1  6069 126 THE DIOXIN RECEPTOR IS SILENCED BY PROMOTER HYPERMETHYLATION IN HUMAN ACUTE LYMPHOBLASTIC LEUKEMIA THROUGH INHIBITION OF SP1 BINDING. THE TRANSCRIPTION FACTOR ARYL HYDROCARBON RECEPTOR (AHR) HAS RELEVANT FUNCTIONS IN CELL PROLIFERATION. INTERESTINGLY, THE AHR CAN EITHER PROMOTE OR INHIBIT PROLIFERATION DEPENDING ON THE CELL PHENOTYPE. ALTHOUGH RECENT DATA REVEAL POTENTIAL PATHWAYS FOR AHR SIGNALING IN CELL PROLIFERATION, THE MECHANISMS THAT REGULATE ITS ACTIVITY IN TUMOR CELLS REMAIN UNKNOWN. HERE, WE HAVE ANALYZED PROMOTER HYPERMETHYLATION AS A POTENTIAL MECHANISM CONTROLLING AHR EXPRESSION IN HUMAN TUMOR CELLS. AHR PROMOTER CPG METHYLATION WAS SPORADIC IN A PANEL OF 19 TUMOR CELL LINES EXCEPT FOR THE CHRONIC MYELOID LEUKEMIA (CML) K562 AND THE ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) REH. WHEN COMPARED WITH NORMAL LYMPHOCYTES, REH HAD VERY LOW CONSTITUTIVE AHR EXPRESSION THAT COULD BE ATTRIBUTED TO PROMOTER HYPERMETHYLATION SINCE TREATMENT WITH THE DNA DEMETHYLATING AGENT 5-AZA-2'-DEOXYCITIDINE (AZA) SIGNIFICANTLY INCREASED AHR MRNA AND PROTEIN. THESE RESULTS IN LEUKEMIA-DERIVED CELL LINES WERE FURTHER CONFIRMED IN PRIMARY ALL, WHERE 33% OF THE PATIENTS (7/21) HAD AHR PROMOTER HYPERMETHYLATION. CHROMATIN IMMUNOPRECIPITATION (CHIP) SHOWED THAT METHYLATION IMPAIRED BINDING OF THE TRANSCRIPTION FACTOR SP1 TO THE AHR PROMOTER, THUS PROVIDING A MECHANISM FOR AHR DOWNREGULATION IN REH CELLS. THEREFORE, PROMOTER HYPERMETHYLATION REPRESENTS A NOVEL EPIGENETIC MECHANISM DOWNREGULATING AHR ACTIVITY IN HEMATOLOGICAL MALIGNANCIES SUCH AS ALL.	2006	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
2  1185  37 COORDINATED CHANGES IN AHRR METHYLATION IN LYMPHOBLASTS AND PULMONARY MACROPHAGES FROM SMOKERS. SMOKING IS ASSOCIATED WITH A WIDE VARIETY OF ADVERSE HEALTH OUTCOMES INCLUDING CANCER, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, DIABETES, DEPRESSION, AND HEART DISEASE. UNFORTUNATELY, THE MOLECULAR MECHANISMS THROUGH WHICH THESE EFFECTS ARE CONVEYED ARE NOT CLEARLY UNDERSTOOD. TO EXAMINE THE POTENTIAL ROLE OF EPIGENETIC FACTORS IN THESE PROCESSES, WE EXAMINED THE RELATIONSHIP OF SMOKING TO GENOME WIDE METHYLATION AND GENE EXPRESSION USING BIOMATERIAL FROM TWO INDEPENDENT SAMPLES, LYMPHOBLAST DNA AND RNA (N = 119) AND LUNG ALVEOLAR MACROPHAGE DNA (N = 19). WE FOUND THAT IN BOTH SAMPLES CURRENT SMOKING STATUS WAS ASSOCIATED WITH SIGNIFICANT CHANGES IN DNA METHYLATION, IN PARTICULAR AT THE ARYL HYDROCARBON RECEPTOR REPRESSOR (AHRR), A KNOWN TUMOR SUPPRESSOR. BOTH BASELINE DNA METHYLATION AND SMOKER ASSOCIATED DNA METHYLATION SIGNATURES AT AHRR WERE HIGHLY CORRELATED (R = 0.94 AND 0.45, RESPECTIVELY). DNA METHYLATION AT THE MOST DIFFERENTIALLY METHYLATED AHRR CPG RESIDUE IN BOTH SAMPLES, CG0557592, WAS SIGNIFICANTLY ASSOCIATED WITH AHRR GENE EXPRESSION. PATHWAY ANALYSIS OF LYMPHOBLAST DATA (GENES WITH MOST SIGNIFICANT METHYLATION CHANGES) DEMONSTRATED ENRICHMENT IN PROTEIN KINASE C PATHWAYS AND IN TGF BETA SIGNALING PATHWAYS. FOR ALVEOLAR MACROPHAGES, PATHWAY ANALYSIS DEMONSTRATED ALTERATIONS IN INFLAMMATION-RELATED PROCESSES. WE CONCLUDE THAT SMOKING IS ASSOCIATED WITH FUNCTIONALLY SIGNIFICANT GENOME WIDE CHANGES IN DNA METHYLATION IN BOTH LYMPHOBLASTS AND PULMONARY MACROPHAGES AND THAT FURTHER INTEGRATED INVESTIGATIONS OF THESE EPIGENETIC EFFECTS OF SMOKING ON CARCINOGENESIS AND OTHER RELATED CO-MORBIDITIES ARE INDICATED.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
3   567  27 BASIC PROPERTIES AND MOLECULAR MECHANISMS OF EXOGENOUS CHEMICAL CARCINOGENS. EXOGENOUS CHEMICAL CARCINOGENESIS IS AN EXTREMELY COMPLEX MULTIFACTORIAL PROCESS DURING WHICH GENE-ENVIRONMENT INTERACTIONS INVOLVING CHRONIC EXPOSURE TO EXOGENOUS CHEMICAL CARCINOGENS (ECCS) AND POLYMORPHISMS OF CANCER SUSCEPTIBILITY GENES ADD FURTHER COMPLEXITY. WE DESCRIBE THE PROPERTIES AND MOLECULAR MECHANISMS OF ECCS THAT CONTRIBUTE TO INDUCE AND GENERATE CANCER. A BASIC AND SPECIFIC PROPERTY OF MANY LIPOPHILIC ORGANIC ECCS INCLUDING POLYCYCLIC AROMATIC HYDROCARBONS AND POLYHALOGENATED AROMATIC HYDROCARBONS IS THEIR ABILITY TO BIOACCUMULATE IN THE ADIPOSE TISSUE FROM WHERE THEY MAY BE RELEASED IN THE BLOOD CIRCULATION