1 4227 96 METHYLATION OF FREE-FLOATING DEOXYRIBONUCLEIC ACID FRAGMENTS IN THE BRONCHOALVEOLAR LAVAGE FLUID OF DOGS WITH CHRONIC BRONCHITIS EXPOSED TO ENVIRONMENTAL TOBACCO SMOKE. BACKGROUND: THE ETIOLOGY OF CANINE CHRONIC BRONCHITIS (CB) IS NOT COMPLETELY UNDERSTOOD, ALTHOUGH EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE (ETS) AFFECTS THE AIRWAY INFLAMMATORY RESPONSES IN SOME DOGS WITH CB. THE MECHANISM BY WHICH THIS OCCURS IS UNKNOWN. FINDINGS: WE INVESTIGATED THE CONCENTRATIONS AND METHYLATION RATES OF FREE-FLOATING DNA FRAGMENTS IN BRONCHOALVEOLAR LAVAGE FLUID (BALF) FROM DOGS WITH CHRONIC BRONCHITIS. BASED ON SERUM COTININE LEVELS, DOGS WITH CB WERE DIVIDED INTO 2 GROUPS: DOGS THAT EITHER HAD OR HAD NOT BEEN EXPOSED TO ETS. OUR RESULTS DEMONSTRATED THAT THE TOTAL NUCLEATED CELL AND MACROPHAGE NUMBERS INCREASED IN BALF OF ETS-EXPOSED DOGS WITH CB. THERE WERE NO SIGNIFICANT DIFFERENCES IN DNA CONCENTRATIONS AND METHYLATION RATES IN BALF BETWEEN THE 2 GROUPS. HOWEVER, 3 OUT OF 8 DOGS EXPOSED TO ETS HAD HIGH DNA METHYLATION RATES IN THEIR BALF SAMPLES. CONCLUSION: OUR RESULTS SUGGEST THAT ETS EXPOSURE LEADS TO EPIGENETIC MODIFICATIONS OF CELLULAR COMPONENTS IN BALF IN DOGS DIAGNOSED WITH CB.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
2 5638 30 SERUM METABOLOMICS REVEALS PATHWAYS AND BIOMARKERS ASSOCIATED WITH ASTHMA PATHOGENESIS. BACKGROUND: ASTHMA IS A CHRONIC INFLAMMATORY DISEASE CAUSED BY COMPLEX INTERACTIONS OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. FOR THIS REASON, NEW APPROACHES ARE REQUIRED TO CLARIFY THE PATHOGENESIS OF ASTHMA BY SYSTEMIC REVIEW. OBJECTIVE: WE APPLIED A (1)H-NMR METABOLOMICS APPROACH TO INVESTIGATE THE ALTERED METABOLIC PATTERN IN SERA FROM PATIENTS WITH ASTHMA AND SOUGHT TO IDENTIFY THE MECHANISM UNDERLYING ASTHMA AND POTENTIAL BIOMARKERS. METHOD: A GLOBAL PROFILE OF SERA FROM PATIENTS WITH ASTHMA (N = 39) AND CONTROLS (N = 26) WAS GENERATED USING (1)H-NMR SPECTROSCOPY COUPLED WITH MULTIVARIATE STATISTICAL ANALYSIS. ENDOGENOUS METABOLITES IN SERUM WERE RAPIDLY MEASURED USING THE TARGET-PROFILING PROCEDURE. RESULTS: MULTIVARIATE STATISTICAL ANALYSIS SHOWED A CLEAR DISTINCTION BETWEEN PATIENTS WITH ASTHMA AND HEALTHY SUBJECTS. SERA OF ASTHMA PATIENTS WERE CHARACTERIZED BY INCREASED LEVELS OF METHIONINE, GLUTAMINE, AND HISTIDINE AND BY DECREASED LEVELS OF FORMATE, METHANOL, ACETATE, CHOLINE, O-PHOSPHOCHOLINE, ARGININE, AND GLUCOSE. THE METABOLITES DETECTED IN THE SERA OF PATIENTS WITH ASTHMA ARE INVOLVED IN HYPERMETHYLATION, RESPONSE TO HYPOXIA, AND IMMUNE REACTION. FURTHERMORE, THE LEVELS OF SERUM METABOLITES FROM PATIENTS WITH ASTHMA CORRELATED WITH ASTHMA SEVERITY; IN PARTICULAR, LIPID METABOLISM WAS ALTERED IN PATIENTS WITH LOWER FORCED EXPIRATORY VOLUME IN 1 S PERCENTAGE (FEV(1)%) PREDICTED VALUES. IN ADDITION, POTENTIAL BIOMARKERS SHOWED STRONG PREDICTIVE POWER IN ROC ANALYSIS, AND THE PRESENCE OF ASTHMA IN EXTERNAL VALIDATION MODELS WAS PREDICTED WITH HIGH ACCURACY (90.9% FOR ASTHMA AND 100% FOR CONTROL SUBJECTS). CONCLUSION & CLINICAL RELEVANCE: THESE DATA SHOWED THAT (1)H-NMR-BASED METABOLITE PROFILING OF SERUM MAY BE USEFUL FOR THE EFFECTIVE DIAGNOSIS OF ASTHMA AND A FURTHER UNDERSTANDING OF ITS PATHOGENESIS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
3 1528 28 DNA METHYLATION CHANGES IN REGIONAL LUNG MACROPHAGES ARE ASSOCIATED WITH METABOLIC DIFFERENCES. A NUMBER OF PULMONARY DISEASES OCCUR WITH UPPER LOBE PREDOMINANCE, INCLUDING CYSTIC FIBROSIS AND SMOKING-RELATED CHRONIC OBSTRUCTIVE PULMONARY DISEASE. IN THE HEALTHY LUNG, SEVERAL PHYSIOLOGIC AND METABOLIC FACTORS EXHIBIT DISPARITY WHEN COMPARING THE UPPER LOBE OF THE LUNG TO LOWER LOBE, INCLUDING DIFFERENCES IN OXYGENATION, VENTILATION, LYMPHATIC FLOW, PH, AND BLOOD FLOW. IN THIS STUDY, WE ASKED WHETHER THESE REGIONAL DIFFERENCES IN THE LUNG ARE ASSOCIATED WITH DNA METHYLATION CHANGES IN LUNG MACROPHAGES THAT COULD POTENTIALLY LEAD TO ALTERED CELL RESPONSIVENESS UPON SUBSEQUENT ENVIRONMENTAL CHALLENGE. ALL ANALYSES WERE PERFORMED USING PRIMARY LUNG MACROPHAGES COLLECTED VIA BRONCHOALVEOLAR LAVAGE FROM HEALTHY HUMAN SUBJECTS WITH NORMAL PULMONARY FUNCTION. EPIGENOME-WIDE DNA METHYLATION WAS EXAMINED VIA INFINIUM METHYLATIONEPIC (850K) ARRAY AND VALIDATED BY TARGETED NEXT-GENERATION BISULFITE SEQUENCING. WE OBSERVED 95 CPG LOCI WITH SIGNIFICANT DIFFERENTIAL METHYLATION IN LUNG MACROPHAGES, COMPARING UPPER LOBE TO LOWER LOBE (ALL FALSE DISCOVERY RATE < 0.05). SEVERAL OF THESE GENES, INCLUDING CLIP4, HSH2D, NR4A1, SNX10, AND TYK2, HAVE BEEN IMPLICATED AS PARTICIPANTS IN INFLAMMATORY/IMMUNE-RELATED BIOLOGICAL PROCESSES. FUNCTIONALLY, WE IDENTIFIED PHENOTYPIC DIFFERENCES IN OXYGEN USE, COMPARING UPPER VERSUS LOWER LUNG MACROPHAGES. OUR RESULTS SUPPORT A HYPOTHESIS THAT EPIGENETIC CHANGES, SPECIFICALLY DNA METHYLATION, AT A MULTITUDE OF GENE LOCI IN LUNG MACROPHAGES ARE ASSOCIATED WITH METABOLIC DIFFERENCES REGIONALLY IN LUNG.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
