1 3060 162 GENOME-WIDE DNA METHYLATION ANALYSIS OF MAMMARY GLAND TISSUES FROM CHINESE HOLSTEIN COWS WITH STAPHYLOCOCCUS AUREUS INDUCED MASTITIS. STAPHYLOCOCCUS AUREUS INTRAMAMMARY INFECTION IS ONE OF THE MOST COMMON CAUSES OF CHRONIC MASTITIS IN DAIRY COWS, WHOSE DEVELOPMENT MAY BE ASSOCIATED WITH EPIGENETIC CHANGES IN THE EXPRESSION OF IMPORTANT HOST DEFENSE GENES. THIS STUDY AIMED TO CONSTRUCT A GENOME-WIDE DNA METHYLATION PROFILE OF THE MAMMARY GLAND OF CHINESE HOLSTEIN COWS (N = 3) FOLLOWING EXPERIMENTALLY INDUCED S. AUREUS MASTITIS, AND TO EXPLORE THE POTENTIAL GENE REGULATORY MECHANISMS AFFECTED BY DNA METHYLATION DURING S. AUREUS MASTITIS. DNA WAS EXTRACTED FROM S. AUREUS-POSITIVE (N = 3) AND S. AUREUS-NEGATIVE (N = 3) MAMMARY GLAND QUARTERS AND SUBJECTED TO METHYLATION-DEPENDENT RESTRICTION-SITE ASSOCIATED DNA SEQUENCING (METHYL-RAD SEQ). RESULTS SHOWED THAT C(M)CGG/C(M)CWGG DNA METHYLATION SITES WERE UNEVENLY DISTRIBUTED AND CONCENTRATED ON CHROMOSOMES 5, 11, AND 19, AND WITHIN INTERGENIC REGIONS AND INTRON REGIONS OF GENES. COMPARED WITH HEALTHY CONTROL QUARTERS, 9,181 SIGNIFICANTLY DIFFERENTIALLY METHYLATED (DM) C(M)CGG SITES AND 1,790 DM C(M)CWGG SITES WERE FOUND IN THE S. AUREUS-POSITIVE QUARTERS (P < 0.05, |LOG2FC| > 1). FURTHERMORE, 363 C(M)CGG DIFFERENTLY METHYLATED GENES (DMGS) AND 301 C(M)CWGG DMGS (ADJUSTED P < 0.05, |LOG2FC| > 1) WERE IDENTIFIED. GENE ONTOLOGY AND KEGG ENRICHMENT ANALYSIS INDICATED THAT C(M)CGG DMGS ARE INVOLVED IN IMMUNE RESPONSE PATHWAYS, WHILE THE C(M)CWGG DMGS WERE MAINLY ENRICHED IN GENE ONTOLOGY TERMS RELATED TO METABOLISM. THE MRNAS OF 526 DIFFERENTIALLY METHYLATED C(M)CGG GENES AND 124 DIFFERENTIALLY METHYLATED C(M)CWGG GENES WERE ALSO SIGNIFICANTLY DIFFERENTIALLY EXPRESSED (RNA-SEQ DATA) IN THE SAME SAMPLES, HEREIN DENOTED DIFFERENTIALLY METHYLATED AND EXPRESSED GENES (DMEGS) (P < 0.05). FUNCTIONAL ENRICHMENT ANALYSIS OF DMEGS REVEALED ROLES RELATED TO BIOLOGICAL PROCESSES, ESPECIALLY THE REGULATION OF IMMUNE RESPONSE TO DISEASES. C(M)CGG DMEGS LIKE IL6R, TNF, BTK, IL1R2, AND TNFSF8 ENRICHED IN SEVERAL IMMUNE-RELATED GO TERMS AND PATHWAYS INDICATED THEIR IMPORTANT ROLES IN HOST IMMUNE RESPONSE AND THEIR POTENTIAL AS CANDIDATE GENES FOR S. AUREUS MASTITIS. THESE RESULTS SUGGEST POTENTIAL REGULATORY ROLES FOR DNA METHYLATION IN BOVINE MAMMARY GLAND PROCESSES DURING S. AUREUS MASTITIS AND SERVES AS A REFERENCE FOR FUTURE EPIGENETIC REGULATION AND MECHANISTIC STUDIES.	2020	
                                                                                                                                                                                                                         
2 2626  46 EPIGENOME-WIDE ASSOCIATION STUDY IDENTIFIES DNA METHYLATION MARKERS FOR ASTHMA REMISSION IN WHOLE BLOOD AND NASAL EPITHELIUM. BACKGROUND: ASTHMA IS A CHRONIC RESPIRATORY DISEASE WHICH IS NOT CURABLE, YET SOME PATIENTS EXPERIENCE SPONTANEOUS REMISSION. WE HYPOTHESIZED THAT EPIGENETIC MECHANISMS MAY BE INVOLVED IN ASTHMA REMISSION. METHODS: CLINICAL REMISSION (CLINR) WAS DEFINED AS THE ABSENCE OF ASTHMA SYMPTOMS AND MEDICATION FOR AT LEAST 12 MONTHS, AND COMPLETE REMISSION (COMR) WAS DEFINED AS CLINR WITH NORMAL LUNG FUNCTION AND ABSENCE OF AIRWAY HYPERRESPONSIVENESS. WE ANALYZED DIFFERENTIAL DNA METHYLATION OF CLINR AND COMR COMPARING TO PERSISTENT ASTHMA (PERSA) IN WHOLE BLOOD SAMPLES (N = 72) AND NASAL BRUSHING SAMPLES (N = 97) IN A LONGITUDINAL COHORT OF WELL CHARACTERIZED ASTHMA PATIENTS. SIGNIFICANT FINDINGS OF WHOLE BLOOD DNA METHYLATION WERE TESTED FOR REPLICATION IN TWO INDEPENDENT COHORTS, LIFELINES AND EPIDEMIOLOGICAL STUDY ON THE GENETICS AND ENVIRONMENT OF ASTHMA (EGEA). RESULTS: WE IDENTIFIED DIFFERENTIALLY METHYLATED CPG SITES ASSOCIATED WITH CLINR (7 CPG SITES) AND COMR (129 CPG SITES) IN WHOLE BLOOD. ONE CPG (CG13378519, CHR1) ASSOCIATED WITH CLINR WAS REPLICATED AND ANNOTATED TO PEX11 (PEROXISOMAL BIOGENESIS FACTOR 11 BETA). THE WHOLE BLOOD DNA METHYLATION LEVELS OF THIS CPG WERE ALSO DIFFERENT BETWEEN CLINR AND HEALTHY