AND TARGET PERIPHERAL TISSUES FOR CARCINOGENESIS. MANY ORGANIC ECCS ARE PROCARCINOGENS AND CONSEQUENTLY NEED TO BE ACTIVATED BY THE CYTOCHROME P450 (CYP) SYSTEM AND/OR OTHER ENZYMES BEFORE THEY CAN ADDUCT DNA AND PROTEINS. BECAUSE THEY CONTRIBUTE NOT ONLY TO THE COCARCINOGENIC AND PROMOTING EFFECTS OF MANY AROMATIC POLLUTANTS BUT ALSO TO THEIR MUTAGENIC EFFECTS, THE ARYL HYDROCARBON RECEPTOR-ACTIVATING AND THE INDUCIBLE CYP SYSTEMS ARE CENTRAL TO EXOGENOUS CHEMICAL CARCINOGENESIS. ANOTHER BASIC PROPERTY OF ECCS IS THEIR ABILITY TO INDUCE STABLE AND BULKY DNA ADDUCTS THAT CANNOT BE SIMPLY REPAIRED BY THE DIFFERENT REPAIR SYSTEMS. IN ADDITION, FOLLOWING ECC EXPOSURE, MUTAGENESIS MAY ALSO BE CAUSED INDIRECTLY BY FREE-RADICAL PRODUCTION AND BY EPIGENETIC ALTERATIONS. AS A RESULT OF COMPLEX MOLECULAR INTERPLAYS, DIRECT AND/OR INDIRECT MUTAGENESIS MAY ESPECIALLY ACCOUNT FOR THE CARCINOGENIC EFFECTS OF MANY EXOGENOUS METALS AND METALLOIDS. BECAUSE OF THESE MOLECULAR PROPERTIES AND ACTION MECHANISMS, WE CONCLUDE THAT ECCS COULD BE MAJOR CONTRIBUTORS TO HUMAN CANCER, WITH OBVIOUSLY GREAT PUBLIC HEALTH CONSEQUENCES.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
4  5066  38 PHTHALATES SUPPRESS TYPE I INTERFERON IN HUMAN PLASMACYTOID DENDRITIC CELLS VIA EPIGENETIC REGULATION. BACKGROUND: EXPOSURE TO ENVIRONMENTAL ENDOCRINE-DISRUPTING CHEMICALS (EDCS) IS ASSOCIATED WITH ALLERGY, CHRONIC INFLAMMATION, AND IMMUNODEFICIENCY. PHTHALATES, THE COMMON EDCS USED IN PLASTIC INDUSTRY, MAY ACT AS ADJUVANTS TO DISRUPT IMMUNE SYSTEM AND ENHANCE ALLERGY. PLASMACYTOID DCS (PDCS) ARE PREDOMINANT CELLS SECRETING TYPE I INTERFERON (IFN) AGAINST INFECTION AND ARE PROFESSIONAL ANTIGEN-PRESENTING CELLS IN REGULATING ADAPTIVE IMMUNITY. HOWEVER, THE EFFECTS OF PHTHALATES ON THE FUNCTION OF PDCS ARE UNKNOWN. METHODS: CIRCULATING PDCS WERE ISOLATED FROM HEALTHY SUBJECTS, WERE PRETREATED WITH DIETHYLHEXYL PHTHALATE (DEHP) AND BUTYL BENZYL PHTHALATE (BBP), AND WERE STIMULATED WITH TOLL-LIKE RECEPTOR (TLR)-9 AGONIST CPG. IFN-ALPHA/IFN-BETA LEVELS, SURFACE MARKERS, AND T-CELL STIMULATORY FUNCTION WERE INVESTIGATED USING ELISA, FLOW CYTOMETRY, AND PDC/T-CELL COCULTURE ASSAY. MECHANISMS WERE INVESTIGATED USING RECEPTOR ANTAGONISTS, PATHWAY INHIBITORS, WESTERN BLOTTING, AND CHROMATIN IMMUNOPRECIPITATION. RESULTS: DIETHYLHEXYL PHTHALATE AND BUTYL BENZYL PHTHALATE SUPPRESSED CPG-INDUCED IFN-ALPHA/IFN-BETA EXPRESSION IN PDCS, AND THE EFFECT WAS REVERSED BY ARYL HYDROCARBON RECEPTOR (AHR) ANTAGONIST. DIETHYLHEXYL PHTHALATE SUPPRESSED CPG-ACTIVATED MITOGEN-ACTIVATED PROTEIN KINASE (MAPK)-MEK1/2-ERK-ELK1 AND NFKAPPAB SIGNALING PATHWAYS. DIETHYLHEXYL PHTHALATE SUPPRESSED CPG-INDUCED INTERFERON REGULATORY FACTOR (IRF)-7 EXPRESSION BY SUPPRESSING HISTONE H3K4 TRIMETHYLATION AT IRF7 GENE PROMOTER REGION THROUGH INHIBITING TRANSLOCATION OF H3K4-SPECIFIC TRIMETHYLTRANSFERASE WDR5 FROM CYTOPLASM INTO NUCLEUS. BUTYL BENZYL PHTHALATE OR DIETHYLHEXYL PHTHALATE-TREATED PDCS SUPPRESSED IFN-GAMMA BUT ENHANCED IL-13 PRODUCTION BY CD4+ T CELLS. CONCLUSION: PHTHALATES MAY INTERFERE WITH IMMUNITY AGAINST INFECTION AND PROMOTE THE DEVIATION OF TH2 RESPONSE TO INCREASE ALLERGY BY ACTING ON HUMAN PDCS VIA SUPPRESSING IFN-ALPHA/IFN-BETA EXPRESSION AND MODULATING THE ABILITY TO STIMULATE T-CELL RESPONSES.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
5  3746  43 INSIGHTS INTO THE EPIGENETICS OF CHRONIC RHINOSINUSITIS WITH AND WITHOUT NASAL POLYPS: A SYSTEMATIC REVIEW. BACKGROUND: EPIGENETICS FACILITATES INSIGHTS ON THE IMPACT OF HOST ENVIRONMENT ON THE GENESIS OF CHRONIC RHINOSINUSITIS (CRS) THROUGH MODULATIONS OF HOST GENE EXPRESSION AND ACTIVITY. EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION CAUSE REVERSIBLE BUT HERITABLE CHANGES IN GENE EXPRESSION OVER GENERATIONS OF PROGENY, WITHOUT ALTERING THE DNA BASE-PAIR SEQUENCES. THESE STUDIES OFFER A CRITICAL UNDERSTANDING OF THE ENVIRONMENT-INDUCED CHANGES THAT RESULT IN HOST PREDISPOSITION TO DISEASE AND MAY HELP IN DEVELOPING NOVEL BIOMARKERS AND THERAPEUTICS. THE GOAL OF THIS SYSTEMATIC REVIEW IS TO SUMMARIZE THE CURRENT EVIDENCE ON EPIGENETICS OF CRS WITH A FOCUS ON CHRONIC RHINOSINUSITIS WITH NASAL POLYPS (CRSWNP) AND HIGHLIGHT GAPS THAT MERIT FURTHER RESEARCH. METHODS: A SYSTEMATIC REVIEW OF THE ENGLISH LANGUAGE LITERATURE WAS PERFORMED TO IDENTIFY INVESTIGATIONS RELATED TO EPIGENETIC STUDIES IN SUBJECTS WITH CRS. RESULTS: THE REVIEW IDENTIFIED 65 STUDIES. THESE HAVE FOCUSED ON DNA METHYLATION AND NON-CODING RNAS, WITH ONLY A FEW ON HISTONE DEACETYLATION, ALTERNATIVE POLYADENYLATION, AND CHROMATIN ACCESSIBILITY. STUDIES INCLUDE THOSE INVESTIGATING IN VIVO AND IN VITRO CHANGES OR BOTH. STUDIES ALSO INCLUDE ANIMAL MODELS OF CRS. ALMOST ALL HAVE BEEN CONDUCTED IN ASIA. THE GENOME-WIDE STUDIES OF DNA METHYLATION FOUND DIFFERENCES IN GLOBAL METHYLATION BETWEEN CRSWNP AND CONTROLS, WHILE OTHERS SPECIFICALLY FOUND SIGNIFICANT DIFFERENCES IN METHYLATION OF THE CPG SITES OF THE THYMIC STROMAL LYMPHOPOIETIN (TSLP), IL-8, AND PLAT. IN ADDITION, DNA METHYLTRANSFERASE INHIBITORS AND HISTONE DEACETYLASE INHIBITORS WERE STUDIED AS POTENTIAL THERAPEUTIC AGENTS. MAJORITY OF THE STUDIES INVESTIGATING NON-CODING RNAS FOCUSED ON MICRO-RNAS (MIRNA) AND FOUND DIFFERENCES IN GLOBAL EXPRESSION OF MIRNA LEVELS. THESE STUDIES ALSO REVEALED SOME PREVIOUSLY KNOWN AS WELL AS NOVEL TARGETS AND PATHWAYS SUCH AS TUMOR NECROSIS FACTOR ALPHA, TGF BETA-1, IL-10, EGR2, ARYL HYDROCARBON RECEPTOR, PI3K/AKT PATHWAY, MUCIN SECRETION, AND VASCULAR PERMEABILITY. OVERALL, THE STUDIES HAVE FOUND A DYSREGULATION IN PATHWAYS/GENES INVOLVING INFLAMMATION, IMMUNE REGULATION, TISSUE REMODELING, STRUCTURAL PROTEINS, MUCIN SECRETION, ARACHIDONIC ACID METABOLISM, AND TRANSCRIPTION. CONCLUSIONS: EPIGENETIC STUDIES IN CRS SUBJECTS SUGGEST THAT THERE IS LIKELY A MAJOR IMPACT OF THE ENVIRONMENT. HOWEVER, THESE ARE ASSOCIATION STUDIES AND DO NOT DIRECTLY IMPLY PATHOGENESIS. LONGITUDINAL STUDIES IN GEOGRAPHICALLY AND RACIALLY DIVERSE POPULATION COHORTS ARE NECESSARY TO QUANTIFY GENETIC VS. ENVIRONMENTAL RISKS FOR CRSWNP AND CRS WITHOUT NASAL POLYPS AND ASSESS HERITABILITY RISK, AS WELL AS DEVELOP NOVEL BIOMARKERS AND THERAPEUTIC AGENTS.	2023	
                                                                                                                                                                                                              
6   846  34 CHILDHOOD EXPOSURE TO AMBIENT POLYCYCLIC AROMATIC HYDROCARBONS IS LINKED TO EPIGENETIC MODIFICATIONS AND IMPAIRED SYSTEMIC IMMUNITY IN T CELLS. BACKGROUND: EVIDENCE SUGGESTS THAT EXPOSURE TO POLYCYCLIC AROMATIC HYDROCARBONS (PAHS) INCREASES ATOPY; IT IS UNCLEAR HOW PAH EXPOSURE IS LINKED TO INCREASED SEVERITY OF ATOPIC DISEASES. OBJECTIVE: WE HYPOTHESIZED THAT AMBIENT PAH EXPOSURE IS LINKED TO IMPAIRMENT OF IMMUNITY IN ATOPIC CHILDREN (DEFINED AS CHILDREN WITH ASTHMA AND/OR ALLERGIC RHINITIS) FROM FRESNO, CALIFORNIA, AN AREA WITH ELEVATED AMBIENT PAHS. METHODS: WE RECRUITED 256 SUBJECTS FROM FRESNO, CA. AMBIENT PAH CONCENTRATIONS (NG/M(3) ) WERE MEASURED USING A SPATIAL-TEMPORAL REGRESSION MODEL OVER MULTIPLE TIME PERIODS. ASTHMA DIAGNOSIS WAS DETERMINED BY CURRENT NHLBI CRITERIA. PHENOTYPING AND FUNCTIONAL IMMUNE MEASUREMENTS WERE PERFORMED FROM ISOLATED CELLS. FOR EPIGENETIC MEASUREMENTS, DNA WAS ISOLATED AND PYROSEQUENCED. RESULTS: WE SHOW THAT HIGHER AVERAGE PAH EXPOSURE WAS SIGNIFICANTLY ASSOCIATED WITH IMPAIRED TREG FUNCTION AND INCREASED METHYLATION IN THE FORKHEAD BOX PROTEIN 3 (FOXP3) LOCUS (P < 0.05), CONDITIONAL ON ATOPIC STATUS. THESE EPIGENETIC MODIFICATIONS WERE SIGNIFICANTLY LINKED TO DIFFERENTIAL PROTEIN EXPRESSION OF FOXP3 (P < 0.001). METHYLATION WAS ASSOCIATED WITH CELLULAR FUNCTIONAL CHANGES, SPECIFICALLY TREG DYSFUNCTION, AND AN INCREASE IN TOTAL PLASMA IGE LEVELS. PROTEIN EXPRESSION OF IL-10 DECREASED AND IFN-GAMMA INCREASED AS THE EXTENT OF PAH EXPOSURE INCREASED. THE STRENGTH OF THE ASSOCIATIONS GENERALLY INCREASED AS THE TIME WINDOW FOR AVERAGE PAH EXPOSURE INCREASED FROM 24 HR TO 1 YEAR, SUGGESTING MORE OF A CHRONIC RESPONSE. SIGNIFICANT ASSOCIATIONS WITH CHRONIC PAH EXPOSURE AND IMMUNE OUTCOMES WERE ALSO OBSERVED IN SUBJECTS WITH ALLERGIC RHINITIS. CONCLUSIONS AND CLINICAL RELEVANCE: COLLECTIVELY, THESE RESULTS DEMONSTRATE THAT INCREASED AMBIENT PAH EXPOSURE IS ASSOCIATED WITH IMPAIRED SYSTEMIC IMMUNITY AND EPIGENETIC MODIFICATIONS IN A KEY LOCUS INVOLVED IN ATOPY: FOXP3, WITH A HIGHER IMPACT ON ATOPIC CHILDREN. THE RESULTS SUGGEST THAT INCREASED ATOPIC CLINICAL SYMPTOMS IN CHILDREN COULD BE LINKED TO INCREASED PAH EXPOSURE IN AIR POLLUTION.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