4 1607 30 DNA METHYLATION, COLON CANCER AND MEDITERRANEAN DIET: RESULTS FROM THE EPIC-ITALY COHORT. THE BIOLOGICAL MECHANISMS THROUGH WHICH ADHERENCE TO MEDITERRANEAN DIET (MD) PROTECTS AGAINST COLON CANCER (CC) ARE POORLY UNDERSTOOD. EVIDENCE SUGGESTS THAT CHRONIC INFLAMMATION MAY BE IMPLICATED IN THE PATHWAY. BOTH DIET AND CC ARE RELATED TO EPIGENETIC REGULATION. WE PERFORMED A NESTED CASE-CONTROL STUDY ON 161 PAIRS FROM THE ITALIAN COMPONENT OF THE EUROPEAN PROSPECTIVE INVESTIGATION INTO CANCER AND NUTRITION (EPIC) COHORT, IN WHICH WE LOOKED FOR THE METHYLATION SIGNALS IN DNA EXTRACTED FROM LEUCOCYTES ASSOCIATED WITH BOTH CC AND MD IN 995 CPGS LOCATED IN 48 INFLAMMATION GENES. THE DNA METHYLATION SIGNALS DETECTED IN THIS ANALYSIS WERE VALIDATED IN A SUBGROUP OF 47 CASE-CONTROL PAIRS AND FURTHER REPLICATED (WHERE VALIDATED) IN 95 NEW PAIRS BY MEANS OF PYROSEQUENCING. AMONG THE CPG SITES SELECTED A-PRIORI IN INFLAMMATION-RELATED GENES, SEVEN CPG SITES WERE FOUND TO BE ASSOCIATED WITH CC STATUS AND WITH MD, IN LINE WITH ITS PROTECTIVE EFFECT. ONLY TWO CPG SITES (CG17968347-SERPINE1 AND CG20674490-RUNX3) WERE VALIDATED USING BISULPHITE PYROSEQUENCING AND, AFTER REPLICATION, WE FOUND THAT DNA METHYLATION OF CG20674490-RUNX3 MAY BE A POTENTIAL MOLECULAR MEDIATOR EXPLAINING THE PROTECTIVE EFFECT OF MD ON CC ONSET. THE USE OF A 'MEET-IN-THE-MIDDLE' APPROACH TO IDENTIFY THE OVERLAP BETWEEN EXPOSURE AND PREDICTIVE MARKERS OF DISEASE IS INNOVATIVE IN STUDIES ON THE RELATIONSHIP BETWEEN DIET AND CANCER, IN WHICH EXPOSURE ASSESSMENT IS DIFFICULT AND THE MECHANISMS THROUGH WHICH THE NUTRIENTS EXERT THEIR PROTECTIVE EFFECT IS LARGELY UNKNOWN.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
5 1345 33 DETECTION OF DIFFERENTIALLY METHYLATED REGIONS USING BAYES FACTOR FOR ORDINAL GROUP RESPONSES. RESEARCHERS IN GENOMICS ARE INCREASINGLY INTERESTED IN EPIGENETIC FACTORS SUCH AS DNA METHYLATION, BECAUSE THEY PLAY AN IMPORTANT ROLE IN REGULATING GENE EXPRESSION WITHOUT CHANGES IN THE DNA SEQUENCE. THERE HAVE BEEN SIGNIFICANT ADVANCES IN DEVELOPING STATISTICAL METHODS TO DETECT DIFFERENTIALLY METHYLATED REGIONS (DMRS) ASSOCIATED WITH BINARY DISEASE STATUS. MOST OF THESE METHODS ARE BEING DEVELOPED FOR DETECTING DIFFERENTIAL METHYLATION RATES BETWEEN CASES AND CONTROLS. WE CONSIDER MULTIPLE SEVERITY LEVELS OF DISEASE, AND DEVELOP A BAYESIAN STATISTICAL METHOD TO DETECT THE REGION WITH INCREASING (OR DECREASING) METHYLATION RATES AS THE DISEASE SEVERITY INCREASES. PATIENTS ARE CLASSIFIED INTO MORE THAN TWO GROUPS, BASED ON THE DISEASE SEVERITY (E.G., STAGES OF CANCER), AND DMRS ARE DETECTED BY USING MOVING WINDOWS ALONG THE GENOME. WITHIN EACH WINDOW, THE BAYES FACTOR IS CALCULATED TO TEST THE HYPOTHESIS OF MONOTONIC INCREASE IN METHYLATION RATES CORRESPONDING TO SEVERITY OF THE DISEASE VERSUS NO DIFFERENCE. A MIXED-EFFECT MODEL IS USED TO INCORPORATE THE CORRELATION OF METHYLATION RATES OF NEARBY CPG SITES IN THE REGION. RESULTS FROM EXTENSIVE SIMULATION INDICATE THAT OUR PROPOSED METHOD IS STATISTICALLY VALID AND REASONABLY POWERFUL. WE DEMONSTRATE OUR APPROACH ON A BISULFITE SEQUENCING DATASET FROM A CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) STUDY.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
6 1519 22 DNA METHYLATION AT ATP11A CG11702988 IS A BIOMARKER OF LUNG DISEASE SEVERITY IN CYSTIC FIBROSIS: A LONGITUDINAL STUDY. CYSTIC FIBROSIS (CF) IS A CHRONIC GENETIC DISEASE THAT MAINLY AFFECTS THE RESPIRATORY AND GASTROINTESTINAL SYSTEMS. NO CURATIVE TREATMENTS ARE AVAILABLE, BUT THE FOLLOW-UP IN SPECIALIZED CENTERS HAS GREATLY IMPROVED THE PATIENT LIFE EXPECTANCY. ROBUST BIOMARKERS ARE REQUIRED TO MONITOR THE DISEASE, GUIDE TREATMENTS, STRATIFY PATIENTS, AND PROVIDE OUTCOME MEASURES IN CLINICAL TRIALS. IN THE PRESENT STUDY, WE OUTLINE A STRATEGY TO SELECT PUTATIVE DNA METHYLATION BIOMARKERS OF LUNG DISEASE SEVERITY IN CYSTIC FIBROSIS PATIENTS. IN THE DISCOVERY STEP, WE SELECTED SEVEN POTENTIAL BIOMARKERS USING A GENOME-WIDE DNA METHYLATION DATASET THAT WE GENERATED IN NASAL EPITHELIAL SAMPLES FROM THE METHYLCF COHORT. IN THE REPLICATION STEP, WE ASSESSED THE SAME BIOMARKERS USING SPUTUM CELL SAMPLES FROM THE METHYLBIOMARK COHORT. OF INTEREST, DNA METHYLATION AT THE CG11702988 SITE (ATP11A GENE) POSITIVELY CORRELATED WITH LUNG FUNCTION AND BMI, AND NEGATIVELY CORRELATED WITH LUNG DISEASE SEVERITY, P. AERUGINOSA CHRONIC INFECTION, AND THE NUMBER OF EXACERBATIONS. THESE RESULTS WERE REPLICATED IN PROSPECTIVE SPUTUM SAMPLES COLLECTED AT FOUR TIME POINTS WITHIN AN 18-MONTH PERIOD AND LONGITUDINALLY. TO CONCLUDE, (I) WE IDENTIFIED A DNA METHYLATION BIOMARKER THAT CORRELATES WITH CF SEVERITY, (II) WE PROVIDED A METHOD TO EASILY ASSESS THIS BIOMARKER, AND (III) WE CARRIED OUT THE FIRST LONGITUDINAL ANALYSIS OF DNA METHYLATION IN CF PATIENTS. THIS NEW EPIGENETIC BIOMARKER COULD BE USED TO STRATIFY CF PATIENTS IN CLINICAL TRIALS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