SUBJECTS. ONE COMR-ASSOCIATED CPG (CG24788483, CHR10) THAT ANNOTATED TO TCF7L2 (TRANSCRIPTION FACTOR 7 LIKE 2) WAS REPLICATED AND ASSOCIATED WITH EXPRESSION OF TCF7L2 GENE. ONE OUT OF SEVEN CLINR-ASSOCIATED CPG SITES AND 8 OUT OF 129 COMR-ASSOCIATED CPG SITES IDENTIFIED FROM WHOLE BLOOD SAMPLES SHOWED NOMINAL SIGNIFICANCE (P < 0.05) AND THE SAME DIRECTION OF EFFECT IN NASAL BRUSHES. CONCLUSION: WE IDENTIFIED DNA METHYLATION MARKERS POSSIBLY ASSOCIATED WITH CLINICAL AND COMPLETE ASTHMA REMISSION IN NASAL BRUSHES AND WHOLE BLOOD, AND TWO CPG SITES IDENTIFIED FROM WHOLE BLOOD CAN BE REPLICATED IN INDEPENDENT COHORTS AND MAY PLAY A ROLE IN PEROXISOME PROLIFERATION AND WNT SIGNALING PATHWAY.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
3 4868  46 OSTEOARTHRITIS RELATED EPIGENETIC VARIATIONS IN MIRNA EXPRESSION AND DNA METHYLATION. OSTEOARTHRITIS (OA) IS CHRONIC ARTHRITIS CHARACTERIZED BY ARTICULAR CARTILAGE DEGRADATION. HOWEVER, A COMPREHENSIVE REGULATORY NETWORK FOR OA-RELATED MICRORNAS AND DNA METHYLATION MODIFICATIONS HAS YET TO BE ESTABLISHED. THUS, WE AIMED TO IDENTIFY EPIGENETIC CHANGES IN MICRORNAS AND DNA METHYLATION AND ESTABLISH THE REGULATORY NETWORK BETWEEN MIRNAS AND DNA METHYLATION. THE MRNA, MIRNA, AND DNA METHYLATION EXPRESSION PROFILES OF HEALTHY OR OSTEOARTHRITIS ARTICULAR CARTILAGE SAMPLES WERE DOWNLOADED FROM GENE EXPRESSION OMNIBUS (GEO) DATABASE, INCLUDING GSE169077, GSE175961, AND GSE162484. THE DIFFERENTIALLY EXPRESSED GENES (DEGS), DIFFERENTIALLY EXPRESSED MIRNAS (DEMS), AND DIFFERENTIALLY METHYLATED GENES (DMGS) WERE ANALYZED BY THE ONLINE TOOL GEO2R. DAVID AND STRING DATABASES WERE APPLIED FOR FUNCTIONAL ENRICHMENT ANALYSIS AND PROTEIN-PROTEIN INTERACTION (PPI) NETWORK. POTENTIAL THERAPEUTIC COMPOUNDS FOR THE TREATMENT OF OA WERE IDENTIFIED BY CONNECTIVITY MAP (CMAP) ANALYSIS. A TOTAL OF 1424 UP-REGULATED DEGS, 1558 DOWN-REGULATED DEGS, 5 DEMS WITH HIGH EXPRESSION, 6 DEMS WITH LOW EXPRESSION, 1436 HYPERMETHYLATED GENES, AND 455 HYPOMETHYLATED GENES WERE SELECTED. A TOTAL OF 136 UP-REGULATED AND 65 DOWNREGULATED GENES WERE IDENTIFIED BY OVERLAPPING DEGS AND DEMS PREDICTED TARGET GENES WHICH WERE ENRICHED IN APOPTOSIS AND CIRCADIAN RHYTHM. A TOTAL OF 39 HYPOMETHYLATED AND 117 HYPERMETHYLATED GENES WERE OBTAINED BY OVERLAPPING DEGS AND DMGS, WHICH WERE ASSOCIATED WITH ECM RECEPTOR INTERACTIONS AND CELLULAR METABOLIC PROCESSES, CELL CONNECTIVITY, AND TRANSCRIPTION. MOREOVER, THE PPI NETWORK SHOWED COL5A1, COL6A1, LAMA4, T3GAL6A, AND TP53 WERE THE MOST CONNECTIVE PROTEINS. AFTER OVERLAPPING OF DEGS, DMGS AND DEMS PREDICTED TARGETED GENES, 4 UP-REGULATED GENES AND 11 DOWN-REGULATED GENES WERE ENRICHED IN THE AXON GUIDANCE PATHWAY. THE TOP TEN GENES RANKED BY PPI NETWORK CONNECTIVITY DEGREE IN THE UP-REGULATED AND DOWNREGULATED OVERLAPPING GENES OF DEGS AND DMGS WERE FURTHER ANALYZED BY THE CMAP DATABASE, AND NINE CHEMICALS WERE PREDICTED AS POTENTIAL DRUGS FOR THE TREATMENT OF OA. IN CONCLUSION, TP53, COL5A1, COL6A1, LAMA4, AND ST3GAL6 MAY PLAY IMPORTANT ROLES IN OA GENESIS AND DEVELOPMENT.	2023	
                                                                                                                                                                                                                                                                                                                                                             
4 1187  44 COPD GWAS VARIANT AT 19Q13.2 IN RELATION WITH DNA METHYLATION AND GENE EXPRESSION. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS AMONG THE MAJOR HEALTH BURDENS IN ADULTS. WHILE CIGARETTE SMOKING IS THE LEADING RISK FACTOR, A GROWING NUMBER OF GENETIC VARIATIONS HAVE BEEN DISCOVERED TO INFLUENCE DISEASE SUSCEPTIBILITY. EPIGENETIC MODIFICATIONS MAY MEDIATE THE RESPONSE OF THE GENOME TO SMOKING AND REGULATE GENE EXPRESSION. CHROMOSOME 19Q13.2 REGION IS ASSOCIATED WITH BOTH SMOKING AND COPD, YET ITS FUNCTIONAL ROLE IS UNCLEAR. OUR STUDY AIMED TO DETERMINE WHETHER RS7937 (RAB4B, EGLN2), A TOP GENETIC VARIANT IN 19Q13.2 REGION IDENTIFIED IN GENOME-WIDE ASSOCIATION STUDIES OF COPD, IS ASSOCIATED WITH DIFFERENTIAL DNA METHYLATION IN BLOOD (N = 1490) AND GENE EXPRESSION IN BLOOD (N = 721) AND LUNGS (N = 1087). WE COMBINED GENETIC AND EPIGENETIC DATA FROM THE ROTTERDAM STUDY (RS) TO PERFORM THE EPIGENOME-WIDE ASSOCIATION ANALYSIS OF RS7937. FURTHER, WE USED GENETIC AND TRANSCRIPTOMIC DATA FROM BLOOD (RS) AND FROM LUNG TISSUE (LUNG EXPRESSION QUANTITATIVE TRAIT LOCI MAPPING STUDY), TO PERFORM THE TRANSCRIPTOME-WIDE ASSOCIATION STUDY OF RS7937. RS7937 WAS SIGNIFICANTLY (FDR < 0.05) AND CONSISTENTLY ASSOCIATED WITH DIFFERENTIAL DNA METHYLATION IN BLOOD AT 4 CPG SITES IN CIS, INDEPENDENT OF SMOKING. ONE METHYLATION SITE (CG11298343-EGLN2) WAS ALSO ASSOCIATED WITH COPD (P = 0.001). ADDITIONALLY, RS7937 WAS ASSOCIATED WITH GENE EXPRESSION LEVELS IN BLOOD IN CIS (EGLN2), 42% MEDIATED THROUGH CG11298343, AND IN LUNG TISSUE, IN CIS AND TRANS (NUMBL, EGLN2, DNMT3A, LOC101929709 AND PAK2). OUR RESULTS SUGGEST THAT CHANGES OF DNA METHYLATION AND GENE EXPRESSION MAY BE INTERMEDIATE STEPS BETWEEN GENETIC VARIANTS AND COPD, BUT FURTHER CAUSAL STUDIES IN LUNG TISSUE SHOULD CONFIRM THIS HYPOTHESIS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
5 2946  33 GENETIC AND EPIGENETIC CHANGES IN THE EUTOPIC ENDOMETRIUM OF WOMEN WITH ENDOMETRIOSIS: ASSOCIATION WITH DECREASED ENDOMETRIAL ALPHAVBETA3 INTEGRIN EXPRESSION. ABOUT 40% OF WOMEN WITH INFERTILITY AND 70% OF WOMEN WITH PELVIC PAIN SUFFER FROM ENDOMETRIOSIS. THE PREGNANCY RATE IN WOMEN UNDERGOING IVF WITH LOW ENDOMETRIAL INTEGRIN ALPHAVBETA3 (LEI) EXPRESSION IS SIGNIFICANTLY LOWER COMPARED TO THE WOMEN WITH HIGH ENDOMETRIAL INTEGRIN ALPHAVBETA3 (HEI). MID-SECRETORY EUTOPIC ENDOMETRIAL BIOPSIES WERE OBTAINED FROM HEALTHY CONTROLS (C; N=3), AND WOMEN WITH HEI (N=4) AND LEI (N=4) AND ENDOMETRIOSIS. CHANGES IN GENE EXPRESSION WERE ASSESSED USING HUMAN GENE ARRAYS AND DNA METHYLATION DATA WERE DERIVED USING 385 K TWO-ARRAY PROMOTER ARRAYS. TRANSCRIPTIONAL ANALYSIS REVEALED THAT LEI AND C GROUPS CLUSTERED SEPARATELY WITH 396 DIFFERENTIALLY EXPRESSED GENES (DEGS) (P<0.01: 275 UP AND 121 DOWN) DEMONSTRATING THAT TRANSCRIPTIONAL AND EPIGENETIC CHANGES ARE DISTINCT IN THE LEI EUTOPIC ENDOMETRIUM COMPARED TO THE C AND HEI GROUP. IN CONTRAST, HEI VS C AND HEI VS LEI COMPARISONS ONLY IDENTIFIED 83 AND 45 DEGS, RESPECTIVELY. THE METHYLATION PROMOTER ARRAY IDENTIFIED 1304 DIFFERENTIALLY METHYLATED REGIONS IN THE LEI VS C COMPARISON. THE OVERLAP OF GENE AND METHYLATION ARRAY DATA IDENTIFIED 14 EPIGENETICALLY DYSREGULATED GENES AND QUANTITATIVE RT-PCR ANALYSIS VALIDATED THE TRANSCRIPTOMIC FINDINGS. THE ANALYSIS ALSO REVEALED THAT ARYL HYDROCARBON RECEPTOR (AHR) WAS HYPOMETHYLATED AND SIGNIFICANTLY OVEREXPRESSED IN LEI SAMPLES COMPARED TO C. FURTHER ANALYSIS VALIDATED THAT AHR TRANSCRIPT AND PROTEIN EXPRESSION ARE SIGNIFICANTLY (P<0.05) INCREASED IN LEI WOMEN COMPARED TO C. THE INCREASE IN AHR, TOGETHER WITH THE ALTERED METHYLATION STATUS OF THE 14 ADDITIONAL GENES, MAY PROVIDE A DIAGNOSTIC TOOL TO IDENTIFY THE SUBSET OF WOMEN WHO HAVE ENDOMETRIOSIS-ASSOCIATED INFERTILITY.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
6 5793  33 STAPHYLOCOCCAL ENTEROTOXIN B INFLUENCES THE DNA METHYLATION PATTERN IN NASAL POLYP TISSUE: A PRELIMINARY STUDY. STAPHYLOCOCCAL ENTEROTOXINS MAY INFLUENCE THE PRO-INFLAMMATORY PATTERN OF CHRONIC SINUS DISEASES VIA EPIGENETIC EVENTS. THIS WORK INTENDED TO INVESTIGATE THE POTENTIAL OF STAPHYLOCOCCAL ENTEROTOXIN B (SEB) TO INDUCE CHANGES IN THE DNA METHYLATION PATTERN. NASAL POLYP TISSUE EXPLANTS WERE CULTURED IN THE PRESENCE AND ABSENCE OF SEB; GENOMIC DNA WAS THEN ISOLATED AND USED FOR WHOLE GENOME METHYLATION ANALYSIS. RESULTS SHOWED THAT SEB STIMULATION ALTERED THE METHYLATION PATTERN OF GENE REGIONS WHEN COMPARED WITH NON STIMULATED TISSUE. DATA ENRICHMENT ANALYSIS HIGHLIGHTED TWO GENES: THE IKBKB AND STAT-5B, BOTH PLAYING A CRUCIAL ROLE IN T- CELL MATURATION/ACTIVATION AND IMMUNE RESPONSE.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