7  1564  35 DNA METHYLATION OF PROXIMAL PLAT PROMOTER IN CHRONIC RHINOSINUSITIS WITH NASAL POLYPS. BACKGROUND NASAL POLYPS (NP) ARE CHARACTERIZED BY PSEUDOCYSTS DERIVED FROM STROMAL TISSUE EDEMA AND CAUSE PERSISTENT INFECTIONS IN PATIENTS WITH CHRONIC RHINOSINUSITIS (CRS). A LOW LEVEL OF TISSUE-TYPE PLASMINOGEN ACTIVATOR (GENE NAME PLAT) IS CONSIDERED A CAUSE OF STROMAL TISSUE EDEMA BECAUSE OF INSUFFICIENT PLASMIN ACTIVATION IN NP; HOWEVER, THE MECHANISM REGULATING PLAT GENE EXPRESSION LEVELS IS STILL UNCLEAR. THE EPIGENETIC MECHANISM REGULATING THE PLAT GENE EXPRESSION HAS BEEN STUDIED IN OTHER TISSUES. OBJECTIVE WE AIMED TO INVESTIGATE THE METHYLATION LEVELS IN THE PROXIMAL PLAT PROMOTER AND THEIR EFFECTS ON GENE EXPRESSION IN NP TISSUE. METHODS WE INVESTIGATED THE METHYLATION LEVELS AT 3 CPG SITES IN THE PROXIMAL PLAT PROMOTER REGIONS (-618, -121, AND -105 WITH RESPECT TO THE TRANSCRIPTION INITIATION SITE) BY BISULFITE PYROSEQUENCING AND THEIR EFFECTS ON THE GENE EXPRESSION BY QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION (QPCR) IN 20 PAIRED SAMPLES OF NP AND INFERIOR TURBINATE TISSUE (IT) FROM PATIENTS WITH CRS. RESULTS THE DNA METHYLATION LEVELS AT ALL CPG SITES WERE HIGHER ( P < .01), AND THE PLAT EXPRESSION WAS LOWER ( P < .001) IN NP COMPARED WITH IT. THE METHYLATION CHANGES AT THE -618 SITE SHOWED A NEGATIVE CORRELATION WITH THE GENE EXPRESSION CHANGES BETWEEN NP AND IT ( R = -.65, P < .01). CONCLUSIONS HYPERMETHYLATION OF PLAT PROMOTER MAY DOWNREGULATE THE GENE EXPRESSION IN NP, LEADING TO EXCESSIVE FIBRIN DEPOSITION BY ABERRANT COAGULATION CASCADE. DNA METHYLATION OF PROXIMAL PLAT PROMOTER MAY CONTRIBUTE TO NP GROWTH AND HAVE A POTENTIAL AS A NEW THERAPEUTIC TARGET.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
8  5744  28 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
9  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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
10  3710  42 INFLUENCES OF POLYCYCLIC AROMATIC HYDROCARBON ON THE EPIGENOME TOXICITY AND ITS APPLICABILITY IN HUMAN HEALTH RISK ASSESSMENT. THE EXISTENCE OF POLYCYCLIC AROMATIC HYDROCARBONS (PAHS) IN AMBIENT AIR IS AN ESCALATING CONCERN WORLDWIDE BECAUSE OF THEIR ABILITY TO CAUSE CANCER AND INDUCE PERMANENT CHANGES IN THE GENETIC MATERIAL. GROWING EVIDENCE IMPLIES THAT DURING EARLY LIFE-SENSITIVE STAGES, THE RISK OF PROGRESSION OF ACUTE AND CHRONIC DISEASES DEPENDS ON EPIGENETIC CHANGES INITIATED BY THE INFLUENCE OF ENVIRONMENTAL CUES. SEVERAL REPORTS DECIPHERED THE RELATIONSHIP BETWEEN EXPOSURE TO ENVIRONMENTAL CHEMICALS AND EPIGENETICS, AND HAVE KNOWN TOXICANTS THAT ALTER THE EPIGENETIC STATES. AMONGST PAHS, BENZO[A]PYRENE (B[A]P) IS ACCEPTED AS A GROUP 1 CANCER-CAUSING AGENT BY THE INTERNATIONAL AGENCY FOR THE RESEARCH ON CANCER (IARC). B[A]P IS A WELL-STUDIED PRO-CARCINOGEN THAT IS METABOLICALLY ACTIVATED BY THE ARYL HYDROCARBON RECEPTOR (AHR)/CYTOCHROME P450 PATHWAY. CYTOCHROME P450 PLAYS A PIVOTAL ROLE IN THE STIMULATION STEP, WHICH IS ESSENTIAL FOR DNA ADDUCT FORMATION. ACCRUING EVIDENCE SUGGESTS THAT EPIGENETIC ALTERATIONS ASSUME A FUNDAMENTAL PART IN PAH-PROMOTED CARCINOGENESIS. THIS INTERACTION BETWEEN PAHS AND EPIGENETIC FACTORS RESULTS IN AN ALTERED PROFILE OF THESE MARKS, GLOBALLY AND LOCUS-SPECIFIC. SOME OF THE EPIGENETIC CHANGES DUE TO EXPOSURE TO PAHS LEAD TO INCREASED DISEASE SUSCEPTIBILITY AND PROGRESSION. IT IS WELL UNDERSTOOD THAT EXPOSURE TO ENVIRONMENTAL CARCINOGENS, SUCH AS PAH TRIGGERS DISEASE PATHWAYS THROUGH CHANGES IN THE GENOME. SEVERAL EVIDENCE REPORTED DUE TO THE EPIGENOME-WIDE ASSOCIATION STUDIES, THAT EARLY LIFE ADVERSE ENVIRONMENTAL EVENTS MAY TRIGGER WIDESPREAD AND PERSISTENT VARIATIONS IN TRANSCRIPTIONAL PROFILING. MOREOVER, THESE VARIATIONS RESPOND TO DNA DAMAGE AND/OR A CONSEQUENCE OF EPIGENETIC MODIFICATIONS THAT NEED FURTHER INVESTIGATION. GROWING