7 6083 36 THE EFFECT OF SMOKING ON DNA METHYLATION OF PERIPHERAL BLOOD MONONUCLEAR CELLS FROM AFRICAN AMERICAN WOMEN. BACKGROUND: REGULAR SMOKING IS ASSOCIATED WITH A WIDE VARIETY OF SYNDROMES WITH PROMINENT INFLAMMATORY COMPONENTS SUCH AS CANCER, OBESITY AND TYPE 2 DIABETES. HEAVY REGULAR SMOKING IS ALSO ASSOCIATED WITH CHANGES IN THE DNA METHYLATION OF PERIPHERAL MONONUCLEAR CELLS. HOWEVER, IN YOUNGER SMOKERS, INFLAMMATORY EPIGENETIC FINDINGS ARE LARGELY ABSENT WHICH SUGGESTS THE INFLAMMATORY RESPONSE(S) TO SMOKING MAY BE DOSE DEPENDENT. TO HELP UNDERSTAND WHETHER PERIPHERAL MONONUCLEAR CELLS HAVE A ROLE IN MEDIATING THESE RESPONSES IN OLDER SMOKERS WITH HIGHER CUMULATIVE SMOKE EXPOSURE, WE EXAMINED GENOME-WIDE DNA METHYLATION IN A GROUP OF WELL CHARACTERIZED ADULT AFRICAN AMERICAN SUBJECTS INFORMATIVE FOR SMOKING, AS WELL AS SERUM C-REACTIVE PROTEIN (CRP) AND INTERLEUKIN-6 RECEPTOR (IL6R) LEVELS. IN ADDITION, COMPLEMENTARY BIOINFORMATIC ANALYSES WERE CONDUCTED TO DELINEATE POSSIBLE PATHWAYS AFFECTED BY LONG-TERM SMOKING. RESULTS: GENOME-WIDE DNA METHYLATION ANALYSIS WITH RESPECT TO SMOKING STATUS YIELDED 910 SIGNIFICANT LOCI AFTER BENJAMINI-HOCHBERG CORRECTION. IN PARTICULAR, TWO LOCI FROM THE AHRR GENE (CG05575921 AND CG23576855) AND ONE LOCUS FROM THE GPR15 GENE (CG19859270) WERE IDENTIFIED AS HIGHLY SIGNIFICANTLY DIFFERENTIALLY METHYLATED BETWEEN SMOKERS AND NON-SMOKERS. THE BIOINFORMATIC ANALYSES SHOWED THAT LONG-TERM CHRONIC SMOKING IS ASSOCIATED WITH ALTERED PROMOTER DNA METHYLATION OF GENES CODING FOR PROTEINS MAPPING TO CRITICAL SUB-NETWORKS MODERATING INFLAMMATION, IMMUNE FUNCTION, AND COAGULATION. CONCLUSIONS: WE CONCLUDE THAT CHRONIC REGULAR SMOKING IS ASSOCIATED WITH CHANGES IN PERIPHERAL MONONUCLEAR CELL METHYLATION SIGNATURE WHICH PERTURB INFLAMMATORY AND IMMUNE FUNCTION PATHWAYS AND MAY CONTRIBUTE TO INCREASED VULNERABILITY FOR COMPLEX ILLNESSES WITH INFLAMMATORY COMPONENTS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
8 3954 26 LONG INTERSPERSED NUCLEAR ELEMENT-1 METHYLATION STATUS IN THE CIRCULATING DNA FROM BLOOD OF PATIENTS WITH MALIGNANT AND CHRONIC INFLAMMATORY LUNG DISEASES. ALONG WITH OTHER MALIGNANT DISEASES, LUNG CANCER ARISES FROM THE PRECANCEROUS LUNG TISSUE STATE. ABERRANT DNA METHYLATION (HYPERMETHYLATION OF CERTAIN GENES AND HYPOMETHYLATION OF RETROTRANSPOSONS) IS KNOWN AS ONE OF THE DRIVING FORCES OF MALIGNANT CELL TRANSFORMATION. EPIGENETIC CHANGES WERE SHOWN TO BE DETECTABLE IN DNA, CIRCULATING IN THE BLOOD (CIRDNA) OF CANCER PATIENTS, INDICATING THE POSSIBILITY TO USE THEM AS CANCER MARKERS. THE CURRENT STUDY IS THE FIRST TO COMPARE THE LONG INTERSPERSED NUCLEAR ELEMENT-1 (LINE-1) METHYLATION LEVEL IN THE BLOOD FROM LUNG CANCER PATIENTS BEFORE TREATMENT VERSUS DIFFERENT CONTROL GROUPS AS HEALTHY SUBJECTS, PATIENTS WITH BRONCHITIS AND PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). THE CONCENTRATION OF LINE-1 METHYLATED FRAGMENTS, REGION 1 (LINE-1 METHYLATED, LINE-1-MET) WAS ESTIMATED BY QUANTITATIVE METHYL-SPECIFIC PCR. THE TOTAL CONCENTRATION OF THE CIRCULATING LINE-1 COPIES WAS MEASURED BY QPCR SPECIFIC FOR LINE-1 REGION 2, WHICH WAS SELECTED DUE TO ITS CPG METHYLATION-INDEPENDENT SEQUENCE (LINE-1-IND). BOTH LINE-1 METHYLATION LEVEL AND LINE-1 METHYLATION INDEX (LINE-1-MET/LINE-1-IND RATIO) WAS DECREASED IN LUNG CANCER PATIENTS COMPARED WITH THE JOINT CONTROL GROUP (HEALTHY SUBJECTS + PATIENTS WITH BRONCHITIS + COPD PATIENTS) (MANN-WHITNEY U-TEST, P = 0.016). WE ALSO FOUND THAT THE TENDENCY OF LINE-1 METHYLATION INDEX DECREASES IN THE CIRDNA FROM LUNG CANCER PATIENTS VERSUS COPD PATIENTS (MANN-WHITNEY U-TEST, P = 0.07). OUR DATA INDICATE THAT THE QUANTITATIVE ANALYSIS OF THE LINE-1 METHYLATION LEVEL IN THE CIRDNA IS VALUABLE FOR DISCRIMINATION OF LUNG CANCER PATIENTS FROM PATIENTS WITH CHRONIC INFLAMMATORY LUNG DISEASES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