7 1422  40 DIFFERENTIAL CPG DNA METHYLATION OF PERIPHERAL B CELLS, CD4(+) T CELLS, AND SALIVARY GLAND TISSUES IN IGG4-RELATED DISEASE. OBJECTIVES: IMMUNOGLOBULIN-G4-RELATED DISEASE (IGG4-RD) IS A DISTINCT SYSTEMIC AUTOIMMUNE-MEDIATED DISEASE MANIFESTING AS CHRONIC INFLAMMATION AND TISSUE FIBROSIS. SINCE THE ROLE OF DNA METHYLATION IN THE PATHOGENESIS OF IGG4-RD IS STILL UNCLEAR, WE CONDUCT THIS STUDY TO INVESTIGATE EPIGENETIC MODIFICATIONS IN IGG4-RD. METHODS: A GENOME-WIDE DNA METHYLATION STUDY WAS CONDUCTED WITH B CELLS, CD4(+) T CELLS, AND SALIVARY GLAND TISSUES FROM IGG4-RD PATIENTS AND MATCHED CONTROLS BY USING THE ILLUMINA HUMANMETHYLATION 850K BEADCHIP. WE FURTHER PERFORMED PYROSEQUENCING AND IMMUNOHISTOCHEMISTRY ASSAYS TO VALIDATE THE METHYLATION STATUS OF SOME TARGETS OF INTEREST. RESULTS: WE IDENTIFIED DIFFERENTIALLY METHYLATED CPG SITES INCLUDING 44 HYPOMETHYLATED AND 166 HYPERMETHYLATED DIFFERENTIALLY METHYLATED PROBES (DMPS) IN B CELLS AND 260 HYPOMETHYLATED AND 112 HYPERMETHYLATED DMPS IN CD4(+) T CELLS FROM 10 IGG4-RD PATIENTS COMPARED WITH 10 HEALTHY CONTROLS. WE ALSO IDENTIFIED 36945 HYPOMETHYLATED AND 78380 HYPERMETHYLATED DMPS IN SALIVARY GLAND TISSUES OF 4 IGG4-RD PATIENTS COMPARED WITH 4 CONTROLS. DPM2 (CG21181453), IQCK (CG10266221), AND ABCC13 (CG05699681, CG04985582) WERE HYPERMETHYLATED AND MBP (CG18455083) WAS HYPOMETHYLATED IN B CELLS, CD4(+) T CELLS, AND SALIVARY GLAND TISSUES OF IGG4-RD PATIENTS. WE ALSO OBSERVED THE HYPOMETHYLATED HLA-DQB2 IN CD4(+) T CELLS FROM IGG4-RD PATIENTS. KYOTO ENCYCLOPEDIA OF GENES AND GENOMES (KEGG) PATHWAY ANALYSIS OF DMPS IN SALIVARY GLAND TISSUES OF IGG4-RD PATIENTS REVEALED ENRICHMENT OF PATHWAYS INVOLVED IN THE REGULATION OF IMMUNE CELL RESPONSES AND FIBROSIS. CONCLUSION: THIS IS THE FIRST DNA METHYLATION STUDY IN PERIPHERAL B CELLS, CD4(+) T CELLS, AND SALIVARY GLAND TISSUES FROM IGG4-RD PATIENTS. OUR FINDINGS HIGHLIGHTED THE ROLE OF EPIGENETIC MODIFICATION OF DNA METHYLATION AND IDENTIFIED SEVERAL GENES AND PATHWAYS POSSIBLY INVOLVED IN IGG4-RD PATHOGENESIS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
8   11  38 15Q12 VARIANTS, SPUTUM GENE PROMOTER HYPERMETHYLATION, AND LUNG CANCER RISK: A GWAS IN SMOKERS. BACKGROUND: LUNG CANCER IS THE LEADING CAUSE OF CANCER-RELATED MORTALITY WORLDWIDE. DETECTION OF PROMOTER HYPERMETHYLATION OF TUMOR SUPPRESSOR GENES IN EXFOLIATED CELLS FROM THE LUNG PROVIDES AN ASSESSMENT OF FIELD CANCERIZATION THAT IN TURN PREDICTS LUNG CANCER. THE IDENTIFICATION OF GENETIC DETERMINANTS FOR THIS VALIDATED CANCER BIOMARKER SHOULD PROVIDE NOVEL INSIGHTS INTO MECHANISMS UNDERLYING EPIGENETIC REPROGRAMMING DURING LUNG CARCINOGENESIS. METHODS: A GENOME-WIDE ASSOCIATION STUDY USING GENERALIZED ESTIMATING EQUATIONS AND LOGISTIC REGRESSION MODELS WAS CONDUCTED IN TWO GEOGRAPHICALLY INDEPENDENT SMOKER COHORTS TO IDENTIFY LOCI AFFECTING THE PROPENSITY FOR CANCER-RELATED GENE METHYLATION THAT WAS ASSESSED BY A 12-GENE PANEL INTERROGATED IN SPUTUM. ALL STATISTICAL TESTS WERE TWO-SIDED. RESULTS: TWO SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) AT 15Q12 (RS73371737 AND RS7179575) THAT DROVE GENE METHYLATION WERE DISCOVERED AND REPLICATED WITH RS73371737 REACHING GENOME-WIDE SIGNIFICANCE (P = 3.3X10(-8)). A HAPLOTYPE CARRYING RISK ALLELES FROM THE TWO 15Q12 SNPS CONFERRED 57% INCREASED RISK FOR GENE METHYLATION (P = 2.5X10(-9)). RS73371737 REDUCED GABRB3 EXPRESSION IN LUNG CELLS AND INCREASED RISK FOR SMOKING-INDUCED CHRONIC MUCOUS HYPERSECRETION. FURTHERMORE, SUBJECTS WITH VARIANT HOMOZYGOTE OF RS73371737 HAD A TWO-FOLD INCREASE IN RISK FOR LUNG CANCER (P = .0043). PATHWAY ANALYSIS IDENTIFIED DNA DOUBLE-STRAND BREAK REPAIR BY HOMOLOGOUS RECOMBINATION (DSBR-HR) AS A MAJOR PATHWAY AFFECTING SUSCEPTIBILITY FOR GENE METHYLATION THAT WAS VALIDATED BY MEASURING CHROMATID BREAKS IN LYMPHOCYTES CHALLENGED BY BLEOMYCIN. CONCLUSIONS: A FUNCTIONAL 15Q12 VARIANT WAS IDENTIFIED AS A RISK FACTOR FOR GENE METHYLATION AND LUNG CANCER. THE ASSOCIATIONS COULD BE MEDIATED BY GABAERGIC SIGNALING THAT DRIVES THE SMOKING-INDUCED MUCOUS CELL METAPLASIA. OUR FINDINGS ALSO SUBSTANTIATE DSBR-HR AS A CRITICAL PATHWAY DRIVING EPIGENETIC GENE SILENCING.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