EVIDENCE HAS ASSOCIATED PAHS WITH EPIGENETIC VARIATIONS INVOLVING ALTERATIONS IN DNA METHYLATION, HISTONE MODIFICATION, AND MICRO RNA (MIRNA) REGULATION. EPIGENETIC ALTERATIONS TO PAH EXPOSURE WERE RELATED TO CHRONIC DISEASES, SUCH AS PULMONARY DISEASE, CARDIOVASCULAR DISEASE, ENDOCRINE DISRUPTOR, NERVOUS SYSTEM DISORDER, AND CANCER. THIS HORMETIC RESPONSE GIVES A NOVEL PERCEPTION CONCERNING THE TOXICITY OF PAHS AND THE BIOLOGICAL REACTION THAT MAY BE A DISTINCT RELIANCE ON EXPOSURE. THIS REVIEW SHEDS LIGHT ON UNDERSTANDING THE LATEST EVIDENCE ABOUT HOW PAHS CAN ALTER EPIGENETIC PATTERNS AND HUMAN HEALTH. IN CONCLUSION, AS SEVERAL EPIGENETIC CHANGE MECHANISMS REMAIN UNCLEAR YET, FURTHER ANALYSES DERIVED FROM PAHS EXPOSURE MUST BE PERFORMED TO FIND NEW TARGETS AND DISEASE BIOMARKERS. IN SPITE OF THE CURRENT LIMITATIONS, NUMEROUS EVIDENCE SUPPORTS THE PERCEPTION THAT EPIGENETICS GRIPS SUBSTANTIAL POTENTIAL FOR ADVANCING OUR KNOWLEDGE ABOUT THE MOLECULAR MECHANISMS OF ENVIRONMENTAL TOXICANTS, ALSO FOR PREDICTING HEALTH-ASSOCIATED RISKS DUE TO ENVIRONMENTAL CIRCUMSTANCES EXPOSURE AND INDIVIDUAL SUSCEPTIBILITY.	2022	

11  3063  27 GENOME-WIDE DNA METHYLATION AND LONG-TERM AMBIENT AIR POLLUTION EXPOSURE IN KOREAN ADULTS. BACKGROUND: AMBIENT AIR POLLUTION IS ASSOCIATED WITH NUMEROUS ADVERSE HEALTH OUTCOMES, BUT THE UNDERLYING MECHANISMS ARE NOT WELL UNDERSTOOD; EPIGENETIC EFFECTS INCLUDING ALTERED DNA METHYLATION COULD PLAY A ROLE. TO EVALUATE ASSOCIATIONS OF LONG-TERM AIR POLLUTION EXPOSURE WITH DNA METHYLATION IN BLOOD, WE CONDUCTED AN EPIGENOME-WIDE ASSOCIATION STUDY IN A KOREAN CHRONIC OBSTRUCTIVE PULMONARY DISEASE COHORT (N = 100 INCLUDING 60 CASES) USING ILLUMINA'S INFINIUM HUMANMETHYLATION450K BEADCHIP. ANNUAL AVERAGE CONCENTRATIONS OF PARTICULATE MATTER </= 10 MUM IN DIAMETER (PM(10)) AND NITROGEN DIOXIDE (NO(2)) WERE ESTIMATED AT PARTICIPANTS' RESIDENTIAL ADDRESSES USING EXPOSURE PREDICTION MODELS. WE USED ROBUST LINEAR REGRESSION TO IDENTIFY DIFFERENTIALLY METHYLATED PROBES (DMPS) AND TWO DIFFERENT APPROACHES, DMRCATE AND COMB-P, TO IDENTIFY DIFFERENTIALLY METHYLATED REGIONS (DMRS). RESULTS: AFTER MULTIPLE TESTING CORRECTION (FALSE DISCOVERY RATE < 0.05), THERE WERE 12 DMPS AND 27 DMRS ASSOCIATED WITH PM(10) AND 45 DMPS AND 57 DMRS RELATED TO NO(2). DMP CG06992688 (OTUB2) AND SEVERAL DMRS WERE ASSOCIATED WITH BOTH EXPOSURES. ELEVEN DMPS IN RELATION TO NO(2) CONFIRMED PREVIOUS FINDINGS IN EUROPEANS; THE REMAINDER WERE NOVEL. METHYLATION LEVELS OF 39 DMPS WERE ASSOCIATED WITH EXPRESSION LEVELS OF NEARBY GENES IN A SEPARATE DATASET OF 3075 INDIVIDUALS. ENRICHED NETWORKS WERE RELATED TO OUTCOMES ASSOCIATED WITH AIR POLLUTION INCLUDING CARDIOVASCULAR AND RESPIRATORY DISEASES AS WELL AS INFLAMMATORY AND IMMUNE RESPONSES. CONCLUSIONS: THIS STUDY PROVIDES EVIDENCE THAT LONG-TERM AMBIENT AIR POLLUTION EXPOSURE IMPACTS DNA METHYLATION. THE DIFFERENTIAL METHYLATION SIGNALS CAN SERVE AS POTENTIAL AIR POLLUTION BIOMARKERS. THESE RESULTS MAY HELP BETTER UNDERSTAND THE INFLUENCES OF AMBIENT AIR POLLUTION ON HUMAN HEALTH.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
12  2406  31 EPIGENETIC RESPONSES TO RHINOVIRUS EXPOSURE IN AIRWAY EPITHELIAL CELLS ARE CORRELATED WITH KEY TRANSCRIPTIONAL PATHWAYS IN CHRONIC RHINOSINUSITIS. BACKGROUND: VIRUSES MAY DRIVE IMMUNE MECHANISMS RESPONSIBLE FOR CHRONIC RHINOSINUSITIS WITH NASAL POLYPOSIS (CRSWNP), BUT LITTLE IS KNOWN ABOUT THE UNDERLYING MOLECULAR MECHANISMS. OBJECTIVES: TO IDENTIFY EPIGENETIC AND TRANSCRIPTIONAL RESPONSES TO A COMMON UPPER RESPIRATORY PATHOGEN, RHINOVIRUS (RV), THAT ARE SPECIFIC TO PATIENTS WITH CRSWNP USING A PRIMARY SINONASAL EPITHELIAL CELL CULTURE MODEL. METHODS: AIRWAY EPITHELIAL CELLS WERE COLLECTED AT SURGERY FROM PATIENTS WITH CRSWNP (CASES) AND FROM CONTROLS WITHOUT SINUS DISEASE, CULTURED, AND THEN EXPOSED TO RV OR VEHICLE FOR 48 H. DIFFERENTIAL GENE EXPRESSION AND DNA METHYLATION (DNAM) BETWEEN CASES AND CONTROLS IN RESPONSE TO RV WERE DETERMINED USING LINEAR MIXED MODELS. WEIGHTED GENE CO-EXPRESSION ANALYSIS (WGCNA) WAS USED TO IDENTIFY (A) CO-REGULATED GENE EXPRESSION AND DNAM SIGNATURES, AND (B) GENES, PATHWAYS, AND REGULATORY MECHANISMS SPECIFIC