (P < .001) AND CONTROL SUBJECTS (P < .001). PERCENTAGE OF DNA METHYLATION OF THE CPG3 SITE WAS CORRELATED NEGATIVELY WITH BOTH TISSUE EOSINOPHILIC CATIONIC PROTEIN (P < .01) AND MYELOPEROXIDASE (P < .05) LEVELS. IL-1BETA (P < .001) AND TNF-ALPHA (P < .01) SIGNIFICANTLY INCREASED IL8 EXPRESSION ACCOMPANIED BY A REDUCTION IN METHYLATION AT THE CPG3 SITE (P < .001). ELECTROPHORETIC MOBILITY SHIFT ASSAYS DEMONSTRATED THAT METHYLATION STATUS OF CPG3 CHANGED THE BINDING OF OCTAMER-BINDING TRANSCRIPTION FACTOR 1 AND NUCLEAR FACTOR KAPPAB. CONCLUSION: DECREASED DNA METHYLATION OF PARTICULARLY CPG SITES IN THE IL8 PROXIMAL PROMOTER MIGHT PLAY A ROLE IN THE PATHOGENESIS OF CRSWNP.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
16  1708  41 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
17  3939  34 LNC-IL7R ALLEVIATES PM(2.5)-MEDIATED CELLULAR SENESCENCE AND APOPTOSIS THROUGH EZH2 RECRUITMENT IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE. BACKGROUND: LONG-TERM EXPOSURE TO PM(2.5) (PARTICULATE MATTER WITH AN AERODYNAMIC DIAMETER OF </= 2.5 MUM) IS ASSOCIATED WITH PULMONARY INJURY AND EMPHYSEMA IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). WE INVESTIGATED MECHANISMS THROUGH WHICH THE LONG NONCODING RNA LNC-IL7R CONTRIBUTES TO CELLULAR DAMAGE BY INDUCING OXIDATIVE STRESS IN COPD PATIENTS EXPOSED TO PM(2.5). METHODS: ASSOCIATIONS OF SERUM LNC-IL7R LEVELS WITH LUNG FUNCTION, EMPHYSEMA, AND PREVIOUS PM(2.5) EXPOSURE IN COPD PATIENTS WERE ANALYZED. REACTIVE OXYGEN SPECIES AND LNC-IL7R LEVELS WERE MEASURED IN PM(2.5)-TREATED CELLS. THE LEVELS OF LNC-IL7R AND CELLULAR SENESCENCE-ASSOCIATED GENES, NAMELY P16(INK4A) AND P21(CIP1/WAF1), WERE DETERMINED THROUGH LUNG TISSUE SECTION STAINING. THE EFFECTS OF P16(INK4A) OR P21(CIP1/WAF1) REGULATION WERE EXAMINED BY PERFORMING LNC-IL7R OVEREXPRESSION AND KNOCKDOWN ASSAYS. THE FUNCTIONS OF LNC-IL7R-MEDIATED CELL PROLIFERATION, CELL CYCLE, SENESCENCE, COLONY FORMATION, AND APOPTOSIS WERE EXAMINED IN CELLS TREATED WITH PM(2.5). CHROMATIN IMMUNOPRECIPITATION ASSAYS WERE CONDUCTED TO INVESTIGATE THE EPIGENETIC REGULATION OF P21(CIP1/WAF1). RESULTS: LNC-IL7R LEVELS DECREASED IN COPD PATIENTS AND WERE NEGATIVELY CORRELATED WITH EMPHYSEMA OR PM(2.5) EXPOSURE. LNC-IL7R LEVELS WERE UPREGULATED IN NORMAL LUNG EPITHELIAL CELLS BUT NOT IN COPD CELLS EXPOSED TO PM(2.5). LOWER LNC-IL7R EXPRESSION IN PM(2.5)-TREATED CELLS INDUCED P16(INK4A) AND P21(CIP1/WAF1) EXPRESSION BY INCREASING OXIDATIVE STRESS. HIGHER LNC-IL7R EXPRESSION PROTECTED AGAINST CELLULAR SENESCENCE AND APOPTOSIS, WHEREAS LOWER LNC-IL7R EXPRESSION AUGMENTED INJURY IN PM(2.5)-TREATED CELLS. LNC-IL7R AND THE ENHANCER OF ZESTE HOMOLOG 2 (EZH2) SYNERGISTICALLY SUPPRESSED P21(CIP1/WAF1) EXPRESSION THROUGH EPIGENETIC MODULATION. CONCLUSION: LNC-IL7R ATTENUATES PM(2.5)-MEDIATED P21(CIP1/WAF1) EXPRESSION THROUGH EZH2 RECRUITMENT, AND ITS DYSFUNCTION MAY AUGMENT CELLULAR INJURY IN COPD.	2022	
                                                                                                                                                                                                                                                                                                                                                                                    