9 1990  41 EPIGENETIC ANALYSIS OF PAGET'S DISEASE OF BONE IDENTIFIES DIFFERENTIALLY METHYLATED LOCI THAT PREDICT DISEASE STATUS. PAGET'S DISEASE OF BONE (PDB) IS CHARACTERIZED BY FOCAL INCREASES IN DISORGANIZED BONE REMODELING. THIS STUDY AIMS TO CHARACTERIZE PDB-ASSOCIATED CHANGES IN DNA METHYLATION PROFILES IN PATIENTS' BLOOD. META-ANALYSIS OF DATA FROM THE DISCOVERY AND CROSS-VALIDATION SET, EACH COMPRISING 116 PDB CASES AND 130 CONTROLS, REVEALED SIGNIFICANT DIFFERENCES IN DNA METHYLATION AT 14 CPG SITES, 4 CPG ISLANDS, AND 6 GENE-BODY REGIONS. THESE LOCI, INCLUDING TWO CHARACTERIZED AS FUNCTIONAL THROUGH EXPRESSION QUANTITATIVE TRAIT-METHYLATION ANALYSIS, WERE ASSOCIATED WITH FUNCTIONS RELATED TO OSTEOCLAST DIFFERENTIATION, MECHANICAL LOADING, IMMUNE FUNCTION, AND VIRAL INFECTION. A MULTIVARIATE CLASSIFIER BASED ON DISCOVERY SAMPLES WAS FOUND TO DISCRIMINATE PDB CASES AND CONTROLS FROM THE CROSS-VALIDATION WITH A SENSITIVITY OF 0.84, SPECIFICITY OF 0.81, AND AN AREA UNDER CURVE OF 92.8%. IN CONCLUSION, THIS STUDY HAS SHOWN FOR THE FIRST TIME THAT EPIGENETIC FACTORS CONTRIBUTE TO THE PATHOGENESIS OF PDB AND MAY OFFER DIAGNOSTIC MARKERS FOR PREDICTION OF THE DISEASE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
10 3296  43 HIGH RESOLUTION INTEGRATIVE ANALYSIS REVEALS WIDESPREAD GENETIC AND EPIGENETIC CHANGES AFTER CHRONIC IN-VITRO ACID AND BILE EXPOSURE IN BARRETT'S EPITHELIUM CELLS. BARRETT'S EPITHELIUM (BE) IS A PREMALIGNANT CONDITION RESULTING FROM CHRONIC GASTROESOPHAGEAL REFLUX THAT MAY PROGRESS TO ESOPHAGEAL ADENOCARCINOMA (EAC). EARLY INTERVENTION HOLDS PROMISE IN PREVENTING BE PROGRESSION. HOWEVER, IDENTIFICATION OF HIGH-RISK BE PATIENTS REMAINS CHALLENGING DUE TO INADEQUATE BIOMARKERS FOR EARLY DIAGNOSIS. WE INVESTIGATED THE EFFECT OF PROLONGED CHRONIC ACID AND BILE EXPOSURE ON TRANSCRIPTOME, METHYLOME, AND MUTATOME OF CELLS IN AN IN-VITRO BE CARCINOGENESIS (BEC) MODEL. TWENTY WEEKS ACID AND BILE EXPOSED CELLS FROM THE BEC MODEL (BEC20W) WERE COMPARED WITH THEIR NAIVE PREDECESSORS HISEQ ILLUMINA BASED RNA SEQUENCING WAS PERFORMED ON RNA FROM BOTH THE CELLS FOR GENE EXPRESSION AND MUTATIONAL ANALYSIS. HELP TAGGING ASSAY WAS PERFORMED FOR DNA METHYLATION ANALYSIS. INGENUITY PATHWAY, GENE ONTOLOGY, AND KEGG PATHWAY ANALYSES WERE THEN PERFORMED ON DATASETS. WIDESPREAD ABERRANT GENETIC AND EPIGENETIC CHANGES WERE OBSERVED IN THE BEC20W CELLS. COMBINATORIAL ANALYSES REVEALED 433 FROM A TOTAL OF 863 DOWNREGULATED GENES HAD ACCOMPANYING HYPERMETHYLATION OF PROMOTERS. SIMULTANEOUSLY, 690 GENES FROM A TOTAL OF 1,492 WERE UPREGULATED WITH ACCOMPANYING PROMOTER HYPOMETHYLATION. IN ADDITION, 763 MUTATIONS WERE IDENTIFIED ON 637 GENES. INGENUITY PATHWAY ANALYSIS, GENE ONTOLOGY, AND KEGG PATHWAY ANALYSES ASSOCIATED THE GENETIC AND EPIGENETIC CHANGES IN BEC20W CELLS WITH CELLULAR AND BIOLOGICAL FUNCTIONS. INTEGRATION OF HIGH RESOLUTION COMPARATIVE ANALYSES OF NAIVE BAR-T AND BEC20W CELLS REVEALED STRIKING GENETIC AND EPIGENETIC CHANGES INDUCED BY CHRONIC ACID AND BILE EXPOSURE THAT MAY DISRUPT NORMAL CELLULAR FUNCTIONS AND PROMOTE CARCINOGENESIS. THIS NOVEL STUDY REVEALS SEVERAL POTENTIAL TARGETS FOR FUTURE BIOMARKERS AND THERAPEUTIC DEVELOPMENT.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