TO CRSWNP. RESULTS: WE IDENTIFIED 5585 DIFFERENTIAL TRANSCRIPTIONAL AND 261 DNAM RESPONSES (FDR <0.10) TO RV BETWEEN CRSWNP CASES AND CONTROLS. THESE DIFFERENTIAL RESPONSES FORMED THREE CO-EXPRESSION/CO-METHYLATION MODULES THAT WERE RELATED TO CRSWNP AND THREE THAT WERE RELATED TO RV (BONFERRONI CORRECTED P < .01). MOST (95%) OF THE DIFFERENTIALLY METHYLATED CPGS (DMCS) WERE IN MODULES RELATED TO CRSWNP, WHEREAS THE DIFFERENTIALLY EXPRESSED GENES (DEGS) WERE MORE EQUALLY DISTRIBUTED BETWEEN THE CRSWNP- AND RV-RELATED MODULES. GENES IN THE CRSWNP-RELATED MODULES WERE ENRICHED IN KNOWN CRS AND/OR VIRAL RESPONSE IMMUNE PATHWAYS. CONCLUSION: RV ACTIVATES SPECIFIC EPIGENETIC PROGRAMS AND CORRELATED TRANSCRIPTIONAL NETWORKS IN THE SINONASAL EPITHELIUM OF INDIVIDUALS WITH CRSWNP. THESE NOVEL OBSERVATIONS SUGGEST EPIGENETIC SIGNATURES SPECIFIC TO PATIENTS WITH CRSWNP MODULATE RESPONSE TO VIRAL PATHOGENS AT THE MUCOSAL ENVIRONMENTAL INTERFACE. DETERMINING HOW VIRAL RESPONSE PATHWAYS ARE INVOLVED IN EPITHELIAL INFLAMMATION IN CRSWNP COULD LEAD TO THERAPEUTIC TARGETS FOR THIS BURDENSOME AIRWAY DISORDER.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
13   972  30 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
14  2643  26 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
15  3079  37 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
16  5683  31 SHORTER TELOMERE LENGTH IN PERIPHERAL BLOOD LYMPHOCYTES OF WORKERS EXPOSED TO POLYCYCLIC AROMATIC HYDROCARBONS. SHORTER TELOMERE LENGTH (TL) IN PERIPHERAL BLOOD LYMPHOCYTES (PBLS) IS PREDICTIVE OF LUNG CANCER RISK. POLYCYCLIC AROMATIC HYDROCARBONS (PAHS) ARE ESTABLISHED LUNG CARCINOGENS THAT CAUSE CHROMOSOME INSTABILITY. WHETHER PAH EXPOSURE AND ITS MOLECULAR EFFECTS ARE LINKED WITH SHORTER TL HAS NEVER BEEN EVALUATED. IN THE PRESENT STUDY, WE INVESTIGATED THE EFFECT OF CHRONIC EXPOSURE TO PAHS ON TL MEASURED IN PBLS OF POLISH MALE NON-CURRENT SMOKING COKEOVEN WORKERS AND MATCHED CONTROLS. PAH EXPOSURE AND MOLECULAR EFFECTS WERE CHARACTERIZED USING MEASURES OF INTERNAL DOSE (URINARY 1-PYRENOL), EFFECTIVE DOSE [ANTI-BENZO[A]PYRENE DIOLEPOXIDE (ANTI-BPDE)-DNA ADDUCT], GENETIC INSTABILITY (MICRONUCLEI, MN) AND DNA METHYLATION [P53 PROMOTER AND ALU AND LONG INTERSPERSED NUCLEAR ELEMENT-1 (LINE-1) REPETITIVE ELEMENTS, AS SURROGATE MEASURES OF GLOBAL METHYLATION] IN PBLS. TL WAS MEASURED BY REAL-TIME POLYMERASE CHAIN REACTION. COKEOVEN WORKERS WERE HEAVILY EXPOSED TO PAHS (79% EXCEEDED THE URINARY 1-PYRENOL BIOLOGICAL EXPOSURE INDEX) AND EXHIBITED LOWER TL (P = 0.038) THAN CONTROLS, AS WELL AS HIGHER LEVELS OF GENETIC AND CHROMOSOMAL ALTERATIONS [I.E. ANTI-BPDE-DNA ADDUCT AND MN (P < 0.0001)] AND EPIGENETIC CHANGES [I.E. P53 GENE-SPECIFIC PROMOTER AND GLOBAL METHYLATION (P <OR= 0.001)]. TL DECREASED WITH LONGER DURATION OF WORK AS COKEOVEN WORKER (P = 0.039) AND IN ALL SUBJECTS WITH HIGHER LEVELS OF ANTI-BPDE-DNA ADDUCT (P = 0.042), P53 HYPOMETHYLATION (P = 0.005) AND MN (P = 0.009). IN MULTIVARIATE ANALYSIS, YEARS OF WORK IN COKERY (P = 0.008) AND P53 HYPOMETHYLATION (P = 0.001) WERE THE PRINCIPAL DETERMINANTS OF SHORTER TL. OUR RESULTS INDICATE THAT SHORTER TL IS ASSOCIATED WITH CHRONIC PAH EXPOSURE. THE INTERRELATIONS WITH OTHER GENETIC AND EPIGENETIC MECHANISMS IN OUR DATA SUGGEST THAT SHORTER TL COULD BE A CENTRAL EVENT IN PAH CARCINOGENESIS.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
17   812  34 CHANGES IN DNA METHYLATION PROFILES OF MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME PATIENTS REFLECT SYSTEMIC DYSFUNCTIONS. BACKGROUND: MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) IS A LIFELONG DEBILITATING DISEASE WITH A COMPLEX PATHOLOGY NOT YET CLEARLY DEFINED. SUSCEPTIBILITY TO ME/CFS INVOLVES GENETIC PREDISPOSITION AND EXPOSURE TO ENVIRONMENTAL FACTORS, SUGGESTING AN EPIGENETIC ASSOCIATION. EPIGENETIC STUDIES WITH OTHER ME/CFS COHORTS HAVE USED ARRAY-BASED TECHNOLOGY TO IDENTIFY DIFFERENTIALLY METHYLATED INDIVIDUAL SITES. CHANGES IN RNA QUANTITIES AND PROTEIN ABUNDANCE HAVE BEEN DOCUMENTED IN OUR PREVIOUS INVESTIGATIONS WITH THE SAME ME/CFS COHORT USED FOR THIS STUDY. RESULTS: DNA FROM A WELL-CHARACTERISED NEW ZEALAND COHORT