9 3652 26 INDIVIDUAL DNA METHYLATION PATTERN SHIFTS IN NANOPARTICLES-EXPOSED WORKERS ANALYZED IN FOUR CONSECUTIVE YEARS. A DNA METHYLATION PATTERN REPRESENTS AN ORIGINAL PLAN OF THE FUNCTION SETTINGS OF INDIVIDUAL CELLS AND TISSUES. THE BASIC STRATEGIES OF ITS DEVELOPMENT AND CHANGES DURING THE HUMAN LIFETIME ARE KNOWN, BUT THE DETAILS RELATED TO ITS MODIFICATION OVER THE YEARS ON AN INDIVIDUAL BASIS HAVE NOT YET BEEN STUDIED. MOREOVER, CURRENT EVIDENCE SHOWS THAT ENVIRONMENTAL EXPOSURE COULD GENERATE CHANGES IN DNA METHYLATION SETTINGS AND, SUBSEQUENTLY, THE FUNCTION OF GENES. IN THIS STUDY, WE ANALYZED THE EFFECT OF CHRONIC EXPOSURE TO NANOPARTICLES (NP) IN OCCUPATIONALLY EXPOSED WORKERS REPEATEDLY SAMPLED IN FOUR CONSECUTIVE YEARS (2016-2019). A DETAILED METHYLATION PATTERN ANALYSIS OF 14 PERSONS (10 EXPOSED AND 4 CONTROLS) WAS PERFORMED ON AN INDIVIDUAL BASIS. A MICROARRAY-BASED APPROACH USING CHIPS, ALLOWING THE ASSESSMENT OF MORE THAN 850 K CPG LOCI, WAS USED. INDIVIDUAL DNA METHYLATION PATTERNS WERE COMPARED BY PRINCIPAL COMPONENT ANALYSIS (PCA). THE RESULTS SHOW THE SHIFT IN DNA METHYLATION PATTERNS IN INDIVIDUAL YEARS IN ALL THE EXPOSED AND CONTROL SUBJECTS. THE OVERALL RANGE OF DIFFERENCES VARIED BETWEEN THE YEARS IN INDIVIDUAL PERSONS. THE DIFFERENCES BETWEEN THE FIRST AND LAST YEAR OF EXAMINATION (A THREE-YEAR TIME PERIOD) SEEM TO BE CONSISTENTLY GREATER IN THE NP-EXPOSED SUBJECTS IN COMPARISON WITH THE CONTROLS. THE SELECTED 14 MOST DIFFERENTLY METHYLATED CG LOCI WERE RELATIVELY STABLE IN THE CHRONICALLY EXPOSED SUBJECTS. IN SUMMARY, THE SPECIFIC TYPE OF LONG-TERM EXPOSURE CAN CONTRIBUTE TO THE FIXING OF RELEVANT EPIGENETIC CHANGES RELATED TO A SPECIFIC ENVIRONMENT AS, E.G., NP INHALATION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
10  810 29 CHANGES IN DNA METHYLATION IN APOE AND ACKR3 GENES IN MULTIPLE SCLEROSIS PATIENTS AND THE RELATIONSHIP WITH THEIR HEAVY METAL BLOOD LEVELS. MULTIPLE SCLEROSIS (MS) IS A CHRONIC INFLAMMATORY DISEASE WITH DEMYELINATED LESIONS IN THE CENTRAL NERVOUS SYSTEM CAUSED BY GENETIC AND ENVIRONMENTAL FACTORS. DNA METHYLATION AS AN EPIGENETIC CHANGE INFLUENCED BY ENVIRONMENTAL FACTORS, INCLUDING HEAVY METALS HAS BEEN IMPLEMENTED IN MS DISEASE. WE INVESTIGATED THE CORRELATION OF DNA METHYLATION CHANGES IN APOE AND ACKR3 GENES IN MS PATIENTS AND THE POSSIBLE ASSOCIATION WITH BLOOD CONCENTRATION OF ARSENIC (AS), CADMIUM (CD) AND LEAD (PB) AS MAJOR HEAVY METAL POLLUTANTS. THIS STUDY INCLUDED 69 RELAPSING-REMITTING MULTIPLE SCLEROSIS (RR-MS) PATIENTS AND 69 AGE/GENDER-MATCHED HEALTHY SUBJECTS. THE HRM REAL-TIME PCR METHOD WAS USED TO INVESTIGATE THE CHANGES IN DNA METHYLATION AND HEAVY METAL CONCENTRATIONS WERE MEASURED BY ELECTROTHERMAL ATOMIC ABSORPTION SPECTROMETRY. OUR RESULTS SHOWED THAT THE METHYLATION PATTERN IN THE ACKR3 GENE OF THE PATIENT GROUP WAS MORE HYPOMETHYLATED, WHILE IN THE CASE OF THE APOE GENE, THIS PATTERN WAS MORE TOWARDS HYPERMETHYLATION COMPARED TO HEALTHY SUBJECTS. MOREOVER, THE BLOOD LEVELS OF AS AND CD METALS, BUT NOT PB, WERE SIGNIFICANTLY HIGHER IN THE PATIENT GROUP COMPARE TO THE CONTROL GROUP (P </= 0.05). THE DATA INDICATE THAT THE INCREASE IN EXPRESSION OF ACKR3 GENE BY HYPOMETHYLATION AND THE DECREASE IN EXPRESSION OF APOE GENE VIA HYPERMETHYLATION ARE POSSIBLY INVOLVED IN THE ONSET AND PROGRESSION OF INFLAMMATORY PROCESSES IN MS PATIENTS. THE LEVEL OF AS CAN ALSO LEAD TO HYPOMETHYLATION BY DISRUPTING THE METHYLATION PATTERNS OF THE ACKR3 GENE, RESULTING IN INCREASED EXPRESSION IN MS PATIENTS. FINALLY, WE HAVE SHOWN THAT EPIGENETIC CHANGES CAN BE AN IMPORTANT FACTOR IN INCREASING AND DECREASING THE EXPRESSION OF GENES INVOLVED IN THE ONSET AND/OR PROGRESSION OF INFLAMMATORY PROCESSES IN MS. FURTHERMORE, EXPOSURE TO HEAVY METALS, ESPECIALLY AS, BY CHANGING THE NATURAL PATTERNS OF DNA METHYLATION CAN BE EFFECTIVE IN THIS DISEASE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
11 2820 22 FINE-MAPPING INFLAMMATORY BOWEL DISEASE LOCI TO SINGLE-VARIANT RESOLUTION. INFLAMMATORY BOWEL DISEASES ARE CHRONIC GASTROINTESTINAL INFLAMMATORY DISORDERS THAT AFFECT MILLIONS OF PEOPLE WORLDWIDE. GENOME-WIDE ASSOCIATION STUDIES HAVE IDENTIFIED 200 INFLAMMATORY BOWEL DISEASE-ASSOCIATED LOCI, BUT FEW HAVE BEEN CONCLUSIVELY RESOLVED TO SPECIFIC FUNCTIONAL VARIANTS. HERE WE REPORT FINE-MAPPING OF 94 INFLAMMATORY BOWEL DISEASE LOCI USING HIGH-DENSITY GENOTYPING IN 67,852 INDIVIDUALS. WE PINPOINT 18 ASSOCIATIONS TO A SINGLE CAUSAL VARIANT WITH GREATER THAN 95% CERTAINTY, AND AN ADDITIONAL 27 ASSOCIATIONS TO A SINGLE VARIANT WITH GREATER THAN 50% CERTAINTY. THESE 45 VARIANTS ARE SIGNIFICANTLY ENRICHED FOR PROTEIN-CODING CHANGES (N = 13), DIRECT DISRUPTION OF TRANSCRIPTION-FACTOR BINDING SITES (N = 3), AND TISSUE-SPECIFIC EPIGENETIC MARKS (N = 10), WITH THE LAST CATEGORY SHOWING ENRICHMENT IN SPECIFIC IMMUNE CELLS AMONG ASSOCIATIONS STRONGER IN CROHN'S DISEASE AND IN GUT MUCOSA AMONG ASSOCIATIONS STRONGER IN ULCERATIVE COLITIS. THE RESULTS OF THIS STUDY SUGGEST THAT HIGH-RESOLUTION FINE-MAPPING IN LARGE SAMPLES CAN CONVERT MANY DISCOVERIES FROM GENOME-WIDE ASSOCIATION STUDIES INTO STATISTICALLY CONVINCING CAUSAL VARIANTS, PROVIDING A POWERFUL SUBSTRATE FOR EXPERIMENTAL ELUCIDATION OF DISEASE MECHANISMS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