11 1846  41 EFFECTS OF TWO TYPES OF ENERGY RESTRICTION ON METHYLATION LEVELS OF ADIPONECTIN RECEPTOR 1 AND LEPTIN RECEPTOR OVERLAPPING TRANSCRIPT IN A MOUSE MAMMARY TUMOUR VIRUS-TRANSFORMING GROWTH FACTOR-ALPHA BREAST CANCER MOUSE MODEL. THE ROLE OF ADIPONECTIN AND LEPTIN SIGNALLING PATHWAYS HAS BEEN SUGGESTED TO PLAY IMPORTANT ROLES IN THE PROTECTIVE EFFECTS OF ENERGY RESTRICTION (ER) ON MAMMARY TUMOUR (MT) DEVELOPMENT. TO STUDY THE EFFECTS OF ER ON THE METHYLATION LEVELS IN ADIPONECTIN RECEPTOR 1 (ADIPOR1) AND LEPTIN RECEPTOR OVERLAPPING TRANSCRIPT (LEPROT) GENES USING THE PYROSEQUENCING METHOD IN MAMMARY FAT PAD TISSUE, MOUSE MAMMARY TUMOUR VIRUS-TRANSFORMING GROWTH FACTOR-ALPHA (MMTV-TGF-ALPHA) FEMALE MICE WERE RANDOMLY ASSIGNED TO AD LIBITUM (AL), CHRONIC ER (CER, 15 % ER) OR INTERMITTENT ER (3 WEEKS AL AND 1 WEEK 60 % ER IN CYCLIC PERIODS) GROUPS AT 10 WEEKS OF AGE UNTIL 82 WEEKS OF AGE. THE METHYLATION LEVELS OF ADIPOR1 IN THE CER GROUP WERE HIGHER THAN THOSE IN THE AL GROUP AT WEEK 49/50 (P < 0.05), WHILE THE LEVELS OF METHYLATION FOR ADIPOR1 AND LEPROT GENES WERE SIMILAR AMONG THE OTHER GROUPS. ALSO, THE METHYLATION LEVELS AT CPG2 AND CPG3 REGIONS OF THE PROMOTER REGION OF THE ADIPOR1 GENE IN THE CER GROUP WERE THREE TIMES HIGHER (P < 0.05), WHILE CPG1 ISLAND OF LEPROT METHYLATION WAS SIGNIFICANTLY LOWER COMPARED WITH THE OTHER GROUPS (P < 0.05). ADIPONECTIN AND LEPTIN GENE EXPRESSION LEVELS WERE CONSISTENT WITH THE METHYLATION LEVELS. WE ALSO OBSERVED A CHANGE WITH AGEING IN METHYLATION LEVELS OF THESE GENES. THESE RESULTS INDICATE THAT DIFFERENT TYPES OF ER MODIFY METHYLATION LEVELS OF ADIPOR1 AND LEPROT IN DIFFERENT WAYS AND CER HAD A MORE SIGNIFICANT EFFECT ON METHYLATION LEVELS OF BOTH GENES. EPIGENETIC REGULATION OF THESE GENES MAY PLAY IMPORTANT ROLES IN THE PREVENTIVE EFFECTS OF ER AGAINST MT DEVELOPMENT AND AGEING PROCESSES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
12 4516  36 MULTI-OMICS CHARACTERIZATION OF INFLAMMATORY BOWEL DISEASE-INDUCED HYPERPLASIA/DYSPLASIA IN THE RAG2(-/-)/IL10(-/-) MOUSE MODEL. EPIGENETIC DYSREGULATION IS HYPOTHESIZED TO PLAY A ROLE IN THE OBSERVED ASSOCIATION BETWEEN INFLAMMATORY BOWEL DISEASE (IBD) AND COLON TUMOR DEVELOPMENT. IN THE PRESENT WORK, DNA METHYLOME, HYDROXYMETHYLOME, AND TRANSCRIPTOME ANALYSES WERE CONDUCTED IN PROXIMAL COLON TISSUES HARVESTED FROM THE HELICOBACTER HEPATICUS (H. HEPATICUS)-INFECTED MURINE MODEL OF IBD. REDUCED REPRESENTATION BISULFITE SEQUENCING (RRBS) AND OXIDATIVE RRBS (OXRRBS) ANALYSES IDENTIFIED 1606 DIFFERENTIALLY METHYLATED REGIONS (DMR) AND 3011 DIFFERENTIALLY HYDROXYMETHYLATED REGIONS (DHMR). THESE DMR/DHMR OVERLAPPED WITH GENES THAT ARE ASSOCIATED WITH GASTROINTESTINAL DISEASE, INFLAMMATORY DISEASE, AND CANCER. RNA-SEQ REVEALED PRONOUNCED EXPRESSION CHANGES OF A NUMBER OF GENES ASSOCIATED WITH INFLAMMATION AND CANCER. SEVERAL GENES INCLUDING DUOX2, TGM2, CDHR5, AND HK2 EXHIBITED CHANGES IN BOTH DNA METHYLATION/HYDROXYMETHYLATION AND GENE EXPRESSION LEVELS. OVERALL, OUR RESULTS SUGGEST THAT CHRONIC INFLAMMATION TRIGGERS CHANGES IN METHYLATION AND HYDROXYMETHYLATION PATTERNS IN THE GENOME, ALTERING THE EXPRESSION OF KEY TUMORIGENESIS GENES AND POTENTIALLY CONTRIBUTING TO THE INITIATION OF COLORECTAL CANCER.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
13 3753  43 INTEGRATED ANALYSIS OF GENE EXPRESSION AND METHYLATION DATA TO IDENTIFY POTENTIAL BIOMARKERS RELATED TO ATHEROSCLEROSIS ONSET. ATHEROSCLEROSIS IS A KIND OF CHRONIC INFLAMMATORY CARDIOVASCULAR DISEASE. EPIGENETIC REGULATION PLAYS A CRUCIAL ROLE IN ATHEROSCLEROSIS. OUR STUDY WAS AIMED AT FINDING POTENTIAL BIOMARKERS ASSOCIATED WITH THE OCCURRENCE OF ATHEROSCLEROSIS. TWO DATASETS WERE DOWNLOADED FROM THE GENE EXPRESSION OMNIBUS (GEO) DATABASE. THE EPIGENOME-WIDE ASSOCIATION STUDY (EWAS) ANALYSIS WAS PERFORMED ON METHYLATION DATA USING CPGASSOC PACKAGE. THE DIFFERENTIAL EXPRESSION ANALYSIS WAS CONDUCTED ON MRNA DATA USING LIMMA PACKAGE. THE GO (GENE ONTOLOGY) AND KEGG (KYOTO ENCYCLOPEDIA OF GENES AND GENOMES) FUNCTIONAL ENRICHMENT WAS DONE IN CLUSTERPROFILER PACKAGE. FINALLY, THE LOGISTIC REGRESSION MODEL WAS CONSTRUCTED USING GENERALIZED LINEAR MODEL (GLM) FUNCTION. BETWEEN ATHEROSCLEROTIC VS. NONATHEROSCLEROTIC SAMPLES, TOTALLY 4980 CYTOSINE-PHOSPHATE-GUANINE (CPG) SITES (ANNOTATED TO 2860 GENES) AND 132 DIFFERENTIALLY EXPRESSED GENES (DEGS) RELATED TO ATHEROSCLEROSIS WERE IDENTIFIED. THE ANNOTATED 2860 GENES AND 132 DEGS WERE SIGNIFICANTLY ENRICHED IN 9 AND 4 KEGG PATHWAYS AND 289 AND 132 GO TERMS, RESPECTIVELY. AFTER CROSS-ANALYSIS, 6 CRUCIAL CPG SITES WERE SCREENED TO BUILD THE MODEL, INCLUDING CG01187920, CG03422911, CG08018825, CG10967350, CG14473924, AND CG25313204. THE DIAGNOSTIC MODEL COULD RELIABLY SEPARATE THE ATHEROSCLEROSIS SAMPLES FROM NONATHEROSCLEROTIC SAMPLES. IN CONCLUSION, THE 6 CPG SITES ARE PROBABLY POTENTIAL DIAGNOSTIC BIOMARKERS FOR ATHEROSCLEROSIS, INCLUDING CG01187920, CG03422911, CG08018825, CG10967350, CG14473924, AND CG25313204.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