18  4899  42 OXIDATIVE STRESS MEDIATES THE APOPTOSIS AND EPIGENETIC MODIFICATION OF THE BCL-2 PROMOTER VIA DNMT1 IN A CIGARETTE SMOKE-INDUCED EMPHYSEMA MODEL. BACKGROUND: EMPHYSEMA IS A CRUCIAL PATHOLOGICAL CHARACTERISTIC OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). OXIDATIVE STRESS, APOPTOSIS AND EPIGENETIC MECHANISMS CONTRIBUTE TO THE PATHOGENESIS OF EMPHYSEMA. HOWEVER, AN ATTEMPT TO ACCURATELY IDENTIFY WHETHER THESE MECHANISMS INTERACT WITH EACH OTHER AND HOW THEY ARE TRIGGERED HAS NEVER BEEN CONDUCTED. METHOD: THE TOTAL REACTIVE OXYGEN SPECIES (ROS) LEVEL, PULMONARY APOPTOSIS AND B-CELL LYMPHOMA/LEUKEMIA-2 (BCL-2) EXPRESSION, AN APOPTOSIS REGULATOR, WERE DETECTED IN SAMPLES FROM COPD PATIENTS. BISULFITE SEQUENCING PCR (BSP) WAS CONDUCTED TO OBSERVE THE ALTERATIONS IN THE METHYLATION OF THE BCL-2 PROMOTER IN SPECIMENS. THE DYSREGULATION OF DNA METHYLTRANSFERASE ENZYME 1 (DNMT1), A VITAL DNA METHYLTRANSFERASE ENZYME, IN THE LUNGS OF PATIENTS WAS CONFIRMED THROUGH WESTERN BLOTTING. TO FIND OUT INTERACTIONS BETWEEN OXIDATIVE STRESS AND DNA METHYLATION IN EMPHYSEMA, MOUSE MODELS WERE BUILT WITH ANTIOXIDANT TREATMENT AND DNMT1 SILENCING, AND WERE EXAMINED WITH THE PULMONARY APOPTOSIS, BCL-2 AND DNMT1 LEVELS, AND EPIGENETIC ALTERATIONS OF BCL-2. RESULTS: HIGHER ROS LEVELS AND PULMONARY APOPTOSIS WERE OBSERVED IN COPD PATIENTS THAN IN HEALTHY CONTROLS. DOWNREGULATED BCL-2 EXPRESSION WITH INCREASED PROMOTER METHYLATION AND DNMT1 PROTEIN EXPRESSION WAS FOUND IN COPD PATIENTS. ANTIOXIDANT TREATMENT REDUCED THE LEVEL OF ROS, DNMT1 PROTEIN AND EMPHYSEMATOUS PROGRESSION IN THE SMOKING MODELS. FOLLOWING DNMT1 BLOCKADE, SMOKING MODELS SHOWED IMPROVED LUNG FUNCTION, PULMONARY APOPTOSIS, EMPHYSEMATOUS PROGRESSION, AND INCREASED BCL-2 PROTEIN LEVEL WITH LESS PROMOTER METHYLATION THAN EMPHYSEMA MICE. CONCLUSION: CIGARETTE-INDUCED OXIDATIVE STRESS MEDIATES PULMONARY APOPTOSIS AND HYPERMETHYLATION OF THE BCL-2 PROMOTER IN EMPHYSEMA MODELS THROUGH DNMT1.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
19  1552  51 DNA METHYLATION IS PREDICTIVE OF MORTALITY IN CURRENT AND FORMER SMOKERS. RATIONALE: SMOKING RESULTS IN AT LEAST A DECADE LOWER LIFE EXPECTANCY. MORTALITY AMONG CURRENT SMOKERS IS TWO TO THREE TIMES AS HIGH AS NEVER SMOKERS. DNA METHYLATION IS AN EPIGENETIC MODIFICATION OF THE HUMAN GENOME THAT HAS BEEN ASSOCIATED WITH BOTH CIGARETTE SMOKING AND MORTALITY.OBJECTIVES: WE SOUGHT TO IDENTIFY DNA METHYLATION MARKS IN BLOOD THAT ARE PREDICTIVE OF MORTALITY IN A SUBSET OF THE COPDGENE (GENETIC EPIDEMIOLOGY OF COPD) STUDY, REPRESENTING 101 DEATHS AMONG 667 CURRENT AND FORMER SMOKERS.METHODS: WE ASSAYED GENOME-WIDE DNA METHYLATION IN NON-HISPANIC WHITE SMOKERS WITH AND WITHOUT CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) USING BLOOD SAMPLES FROM THE COPDGENE ENROLLMENT VISIT. WE TESTED WHETHER DNA METHYLATION WAS ASSOCIATED WITH MORTALITY IN MODELS ADJUSTED FOR COPD STATUS, AGE, SEX, CURRENT SMOKING STATUS, AND PACK-YEARS OF CIGARETTE SMOKING. REPLICATION WAS PERFORMED IN A SUBSET OF 231 INDIVIDUALS FROM THE ECLIPSE (EVALUATION OF COPD LONGITUDINALLY TO IDENTIFY PREDICTIVE SURROGATE