OF 10 ME/CFS PATIENTS AND 10 AGE-/SEX-MATCHED HEALTHY CONTROLS WAS ISOLATED FROM PERIPHERAL BLOOD MONONUCLEAR (PBMC) CELLS, AND USED TO GENERATE REDUCED GENOME-SCALE DNA METHYLATION MAPS USING REDUCED REPRESENTATION BISULPHITE SEQUENCING (RRBS). THE SEQUENCING DATA WERE ANALYSED UTILISING THE DMAP ANALYSIS PIPELINE TO IDENTIFY DIFFERENTIALLY METHYLATED FRAGMENTS, AND THE METHYLKIT PIPELINE WAS USED TO QUANTIFY METHYLATION DIFFERENCES AT INDIVIDUAL CPG SITES. DMAP IDENTIFIED 76 DIFFERENTIALLY METHYLATED FRAGMENTS AND METHYLKIT IDENTIFIED 394 DIFFERENTIALLY METHYLATED CYTOSINES THAT INCLUDED BOTH HYPER- AND HYPO-METHYLATION. FOUR CLUSTERS WERE IDENTIFIED WHERE DIFFERENTIALLY METHYLATED DNA FRAGMENTS OVERLAPPED WITH OR WERE WITHIN CLOSE PROXIMITY TO MULTIPLE DIFFERENTIALLY METHYLATED INDIVIDUAL CYTOSINES. THESE CLUSTERS IDENTIFIED REGULATORY REGIONS FOR 17 PROTEIN ENCODING GENES RELATED TO METABOLIC AND IMMUNE ACTIVITY. ANALYSIS OF DIFFERENTIALLY METHYLATED GENE BODIES (EXONS/INTRONS) IDENTIFIED 122 UNIQUE GENES. COMPARISON WITH OTHER STUDIES ON PBMCS FROM ME/CFS PATIENTS AND CONTROLS WITH ARRAY TECHNOLOGY SHOWED 59% OF THE GENES IDENTIFIED IN THIS STUDY WERE ALSO FOUND IN ONE OR MORE OF THESE STUDIES. FUNCTIONAL PATHWAY ENRICHMENT ANALYSIS IDENTIFIED 30 ASSOCIATED PATHWAYS. THESE INCLUDED IMMUNE, METABOLIC AND NEUROLOGICAL-RELATED FUNCTIONS DIFFERENTIALLY REGULATED IN ME/CFS PATIENTS COMPARED TO THE MATCHED HEALTHY CONTROLS. CONCLUSIONS: MAJOR DIFFERENCES WERE IDENTIFIED IN THE DNA METHYLATION PATTERNS OF ME/CFS PATIENTS THAT CLEARLY DISTINGUISHED THEM FROM THE HEALTHY CONTROLS. OVER HALF FOUND IN GENE BODIES WITH RRBS IN THIS STUDY HAD BEEN IDENTIFIED IN OTHER ME/CFS STUDIES USING THE SAME CELLS BUT WITH ARRAY TECHNOLOGY. WITHIN THE ENRICHED FUNCTIONAL IMMUNE, METABOLIC AND NEUROLOGICAL PATHWAYS, A NUMBER OF ENRICHED NEUROTRANSMITTER AND NEUROPEPTIDE REACTOME PATHWAYS HIGHLIGHTED A DISTURBED NEUROLOGICAL PATHOPHYSIOLOGY WITHIN THE PATIENT GROUP.	2020	
                                                                                                                                                                                                                                                                                                 
18  3056  27 GENOME-WIDE DNA METHYLATION ANALYSIS IMPLICATES ENRICHMENT OF INTERFERON PATHWAY IN AFRICAN AMERICAN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS AND EUROPEAN AMERICANS WITH LUPUS NEPHRITIS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC, MULTISYSTEM, INFLAMMATORY AUTOIMMUNE DISEASE THAT DISPROPORTIONATELY AFFECTS WOMEN. TRENDS IN SLE PREVALENCE AND CLINICAL COURSE DIFFER BY ANCESTRY, WITH THOSE OF AFRICAN AMERICAN ANCESTRY PRESENTING WITH MORE ACTIVE, SEVERE AND RAPIDLY PROGRESSIVE DISEASE THAN EUROPEAN AMERICANS. PREVIOUS RESEARCH ESTABLISHED ALTERED EPIGENETIC SIGNATURES IN SLE PATIENTS COMPARED TO CONTROLS. HOWEVER, THE CONTRIBUTION OF ABERRANT DNA METHYLATION (DNAM) TO THE RISK OF SLE BY ANCESTRY AND DIFFERENCES AMONG PATIENTS WITH SLE-ASSOCIATED LUPUS NEPHRITIS (LN) HAS NOT BEEN WELL DESCRIBED. WE EVALUATED THE DNA METHYLOMES OF 87 INDIVIDUALS INCLUDING 41 SLE PATIENTS, WITH AND WITHOUT LN, AND 46 CONTROLS ENROLLED IN AN ANCESTRY DIVERSE, WELL-CHARACTERIZED COHORT STUDY OF ESTABLISHED SLE (41 SLE PATIENTS [20 SLE-LN+, 21 SLE-LN-] AND 46 SEX-, RACE- AND AGE-MATCHED CONTROLS; 55% AFRICAN AMERICAN, 45% EUROPEAN AMERICAN). PARTICIPANTS WERE GENOTYPED USING THE INFINIUM GLOBAL DIVERSITY ARRAY (GDA), AND GENETIC ANCESTRY WAS ESTIMATED USING PRINCIPAL COMPONENTS. GENOME-WIDE DNA METHYLATION WAS INITIALLY MEASURED USING THE ILLUMINA METHYLATIONEPIC 850K BEADCHIP ARRAY FOLLOWED BY METHYLATION-SPECIFIC QPCR TO VALIDATE THE METHYLATION STATUS AT PUTATIVE LOCI. DIFFERENTIALLY METHYLATED POSITIONS (DMP) WERE IDENTIFIED USING A CASE-CONTROL APPROACH ADJUSTED FOR ANCESTRY. WE IDENTIFIED A TOTAL OF 51 DMPS IN CPGS AMONG SLE PATIENTS COMPARED TO CONTROLS. GENES PROXIMAL TO THESE CPGS WERE HIGHLY ENRICHED FOR INVOLVEMENT IN TYPE I INTERFERON SIGNALING. DMPS AMONG EUROPEAN AMERICAN SLE PATIENTS WITH LN WERE SIMILAR TO AFRICAN AMERICAN SLE PATIENTS WITH AND WITHOUT LN. OUR FINDINGS WERE VALIDATED USING AN ORTHOGONAL, METHYL-SPECIFIC PCR FOR THREE SLE-ASSOCIATED DMPS NEAR OR PROXIMAL TO MX1, USP18, AND IFITM1. OUR STUDY CONFIRMS PREVIOUS REPORTS THAT DMPS IN CPGS ASSOCIATED WITH SLE ARE ENRICHED IN TYPE I INTERFERON GENES. HOWEVER, WE SHOW THAT EUROPEAN AMERICAN SLE PATIENTS WITH LN HAVE SIMILAR DNAM PATTERNS TO AFRICAN AMERICAN SLE PATIENTS IRRESPECTIVE OF LN, SUGGESTING THAT ABERRANT DNAM ALTERS ACTIVITY OF TYPE I INTERFERON PATHWAY LEADING TO MORE SEVERE DISEASE INDEPENDENT OF ANCESTRY.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