12 2653 26 EPIGENOTYPING IN PERIPHERAL BLOOD CELL DNA AND BREAST CANCER RISK: A PROOF OF PRINCIPLE STUDY. BACKGROUND: EPIGENETIC CHANGES ARE EMERGING AS ONE OF THE MOST IMPORTANT EVENTS IN CARCINOGENESIS. TWO ALTERATIONS IN THE PATTERN OF DNA METHYLATION IN BREAST CANCER (BC) HAVE BEEN PREVIOUSLY REPORTED; ACTIVE ESTROGEN RECEPTOR-ALPHA (ER-ALPHA) IS ASSOCIATED WITH DECREASED METHYLATION OF ER-ALPHA TARGET (ERT) GENES, AND POLYCOMB GROUP TARGET (PCGT) GENES ARE MORE LIKELY THAN OTHER GENES TO HAVE PROMOTER DNA HYPERMETHYLATION IN CANCER. HOWEVER, WHETHER DNA METHYLATION IN NORMAL UNRELATED CELLS IS ASSOCIATED WITH BC RISK AND WHETHER THESE IMPRINTS CAN BE RELATED TO FACTORS WHICH CAN BE MODIFIED BY THE ENVIRONMENT, IS UNCLEAR. METHODOLOGY/PRINCIPAL FINDINGS: USING QUANTITATIVE METHYLATION ANALYSIS IN A CASE-CONTROL STUDY (N = 1,083) WE FOUND THAT DNA METHYLATION OF PERIPHERAL BLOOD CELL DNA PROVIDES GOOD PREDICTION OF BC RISK. WE ALSO REPORT THAT INVASIVE DUCTAL AND INVASIVE LOBULAR BC IS CHARACTERIZED BY TWO DIFFERENT SETS OF GENES, THE LATTER PARTICULAR BY GENES INVOLVED IN THE DIFFERENTIATION OF THE MESENCHYME (PITX2, TITF1, GDNF AND MYOD1). FINALLY WE DEMONSTRATE THAT ONLY ERT GENES PREDICT ER POSITIVE BC; LACK OF PERIPHERAL BLOOD CELL DNA METHYLATION OF ZNF217 PREDICTED BC INDEPENDENT OF AGE AND FAMILY HISTORY (ODDS RATIO 1.49; 95% CONFIDENCE INTERVAL 1.12-1.97; P = 0.006) AND WAS ASSOCIATED WITH ER-ALPHA BIOACTIVITY IN THE CORRESPONDING SERUM. CONCLUSION/SIGNIFICANCE: THIS FIRST LARGE-SCALE EPIGENOTYPING STUDY DEMONSTRATES THAT DNA METHYLATION MAY SERVE AS A LINK BETWEEN THE ENVIRONMENT AND THE GENOME. FACTORS THAT CAN BE MODULATED BY THE ENVIRONMENT (LIKE ESTROGENS) LEAVE AN IMPRINT IN THE DNA OF CELLS THAT ARE UNRELATED TO THE TARGET ORGAN AND INDICATE THE PREDISPOSITION TO DEVELOP A CANCER. FURTHER RESEARCH WILL NEED TO DEMONSTRATE WHETHER DNA METHYLATION PROFILES WILL BE ABLE TO SERVE AS A NEW TOOL TO PREDICT THE RISK OF DEVELOPING CHRONIC DISEASES WITH SUFFICIENT ACCURACY TO GUIDE PREVENTIVE MEASURES.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
13 1537 29 DNA METHYLATION IN ADOLESCENTS WITH ANXIETY DISORDER: A LONGITUDINAL STUDY. ANXIETY DISORDERS (AD) TYPICALLY MANIFEST IN CHILDREN AND ADOLESCENTS AND MIGHT PERSIST INTO ADULTHOOD. HOWEVER, THERE ARE STILL FEW DATA CONCERNING EPIGENETIC MECHANISMS ASSOCIATED WITH ONSET, PERSISTENCE OR REMISSION OF AD OVER TIME. WE INVESTIGATED A COHORT OF ADOLESCENTS AND YOUNG ADULTS AT BASELINE (AGE; 13.19 +/- 2.38) AND AFTER 5 YEARS AND CLASSIFIED THEM ACCORDING TO THE AD DIAGNOSIS AND THEIR LONGITUDINAL TRAJECTORIES INTO 4 GROUPS: (1) TYPICALLY DEVELOPING COMPARISONS (TDC; CONTROL GROUP, N = 14); (2) INCIDENT (AD IN THE SECOND EVALUATION ONLY, N = 11); (3) PERSISTENT (AD IN BOTH EVALUATIONS, N = 14) AND (4) REMITTENT (AD IN THE FIRST EVALUATION ONLY, N = 8). DNA METHYLATION WAS EVALUATED WITH THE INFINIUM HUMANMETHYLATION450 BEADCHIP FROM SALIVA SAMPLES COLLECTED AT BOTH EVALUATIONS. GENE SET ENRICHMENT ANALYSIS WAS APPLIED TO CONSIDER BIOLOGICAL PATHWAYS. WE FOUND DECREASED DNA METHYLATION IN TDC GROUP WHILE THE CHRONIC CASES OF AD PRESENTED HYPERMETHYLATION IN CENTRAL NERVOUS SYSTEM DEVELOPMENT PATHWAYS. MOREOVER, WE SHOWED THAT THIS PERSISTENT GROUP ALSO PRESENTED HYPERMETHYLATION WHILE THE OTHER THREE GROUPS WERE ASSOCIATED WITH HYPOMETHYLATION IN NERVOUS SYSTEM DEVELOPMENT PATHWAY. INCIDENCE AND REMISSION GROUPS WERE ASSOCIATED WITH INCREASED AND DECREASED METHYLATION IN NEURON DEVELOPMENT PATHWAYS, RESPECTIVELY. LARGER STUDIES ARE LIKELY TO DETECT SPECIFIC GENES RELEVANT TO AD.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