14 1598  38 DNA METHYLATION SIGNATURE IN MONONUCLEAR CELLS AND PROINFLAMMATORY CYTOKINES MAY DEFINE MOLECULAR SUBTYPES IN SPORADIC MENIERE DISEASE. MENIERE DISEASE (MD) IS A MULTIFACTORIAL DISORDER OF THE INNER EAR CHARACTERIZED BY VERTIGO ATTACKS ASSOCIATED WITH SENSORINEURAL HEARING LOSS AND TINNITUS WITH A SIGNIFICANT HERITABILITY. ALTHOUGH MD HAS BEEN ASSOCIATED WITH SEVERAL GENES, NO EPIGENETIC STUDIES HAVE BEEN PERFORMED ON MD. HERE WE PERFORMED WHOLE-GENOME BISULFITE SEQUENCING IN 14 MD PATIENTS AND SIX HEALTHY CONTROLS, WITH THE AIM OF IDENTIFYING AN MD METHYLATION SIGNATURE AND POTENTIAL DISEASE MECHANISMS. WE OBSERVED A HIGH NUMBER OF DIFFERENTIALLY METHYLATED CPGS (DMC) WHEN COMPARING MD PATIENTS TO CONTROLS (N= 9545), SEVERAL OF THEM IN HEARING LOSS GENES, SUCH AS PCDH15,&NBSP;ADGRV1 AND CDH23. BIOINFORMATIC ANALYSES OF DMCS AND CIS-REGULATORY REGIONS PREDICTED PHENOTYPES RELATED TO ABNORMAL EXCITATORY POSTSYNAPTIC CURRENTS, ABNORMAL NMDA-MEDIATED RECEPTOR CURRENTS AND ABNORMAL GLUTAMATE-MEDIATED RECEPTOR CURRENTS WHEN COMPARING MD TO CONTROLS. MOREOVER, WE IDENTIFIED VARIOUS DMCS IN GENES PREVIOUSLY ASSOCIATED WITH COCHLEOVESTIBULAR PHENOTYPES IN MICE. WE HAVE ALSO FOUND 12 UNDERMETHYLATED REGIONS (UMR) THAT WERE EXCLUSIVE TO MD, INCLUDING TWO UMR IN AN INTER CPG ISLAND IN THE PHB GENE. WE SUGGEST THAT THE DNA METHYLATION SIGNATURE ALLOWS DISTINGUISHING BETWEEN MD PATIENTS AND CONTROLS. THE ENRICHMENT ANALYSIS CONFIRMS PREVIOUS FINDINGS OF A CHRONIC INFLAMMATORY PROCESS UNDERLYING MD.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
15 5887  40 SYSTEMIC STEROID EXPOSURE IS ASSOCIATED WITH DIFFERENTIAL METHYLATION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE. RATIONALE: SYSTEMIC GLUCOCORTICOIDS ARE USED THERAPEUTICALLY TO TREAT A VARIETY OF MEDICAL CONDITIONS. EPIGENETIC PROCESSES SUCH AS DNA METHYLATION MAY REFLECT EXPOSURE TO GLUCOCORTICOIDS AND MAY BE INVOLVED IN MEDIATING THE RESPONSES AND SIDE EFFECTS ASSOCIATED WITH THESE MEDICATIONS. OBJECTIVES: TO TEST THE HYPOTHESIS THAT DIFFERENCES IN DNA METHYLATION ARE ASSOCIATED WITH CURRENT SYSTEMIC STEROID USE. METHODS: WE OBTAINED DNA METHYLATION DATA AT 27,578 CPG SITES IN 14,475 GENES THROUGHOUT THE GENOME IN TWO LARGE, INDEPENDENT COHORTS: THE INTERNATIONAL COPD GENETICS NETWORK (N(DISCOVERY) = 1,085) AND THE BOSTON EARLY ONSET COPD STUDY (N(REPLICATION) = 369). SITES WERE TESTED FOR ASSOCIATION WITH CURRENT SYSTEMIC STEROID USE USING GENERALIZED LINEAR MIXED MODELS. MEASUREMENTS AND MAIN RESULTS: A TOTAL OF 511 SITES DEMONSTRATED SIGNIFICANT DIFFERENTIAL METHYLATION BY SYSTEMIC CORTICOSTEROID USE IN ALL THREE OF OUR PRIMARY MODELS. PYROSEQUENCING VALIDATION CONFIRMED ROBUST DIFFERENTIAL METHYLATION AT CPG SITES ANNOTATED TO GENES SUCH AS SLC22A18, LRP3, HIPK3, SCNN1A, FXYD1, IRF7, AZU1, SIT1, GPR97, ABHD16B, AND RABGEF1. FUNCTIONAL ANNOTATION CLUSTERING DEMONSTRATED SIGNIFICANT ENRICHMENT IN INTRINSIC MEMBRANE COMPONENTS, HEMOSTASIS AND COAGULATION, CELLULAR ION HOMEOSTASIS, LEUKOCYTE AND LYMPHOCYTE ACTIVATION AND CHEMOTAXIS, PROTEIN TRANSPORT, AND RESPONSES TO NUTRIENTS. CONCLUSIONS: OUR ANALYSES SUGGEST THAT SYSTEMIC STEROID USE IS ASSOCIATED WITH SITE-SPECIFIC DIFFERENTIAL METHYLATION THROUGHOUT THE GENOME. DIFFERENTIALLY METHYLATED CPG SITES WERE FOUND IN BIOLOGICALLY PLAUSIBLE AND PREVIOUSLY UNSUSPECTED PATHWAYS; THESE GENES AND PATHWAYS MAY BE RELEVANT IN THE DEVELOPMENT OF NOVEL TARGETED THERAPIES.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