19  1620  37 DNA METHYLTRANSFERASE-MEDIATED TRANSCRIPTIONAL SILENCING IN MALIGNANT GLIOMA: A COMBINED WHOLE-GENOME MICROARRAY AND PROMOTER ARRAY ANALYSIS. EPIGENETIC INACTIVATION OF TUMOR SUPPRESSOR GENES IS A COMMON FEATURE IN HUMAN CANCER. PROMOTER HYPERMETHYLATION AND HISTONE DEACETYLATION ARE REVERSIBLE EPIGENETIC MECHANISMS ASSOCIATED WITH TRANSCRIPTIONAL REGULATION. DNA METHYLTRANSFERASES (DNMT1 AND DNMT3B) REGULATE AND MAINTAIN PROMOTER METHYLATION AND ARE OVEREXPRESSED IN HUMAN CANCER. WE PERFORMED WHOLE-GENOME MICROARRAY ANALYSIS TO IDENTIFY GENES WITH ALTERED EXPRESSION AFTER RNAI-INDUCED SUPPRESSION OF DNMT IN A GLIOBLASTOMA MULTIFORME (GBM) CELL LINE. WE THEN IDENTIFIED GENES WITH BOTH DECREASED EXPRESSION AND EVIDENCE OF PROMOTER CPG ISLAND HYPERMETHYLATION IN GBM TISSUE SAMPLES USING A COMBINED WHOLE-GENOME MICROARRAY TRANSCRIPTOME ANALYSIS IN CONJUNCTION WITH A PROMOTER ARRAY ANALYSIS AFTER DNA IMMUNOPRECIPITATION WITH ANTI-5-METHYLCYTIDINE. DNMT1 AND 3B KNOCKDOWN RESULTED IN THE RESTORED EXPRESSION OF 308 GENES THAT ALSO CONTAINED PROMOTER REGION HYPERMETHYLATION. OF THESE, 43 WERE ALSO FOUND TO BE DOWNREGULATED IN GBM TISSUE SAMPLES. THREE DOWNREGULATED GENES WITH HYPERMETHYLATED PROMOTERS AND RESTORED EXPRESSION IN RESPONSE TO ACUTE DNMT SUPPRESSION WERE ASSAYED FOR METHYLATION CHANGES USING BISULFITE SEQUENCE ANALYSIS OF THE PROMOTER REGION AFTER CHRONIC DNMT SUPPRESSION. RESTORATION OF GENE EXPRESSION WAS NOT ASSOCIATED WITH CHANGES IN PROMOTER REGION METHYLATION, BUT RATHER WITH CHANGES IN HISTONE METHYLATION AND CHROMATIN CONFORMATION. TWO OF THE IDENTIFIED GENES EXHIBITED GROWTH SUPPRESSIVE ACTIVITY IN IN VITRO ASSAYS. COMBINING TARGETED GENETIC MANIPULATIONS WITH COMPREHENSIVE GENOMIC AND EXPRESSION ANALYSES PROVIDES A POTENTIALLY POWERFUL NEW APPROACH FOR IDENTIFYING EPIGENETICALLY REGULATED GENES IN GBM.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
20  5960  27 TELOMERE LENGTH IN HEPATOCELLULAR CARCINOMA AND PAIRED ADJACENT NON-TUMOR TISSUES BY QUANTITATIVE PCR. TELOMERE SHORTENING LIMITS THE PROLIFERATIVE CAPACITY OF HUMAN CELLS, RESTRAINS THE REGENERATIVE CAPACITY OF ORGAN SYSTEMS DURING CHRONIC DISEASES AND AGING AND ALSO INDUCES CHROMOSOMAL INSTABILITY AS WELL AS INITIATION OF CANCER. PREVIOUS STUDIES DEMONSTRATED THAT TELOMERES ARE OFTEN SIGNIFICANTLY SHORTER IN TUMOR TISSUE, INCLUDING HEPATOCELLULAR CARCINOMA (HCC), COMPARED TO THE SURROUNDING TISSUE, BUT TELOMERE LENGTH IN HCC TISSUES WAS NOT CORRELATED WITH SEVERAL CLINICAL PARAMETERS, SUCH AS AGE, SEX, HBV OR HCV INFECTIONS AND TUMOR SIZE. IN THE PRESENT STUDY, THE TELOMERE LENGTH RATIO OF 36 PAIRED HCC, AND THEIR ADJACENT NON-TUMOR TISSUES WAS MEASURED BY QUANTITATIVE PCR (Q-PCR). THE MEAN TELOMERE LENGTHS (SD) FOR HCC AND ADJACENT NON-TUMOR TISSUES WERE 0.26 (0.10) AND 0.47 (0.20) RESPECTIVELY (T = 6.22, P < 0.0001). THERE WAS A LARGE DIFFERENCE IN THE DISTRIBUTION OF SUBJECTS BASED ON TELOMERE LENGTH IN TUMOR AND ADJACENT NON-TUMOR TISSUES. THE NUMBER OF TUMORS WITH TELOMERE LENGTH SHORTER THAN 0.50 WAS MUCH HIGHER THAN THAT OF ADJACENT NON-TUMOR TISSUES; MORE THAN 90% OF THE TISSUES WITH TELOMERE LENGTH > OR = 0.50 WERE ADJACENT NON-TUMOR TISSUES. THE CORRELATIONS BETWEEN TELOMERE LENGTH AND AFLATOXIN B1- AND POLYCYCLIC AROMATIC HYDROCARBON-DNA ADDUCTS LEVEL, P53 MUTATIONS AND P16 HYPERMETHYLATION STATUS WERE ALSO TESTED, BUT NO SIGNIFICANT ASSOCIATIONS WERE FOUND. THE RELATIONSHIP BETWEEN TELOMERE LENGTH SHORTENING, CHEMICAL CARCINOGEN EXPOSURE, AND GENETIC AND EPIGENETIC CHANGES IN HEPATOCARCINOGENESIS NEEDS FURTHER INVESTIGATION.	2007