14 6794 30 [EFFECT OF BENZO(A)PYRENE ON THE EXPRESSION OF AHR-REGULATED MICRORNA IN FEMALE AND MALE RAT LUNGS]. SMOKING IS THE MAIN RISK FACTOR FOR LUNG CANCER, MAINLY DUE TO PRESENCE OF NITROSAMINES AND POLYCYCLIC AROMATIC HYDROCARBONS, INCLUDING BENZO[A]PYRENE (BP) IN TOBACCO SMOKE COMPOSITION. THE GENOTOXIC EFFECT OF BP IS BASED ON THE HIGH DNA-BINDING ABILITY OF ITS METABOLITES, WHILE THE EPIGENETIC EFFECTS ARE MEDIATED BY A CHANGE IN THE EXPRESSION OF CANCER RELATED GENES OR REGULATORY RNAS. IT HAS BEEN SHOWN THAT WOMEN HAVE A HIGHER RISK TO DEVELOP LUNG CANCER UPON SMOKING RATHER THAN MEN. WE HYPOTHESIZED THAT CROSSTALK BETWEEN SIGNALING PATHWAYS ACTIVATED BY BP AND ESTROGENS COULD UNDERLIE THE SEX-DEPENDENT DIFFERENCES IN MIRNAS EXPRESSION. TO TEST THIS HYPOTHESIS, MALE AND FEMALE RATS WERE SUBJECTED TO SHORT-TERM OR LONG-TERM BP EXPOSURE. USING IN SILICO ANALYSIS, MIRNAS CONTAINING THE ER- AND AHR-BINDING SITES IN THE PROMOTERS OF THE GENES (OR HOST GENES) WERE SELECTED. DURING CHRONIC EXPOSURE OF BP THE EXPRESSION OF MIR-22-3P, -29A-3P, -126A-3P, -193B-5P IN THE LUNGS OF MALE RATS WERE SIGNIFICANTLY INCREASED, WHILE THE LEVEL OF MIRNA-483-3P WERE DECREASED. EXPRESSION OF MIRNA-483-3P WAS UP-REGULATED DURING CHRONIC BP EXPOSURE IN THE LUNGS OF FEMALE RATS AND THE LEVELS OF OTHER STUDIED MIRNAS WERE UNCHANGED. IN TURN, CHANGES IN THE EXPRESSION OF MIRNAS WERE FOLLOWED BY CHANGES IN THE EXPRESSION OF THEIR TARGET GENES, INCLUDING PTEN, EMP2, IGF1, ITGA6, SLC34A2, AND THE OBSERVED CHANGES IN FEMALE AND MALE RAT LUNGS WERE VARIED. THUS, OUR RESULTS SUGGEST THAT SEX-DEPENDENT EPIGENETIC EFFECTS OF BP MAY BE BASED ON DIFFERENT EXPRESSION OF AHR- AND ER- REGULATED MIRNAS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
15  348 34 ALTERED DNA METHYLATION IS ASSOCIATED WITH ABERRANT GENE EXPRESSION IN PARENCHYMAL BUT NOT AIRWAY FIBROBLASTS ISOLATED FROM INDIVIDUALS WITH COPD. BACKGROUND: CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A HETEROGENEOUS DISEASE OF THE LUNGS THAT IS CURRENTLY THE FOURTH LEADING CAUSE OF DEATH WORLDWIDE. GENETIC FACTORS ACCOUNT FOR ONLY A SMALL AMOUNT OF COPD RISK, BUT EPIGENETIC MECHANISMS, INCLUDING DNA METHYLATION, HAVE THE POTENTIAL TO MEDIATE THE INTERACTIONS BETWEEN AN INDIVIDUAL'S GENETICS AND ENVIRONMENTAL EXPOSURE. DNA METHYLATION IS HIGHLY CELL TYPE-SPECIFIC, AND INDIVIDUAL CELL TYPE STUDIES OF DNA METHYLATION IN COPD ARE SPARSE. FIBROBLASTS ARE PRESENT WITHIN THE AIRWAY AND PARENCHYMA OF THE LUNG AND CONTRIBUTE TO THE ABERRANT DEPOSITION OF EXTRACELLULAR MATRIX IN COPD. NO ASSESSMENT OR COMPARISON OF GENOME-WIDE DNA METHYLATION PROFILES IN THE AIRWAY AND PARENCHYMAL FIBROBLASTS FROM INDIVIDUALS WITH AND WITHOUT COPD HAS BEEN UNDERTAKEN. THESE DATA PROVIDE VALUABLE INSIGHT INTO THE MOLECULAR MECHANISMS CONTRIBUTING TO COPD AND THE DIFFERING PATHOLOGIES OF SMALL AIRWAYS DISEASE AND EMPHYSEMA IN COPD. METHODS: GENOME-WIDE DNA METHYLATION WAS EVALUATED AT OVER 485,000 CPG SITES USING THE ILLUMINA INFINIUM HUMANMETHYLATION450 BEADCHIP ARRAY IN THE AIRWAY (NON-COPD N = 8, COPD N = 7) AND PARENCHYMAL FIBROBLASTS (NON-COPD N = 17, COPD N = 29) ISOLATED FROM INDIVIDUALS WITH AND WITHOUT COPD. TARGETED GENE EXPRESSION WAS ASSESSED BY QPCR IN MATCHED RNA SAMPLES. RESULTS: DIFFERENTIALLY METHYLATED DNA REGIONS WERE IDENTIFIED BETWEEN CELLS ISOLATED FROM INDIVIDUALS WITH AND WITHOUT COPD IN BOTH AIRWAY AND PARENCHYMAL FIBROBLASTS. ONLY IN PARENCHYMAL FIBROBLASTS WAS DIFFERENTIAL DNA METHYLATION ASSOCIATED WITH DIFFERENTIAL GENE EXPRESSION. A SECOND ANALYSIS OF DIFFERENTIAL DNA METHYLATION VARIABILITY IDENTIFIED 359 INDIVIDUAL DIFFERENTIALLY VARIABLE CPG SITES IN PARENCHYMAL FIBROBLASTS. NO DIFFERENTIALLY VARIABLE CPG SITES WERE IDENTIFIED IN THE AIRWAY FIBROBLASTS. FIVE DIFFERENTIALLY VARIABLE-METHYLATED CPG SITES, ASSOCIATED WITH THREE GENES, WERE SUBSEQUENTLY ASSESSED FOR GENE EXPRESSION DIFFERENCES. TWO GENES (OAT AND GRIK2) DISPLAYED SIGNIFICANTLY INCREASED GENE EXPRESSION IN CELLS ISOLATED FROM INDIVIDUALS WITH COPD. CONCLUSIONS: DIFFERENTIAL AND VARIABLE DNA METHYLATION WAS ASSOCIATED WITH COPD STATUS IN THE PARENCHYMAL FIBROBLASTS BUT NOT AIRWAY FIBROBLASTS. ABERRANT DNA METHYLATION WAS ASSOCIATED WITH ALTERED GENE EXPRESSION IMPARTING BIOLOGICAL FUNCTION TO DNA METHYLATION CHANGES. CHANGES IN DNA METHYLATION ARE THEREFORE IMPLICATED IN THE MOLECULAR MECHANISMS UNDERLYING COPD PATHOGENESIS AND MAY REPRESENT NOVEL THERAPEUTIC TARGETS.	2018	