ENDPOINTS) STUDY.MEASUREMENTS AND MAIN RESULTS: WE IDENTIFIED SEVEN CPG SITES ASSOCIATED WITH MORTALITY (FALSE DISCOVERY RATE < 20%) THAT REPLICATED IN THE ECLIPSE COHORT (P < 0.05). NONE OF THESE MARKS WERE ASSOCIATED WITH LONGITUDINAL LUNG FUNCTION DECLINE IN SURVIVORS, SMOKING HISTORY, OR CURRENT SMOKING STATUS. HOWEVER, DIFFERENTIAL METHYLATION OF TWO REPLICATED PIK3CD (PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT DELTA) SITES WERE ASSOCIATED WITH LUNG FUNCTION AT ENROLLMENT (P < 0.05). WE ALSO OBSERVED ASSOCIATIONS BETWEEN DNA METHYLATION AND GENE EXPRESSION FOR THE PIK3CD SITES.CONCLUSIONS: THIS STUDY IS THE FIRST TO IDENTIFY VARIABLE DNA METHYLATION ASSOCIATED WITH ALL-CAUSE MORTALITY IN SMOKERS WITH AND WITHOUT COPD. EVALUATING PREDICTIVE EPIGENOMIC MARKS OF SMOKERS IN PERIPHERAL BLOOD MAY ALLOW FOR TARGETED RISK STRATIFICATION AND AID IN DELIVERY OF FUTURE TAILORED THERAPEUTIC INTERVENTIONS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
20  1194  51 CORRELATION OF EPIGENETIC CHANGE AND IDENTIFICATION OF RISK FACTORS FOR ORAL SUBMUCOUS FIBROSIS. BACKGROUND: DNA METHYLATION OF CERTAIN GENES IS AN EPIGENETIC CHANGE THAT IS ESSENTIAL FOR TUMORIGENESIS. ORAL SUBMUCOUS FIBROSIS (OSF) IS A PRECANCEROUS CONDITION OF ORAL MUCOSA WITH INFLAMMATION AND PROGRESSIVE FIBROSIS OF THE LAMINA PROPRIA AND DEEPER CONNECTIVE TISSUE. THE HYPERMETHYLATION OF E-CADHERIN AND CYCLOOXYGENASE 2 (COX-2) IN CHRONIC INFLAMMATION MAY DEMONSTRATE A MILD LESION/MUTATION AT EPIGENETIC LEVELS. THIS STUDY COMPARES THE HYPERMETHYLATION STATUS OF E-CADHERIN AND COX-2 GENES IN PATIENTS WITH ORAL CANCER AND PATIENTS WITH OSF AND ALSO AIMS TO IDENTIFY RISK FACTORS FOR THE DEVELOPMENT OF OSF. METHODS: DNA WAS EXTRACTED FROM BLOOD SAMPLES OF 50 HEALTHY SUBJECTS, 50 PATIENTS WITH OSF AND 60 PATIENTS WITH ORAL CANCER. METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION FOR E-CADHERIN AND COX-2 WAS PERFORMED ON THESE SAMPLES AND THE PRODUCTS WERE ANALYZED ON 2% AGAROSE GEL. SURVEYS ABOUT ORAL HEALTH HABITS AND CLINICAL PERIODONTAL EXAMINATIONS IN PATIENTS WITH OSF AND HEALTHY SUBJECTS WERE ALSO CONDUCTED BY WELL-TRAINED DENTISTS, AND LOGISTIC REGRESSION WAS PERFORMED TO IDENTIFY RISK FACTORS FOR OSF. RESULTS: HYPERMETHYLATION OF E-CADHERIN AND COX-2 WAS OBSERVED IN 36% AND 22% OF ORAL CANCER SAMPLES, RESPECTIVELY. IN PATIENTS WITH OSF, THE RATES WERE 52% AND 30%, AND IN HEALTHY CONTROLS THE RATES WERE 4% AND 6%. HYPERMETHYLATION WAS SHOWN TO BE CORRELATED BETWEEN THE 3 GROUPS WITH STATISTICAL SIGNIFICANCE (P<0.01). METHYLATION OF CPG ISLANDS IN E-CADHERIN AND COX-2 OCCURRED MORE FREQUENTLY IN PATIENTS WITH OSF THAN IN THE CONTROL GROUP, BUT LESS FREQUENTLY THAN IN PATIENTS WITH ORAL CANCER. IN THE LOGISTIC REGRESSION ANALYSIS, SMOKING, BRUSHING MORE THAN TWICE DAILY, PERIODONTAL PROBING DEPTH AND PLAQUE INDEX WERE IDENTIFIED AS 4 MAJOR RISK FACTORS FOR OSF. CONCLUSIONS: THESE DATA CONFIRM THAT E-CADHERIN AND COX-2 EXPRESSIONS ARE RELATED TO OSF. THE EPIGENETIC CHANGES PRESENTED IN PATIENTS WITH CHRONIC INFLAMMATION MIGHT DEMONSTRATE AN IRREVERSIBLE DESTRUCTION IN THE TISSUES OR ORGANS SIMILAR TO THE EFFECTS OF CANCER. CHRONIC OSF WAS SIGNIFICANTLY ASSOCIATED WITH HYPERMETHYLATION, A CANCER RISK FACTOR.	2012