16 2631 31 EPIGENOME-WIDE ASSOCIATION STUDY OF WHOLE BLOOD GENE EXPRESSION IN FRAMINGHAM HEART STUDY PARTICIPANTS PROVIDES MOLECULAR INSIGHT INTO THE POTENTIAL ROLE OF CHRNA5 IN CIGARETTE SMOKING-RELATED LUNG DISEASES. BACKGROUND: DNA METHYLATION IS A KEY EPIGENETIC MODIFICATION THAT CAN DIRECTLY AFFECT GENE REGULATION. DNA METHYLATION IS HIGHLY INFLUENCED BY ENVIRONMENTAL FACTORS SUCH AS CIGARETTE SMOKING, WHICH IS CAUSALLY RELATED TO CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND LUNG CANCER. TO DATE, THERE HAVE BEEN FEW LARGE-SCALE, COMBINED ANALYSES OF DNA METHYLATION AND GENE EXPRESSION AND THEIR INTERRELATIONS WITH LUNG DISEASES. RESULTS: WE PERFORMED AN EPIGENOME-WIDE ASSOCIATION STUDY OF WHOLE BLOOD GENE EXPRESSION IN ~ 6000 INDIVIDUALS FROM FOUR COHORTS. WE DISCOVERED AND REPLICATED NUMEROUS CPGS ASSOCIATED WITH THE EXPRESSION OF CIS GENES WITHIN 500 KB OF EACH CPG, WITH 148 TO 1,741 CIS CPG-TRANSCRIPT PAIRS IDENTIFIED ACROSS COHORTS. WE FOUND THAT THE CLOSER A CPG RESIDED TO A TRANSCRIPTION START SITE, THE LARGER ITS EFFECT SIZE, AND THAT 36% OF CIS CPG-TRANSCRIPT PAIRS SHARE THE SAME CAUSAL GENETIC VARIANT. MENDELIAN RANDOMIZATION ANALYSES REVEALED THAT HYPOMETHYLATION AND LOWER EXPRESSION OF CHRNA5, WHICH ENCODES A SMOKING-RELATED NICOTINIC RECEPTOR, ARE CAUSALLY LINKED TO INCREASED RISK OF COPD AND LUNG CANCER. THIS PUTATIVELY CAUSAL RELATIONSHIP WAS FURTHER VALIDATED IN LUNG TISSUE DATA. CONCLUSIONS: OUR RESULTS PROVIDE A LARGE AND COMPREHENSIVE ASSOCIATION STUDY OF WHOLE BLOOD DNA METHYLATION WITH GENE EXPRESSION. EXPRESSION PLATFORM DIFFERENCES RATHER THAN POPULATION DIFFERENCES ARE CRITICAL TO THE REPLICATION OF CIS CPG-TRANSCRIPT PAIRS. THE LOW REPRODUCIBILITY OF TRANS CPG-TRANSCRIPT PAIRS SUGGESTS THAT DNA METHYLATION REGULATES NEARBY RATHER THAN REMOTE GENE EXPRESSION. THE PUTATIVELY CAUSAL ROLES OF METHYLATION AND EXPRESSION OF CHRNA5 IN RELATION TO COPD AND LUNG CANCER PROVIDE EVIDENCE FOR A MECHANISTIC LINK BETWEEN PATTERNS OF SMOKING-RELATED EPIGENETIC VARIATION AND LUNG DISEASES, AND HIGHLIGHT POTENTIAL THERAPEUTIC TARGETS FOR LUNG DISEASES AND SMOKING CESSATION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
17 2908 25 GENE EXPRESSION PROFILE OF NORMAL BREAST TISSUE AND BODY MASS INDEX. BACKGROUND: IN HUMAN BREAST, ADIPOSE TISSUE REPRESENTS UP TO 80% OF THE TOTAL VOLUME AND PLAYS A CRITICAL ROLE IN MAMMARY GLAND REMODELING. GIVEN THE EMERGING ROLE OF OBESITY IN BREAST CANCER GROWTH AND DEVELOPMENT, WE EXPLORED THE RELATIONSHIP BETWEEN BODY MASS INDEX (BMI), AS A PROXY OF WOMAN'S OBESITY STATUS, AND THE EXPRESSION IN NORMAL BREAST TISSUE FROM HEALTHY WOMEN OF A SELECTED PANEL OF GENES, KNOWN TO BE INVOLVED IN MAMMARY GLAND HOMEOSTASIS. METHODS: TWO INDEPENDENT PUBLICLY AVAILABLE DATASETS, COMPOSED OF 180 SPECIMENS OF NORMAL BREAST TISSUE FROM REDUCTION MAMMOPLASTY WERE INTERROGATED. DIFFERENTIAL GENE EXPRESSION AMONG BMI CLASSES WAS EVALUATED BY ANOVA, AND PARTIAL CORRELATION COEFFICIENT WAS USED TO ASSAY THE CORRELATION BETWEEN GENES CONTROLLING FOR BMI. RESULTS: DESPITE THE DIFFERENCES IN MICROARRAY PLATFORMS AND ANALYTICAL PROCEDURES, THE TWO DATASETS SHARED A CORE OF 9 GENES DIFFERENTIALLY EXPRESSED IN BMI CLASSES AND SIGNIFICANTLY CORRELATED WITH BMI. FOUR (44%) OF THESE GENES BELONG TO THE FUNCTIONAL CLASS OF CYTOKINES AND CYTOKINE RECEPTORS (IL1R1, IL2RA, IL12A, AND IL12RB2). THE OTHERS BELONG TO THE FUNCTIONAL CLASS OF THE EPIGENETIC REGULATION (MEDAG AND SETD7), SIGNAL TRANSDUCTION (STAT1), CELL ADHESION (ITGAV), AND ENZYMATIC ACTIVITY (STS). CONCLUSIONS: ALTHOUGH EXPLORATORY, PRESENT FINDINGS ARE IN AGREEMENT WITH THE ROLE OF INFLAMMATION MODULATORS IN THE HOMEOSTASIS OF NORMAL BREAST TISSUE AND THE BELIEVE THAT AN INCREASE IN BODY ADIPOSE TISSUE MAY HAVE A POTENTIALLY DANGEROUS LOCAL EFFECT, THROUGH THE INCREASED EXPRESSION OF INFLAMMATION-RELATED GENES AND THE ESTABLISHMENT OF A LOW-GRADE CHRONIC INFLAMMATION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
18 5287 29 PROSPECTIVE EPIGENOME AND TRANSCRIPTOME ANALYSES OF CORD AND PERIPHERAL BLOOD FROM PRETERM INFANTS AT RISK OF BRONCHOPULMONARY DYSPLASIA. BRONCHOPULMONARY DYSPLASIA (BPD) IS A PREVALENT CHRONIC LUNG DISEASE OF PREMATURITY WITH LIMITED TREATMENT OPTIONS. TO UNCOVER BIOMARKERS OF BPD RISK, THIS STUDY INVESTIGATED EPIGENETIC AND TRANSCRIPTOMIC SIGNATURES OF PREMATURITY AT BIRTH AND DURING THE NEONATAL PERIOD AT DAY 14 AND 28. PERIPHERAL BLOOD DNAS FROM PRETERM INFANTS WERE APPLIED TO METHYLATION ARRAYS AND CELL-TYPE COMPOSITION WAS ESTIMATED BY DECONVOLUTION. COVARIATE-ADJUSTED ROBUST LINEAR REGRESSION ELUCIDATED BPD- AND PROLONGED OXYGEN (>/= 14 DAYS) EXPOSURE-ASSOCIATED CPGS. RNAS FROM CORD AND PERIPHERAL BLOOD WERE SEQUENCED, AND DIFFERENTIALLY EXPRESSED GENES (DEGS) FOR BPD OR OXYGEN EXPOSURE WERE DETERMINED. ESTIMATED NEUTROPHIL-LYMPHOCYTE RATIOS IN PERIPHERAL BLOOD AT DAY 14 IN BPD INFANTS WERE SIGNIFICANTLY HIGHER THAN NONBPD INFANTS, SUGGESTING AN HEIGHTENED INFLAMMATORY RESPONSE IN DEVELOPING BPD. BPD-DEGS IN CORD BLOOD INDICATED LYMPHOPOIESIS INHIBITION, ALTERED TH1/TH2 RESPONSES, DNA DAMAGE, AND ORGAN DEGENERATION. ON DAY 14, BPD-ASSOCIATED CPGS WERE HIGHLY ENRICHED IN NEUTROPHIL ACTIVATION, INFECTION, AND CD4 + T CELL QUANTITY, AND BPD-DEGS WERE INVOLVED IN DNA DAMAGE, CELLULAR SENESCENCE, T CELL HOMEOSTASIS, AND HYPER-CYTOKINESIS. ON DAY 28, BPD-ASSOCIATED CPGS ALONG WITH BPD-DEGS WERE ENRICHED FOR PHAGOCYTOSIS, NEUROLOGICAL DISORDER, AND NUCLEOTIDE METABOLISM. OXYGEN SUPPLEMENTATION MARKEDLY DOWNREGULATED MITOCHONDRIAL BIOGENESIS GENES AND ALTERED CPGS ANNOTATED TO DEVELOPMENTAL GENES. PREMATURITY-ALTERED DNA METHYLATION COULD CAUSE ABNORMAL LYMPHOPOIESIS, CELLULAR ASSEMBLY AND CELL CYCLE PROGRESSION TO INCREASE BPD RISK. SIMILAR PATHWAYS BETWEEN EPIGENOME AND TRANSCRIPTOME NETWORKS SUGGEST COORDINATION OF THE TWO IN DYSREGULATING LEUKOPOIESIS, ADAPTIVE IMMUNITY, AND INNATE IMMUNITY. THE RESULTS PROVIDE MOLECULAR INSIGHTS INTO BIOMARKERS FOR EARLY DETECTION AND PREVENTION OF BPD.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
19 1567 32 DNA METHYLATION OF THE KLF14 GENE REGION IN WHOLE BLOOD CELLS PROVIDES PREDICTION FOR THE CHRONIC INFLAMMATION IN THE ADIPOSE TISSUE. KRUPPEL-LIKE FACTOR 14 (KLF14) GENE, WHICH APPEARS TO BE A MASTER REGULATOR OF GENE EXPRESSION IN THE ADIPOSE TISSUE AND HAVE PREVIOUSLY BEEN ASSOCIATED WITH BMI AND TYPE 2 DIABETES (T2D) BY LARGE GENOME-WIDE ASSOCIATION STUDIES. IN ORDER TO FIND PREDICTIVE BIOMARKERS FOR THE DEVELOPMENT OF T2D, IT IS NECESSARY TO TAKE EPIGENOMIC CHANGES AFFECTED BY ENVIRONMENTAL FACTORS INTO ACCOUNT. THIS STUDY FOCUSES ON AGEING AND OBESITY, WHICH ARE T2D RISK FACTORS, AND EXAMINES EPIGENETIC CHANGES AND INFLAMMATORY CHANGES. WE INVESTIGATED DNA METHYLATION CHANGES IN THE KLF14 PROMOTER REGION IN DIFFERENT ORGANS OF MICE FOR COMPARING AGING AND WEIGHT. WE FOUND THAT METHYLATION LEVELS OF THESE SITES WERE INCREASED WITH AGING AND WEIGHT IN THE SPLEEN, THE ADIPOSE TISSUE, THE KIDNEY, THE LUNG, THE COLON AND THE WHOLE BLOOD CELLS. IN ADDITION, IN THE SPLEEN, THE ADIPOSE TISSUE AND THE WHOLE BLOOD, THESE EPIGENETIC CHANGES WERE ALSO SIGNIFICANTLY ASSOCIATED WITH INFLAMMATORY LEVELS. MOREOVER, NOT ONLY KLF14, BUT ALSO EXPRESSION LEVELS OF SOME DOWNSTREAM GENES WERE DECREASED WITH METHYLATION IN THE SPLEEN, THE ADIPOSE TISSUE AND THE WHOLE BLOOD CELLS. TAKEN TOGETHER, OUR RESULTS SUGGEST THAT METHYLATION CHANGES OF KLF14 IN THOSE TISSUES MAY BE ASSOCIATED WITH CHANGES IN GENE EXPRESSION AND INFLAMMATION ON THE ADIPOSE TISSUE OF OBESITY AND T2D. IN ADDITION, THE METHYLATION CHANGES IN THE WHOLE BLOOD CELLS MAY SERVE AS A PREDICTIVE EPIGENETIC BIOMARKER FOR THE DEVELOPMENT OF T2D.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
20 1591 33 DNA METHYLATION PROFILING IN PERIPHERAL LUNG TISSUES OF SMOKERS AND PATIENTS WITH COPD. BACKGROUND: EPIGENETICS CHANGES HAVE BEEN SHOWN TO BE AFFECTED BY CIGARETTE SMOKING. CIGARETTE SMOKE (CS)-MEDIATED DNA METHYLATION CAN POTENTIALLY AFFECT SEVERAL CELLULAR AND PATHOPHYSIOLOGICAL PROCESSES, ACUTE EXACERBATIONS, AND COMORBIDITY IN THE LUNGS OF PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). WE SOUGHT TO DETERMINE WHETHER GENOME-WIDE LUNG DNA METHYLATION PROFILES OF SMOKERS AND PATIENTS WITH COPD WERE SIGNIFICANTLY DIFFERENT FROM NON-SMOKERS. WE ISOLATED DNA FROM PARENCHYMAL LUNG TISSUES OF PATIENTS INCLUDING EIGHT LIFELONG NON-SMOKERS, EIGHT CURRENT SMOKERS, AND EIGHT PATIENTS WITH COPD AND ANALYZED THE SAMPLES USING ILLUMINA'S INFINIUM HUMANMETHYLATION450 BEADCHIP. RESULTS: OUR DATA REVEALED THAT THE DIFFERENTIALLY METHYLATED GENES WERE RELATED TO TOP CANONICAL PATHWAYS (E.G., G BETA GAMMA SIGNALING, MECHANISMS OF CANCER, AND NNOS SIGNALING IN NEURONS), DISEASE AND DISORDERS (ORGANISMAL INJURY AND ABNORMALITIES, CANCER, AND RESPIRATORY DISEASE), AND MOLECULAR AND CELLULAR FUNCTIONS (CELL DEATH AND SURVIVAL, CELLULAR ASSEMBLY AND ORGANIZATION, CELLULAR FUNCTION AND MAINTENANCE) IN PATIENTS WITH COPD. THE GENOME-WIDE DNA METHYLATION ANALYSIS IDENTIFIED SUGGESTIVE GENES, SUCH AS NOS1AP, TNFAIP2, BID, GABRB1, ATXN7, AND THOC7 WITH DNA METHYLATION CHANGES IN COPD LUNG TISSUES THAT WERE FURTHER VALIDATED BY PYROSEQUENCING. PYROSEQUENCING VALIDATION CONFIRMED HYPER-METHYLATION IN SMOKERS AND PATIENTS WITH COPD AS COMPARED TO NON-SMOKERS. HOWEVER, WE DID NOT DETECT SIGNIFICANT DIFFERENCES IN DNA METHYLATION FOR TNFAIP2, ATXN7, AND THOC7 GENES IN SMOKERS AND COPD GROUPS DESPITE THE CHANGES OBSERVED IN THE GENOME-WIDE ANALYSIS. CONCLUSIONS: OUR STUDY SUGGESTS THAT DNA METHYLATION IN SUGGESTIVE GENES, SUCH AS NOS1AP, BID, AND GABRB1 MAY BE USED AS EPIGENETIC SIGNATURES IN SMOKERS AND PATIENTS WITH COPD IF THE SAME IS VALIDATED IN A LARGER COHORT. FUTURE STUDIES ARE REQUIRED TO CORRELATE DNA METHYLATION STATUS WITH TRANSCRIPTOMICS OF SELECTIVE GENES IDENTIFIED IN THIS STUDY AND ELUCIDATE THEIR ROLE AND INVOLVEMENT IN THE PROGRESSION OF COPD AND ITS EXACERBATIONS.	2017