16 3494  34 IDENTIFICATION OF MICRORNAS WITH DYSREGULATED EXPRESSION IN STATUS EPILEPTICUS INDUCED EPILEPTOGENESIS. THE INVOLVEMENT OF MIRNA IN MESIAL TEMPORAL LOBE EPILEPSY (MTLE) PATHOGENESIS HAS INCREASINGLY BECOME A FOCUS OF EPIGENETIC STUDIES. DESPITE ADVANCES, THE NUMBER OF KNOWN MIRNAS WITH A CONSISTENT EXPRESSION RESPONSE DURING EPILEPTOGENESIS IS STILL SMALL. ADDRESSING THIS SITUATION REQUIRES ADDITIONAL MIRNA PROFILING STUDIES COUPLED TO DETAILED INDIVIDUAL EXPRESSION ANALYSES. HERE, WE PERFORM A MIRNA MICROARRAY ANALYSIS OF THE HIPPOCAMPUS OF WISTAR RATS 24 HOURS AFTER INTRA-HIPPOCAMPAL PILOCARPINE-INDUCED STATUS EPILEPTICUS (H-PILO SE). WE IDENTIFIED 73 MIRNAS THAT UNDERGO SIGNIFICANT CHANGES, OF WHICH 36 WERE UP-REGULATED AND 37 WERE DOWN-REGULATED. TO VALIDATE, WE SELECTED 5 OF THESE (10A-5P, 128A-3P, 196B-5P, 352 AND 324-3P) FOR RT-QPCR ANALYSIS. OUR RESULTS CONFIRMED THAT MIR-352 AND 196B-5P LEVELS WERE SIGNIFICANTLY HIGHER AND MIR-128A-3P LEVELS WERE SIGNIFICANTLY LOWER IN THE HIPPOCAMPUS OF H-PILO SE RATS. WE ALSO EVALUATED WHETHER THE 3 MIRNAS SHOW A DYSREGULATED HIPPOCAMPAL EXPRESSION AT THREE TIME PERIODS (0H, 24H AND CHRONIC PHASE) AFTER SYSTEMIC PILOCARPINE-INDUCED STATUS EPILEPTICUS (S-PILO SE). WE DEMONSTRATE THAT MIR-128A-3P TRANSCRIPTS ARE SIGNIFICANTLY REDUCED AT ALL TIME POINTS COMPARED TO THE NAIVE GROUP. MOREOVER, MIR-196B-5P WAS SIGNIFICANTLY HIGHER ONLY AT 24H POST-SE, WHILE MIR-352 TRANSCRIPTS WERE SIGNIFICANTLY UP-REGULATED AFTER 24H AND IN CHRONIC PHASE (EPILEPTIC) RATS. FINALLY, WHEN WE COMPARED HIPPOCAMPI OF EPILEPTIC AND NON-EPILEPTIC HUMANS, WE OBSERVED THAT TRANSCRIPT LEVELS OF MIRNAS SHOW SIMILAR TRENDS TO THE ANIMAL MODELS. IN SUMMARY, WE SUCCESSFULLY IDENTIFIED TWO NOVEL DYSREGULATED MIRNAS (196B-5P AND 352) AND CONFIRMED MIR-128A-3P DOWNREGULATION IN SE-INDUCED EPILEPTOGENESIS. FURTHER FUNCTIONAL ASSAYS ARE REQUIRED TO UNDERSTAND THE ROLE OF THESE MIRNAS IN MTLE PATHOGENESIS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
17 5621  32 SCREENING METHYLATION OF DNA REPAIR GENES IN THE ORAL MUCOSA OF CHRONIC SMOKERS. OBJECTIVE: THE AIM OF THIS STUDY WAS TO EVALUATE THE EPIGENETIC CHANGES IN THE PROCESS OF ORAL CARCINOGENESIS BY SCREENING THE METHYLATION OF REPAIR GENES IN CHRONIC SMOKERS. DESIGN: TWO GROUPS WERE FORMED: GROUP 1: 16 SMOKERS WITH CONSUMPTION OF 20 CIGARETTES/DAY FOR AT LEAST 10 YEARS; AND GROUP 2: 10 NON-SMOKING. EXFOLIATIVE CYTOLOGY OF THE TONGUE WAS PERFORMED, AND THE EXTRACTED DNA WAS TREATED BY ENZYMES. THE PCR ARRAY SYSTEM PERFORMED METHYLATION SCREENING TO EVALUATE 22 DNA REPAIR GENES, AND THE RESULTS WERE VALIDATED BY RT-QPCR FOR EACH GENE WITH METHYLATION LEVELS >/=10%. RESULTS: HIGHEST PERCENTAGES OF METHYLATION WERE OBSERVED FOR MLH3 AND XRCC1 GENES (11-20% METHYLATION) AND IN ONE CASE FOR MRE11A AND PMS2 (>50% METHYLATION). STATISTICAL ANALYSIS SHOWED SIGNIFICANT DIFFERENCES IN THE EXPRESSION OF THE GENES MRE11A (P = 0.0002), PMS2(P = 0.0068), XRCC1 (P = 0.0080) AND MLH3 (0.0057) BETWEEN THE TWO GROUPS. CONCLUSION: THE EFFECTS OF CHRONIC SMOKING ON ORAL MUCOSA LED TO THE METHYLATION OF GENES MRE11A PMS2, XRCC1 AND MLH3, BUT RESULTED IN A REDUCTION OF GENE EXPRESSION OF MRE11A AND PMS2, WHICH SHOWED >/=50% METHYLATION. THESE RESULTS PROVIDE EVIDENCE THAT SMOKING CAUSE METHYLATION AND REDUCED EXPRESSION OF REPAIR GENES.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
18 3073  57 GENOME-WIDE DNA METHYLATION STATUS OF MONGOLIANS EXHIBITS SIGNS OF CELLULAR STRESS RESPONSE RELATED TO THEIR NOMADIC LIFESTYLE. BACKGROUND: EPIGENETICS IS CRUCIAL FOR CONNECTING ENVIRONMENTAL STRESSES WITH PHYSIOLOGICAL RESPONSES IN HUMANS. MONGOLIA, WHERE NOMADIC LIVESTOCK PASTORALISM HAS BEEN THE PRIMAL LIVELIHOOD, HAS A HIGHER PREVALENCE OF VARIOUS CHRONIC DISEASES THAN THE SURROUNDING EAST ASIAN REGIONS, WHICH ARE MORE SUITABLE FOR CROP FARMING. THE GENES RELATED TO DIETARY STRESS AND PATHOGENESIS OF RELATED DISORDERS MAY HAVE VARYING EPIGENETIC STATUSES AMONG THE HUMAN POPULATIONS WITH DIVERSE DIETARY CULTURES. HENCE, TO UNDERSTAND SUCH EPIGENETIC DIFFERENCES, WE CONDUCTED A COMPARATIVE ANALYSIS OF GENOME-WIDE DNA METHYLATION OF MONGOLIANS AND CROP-FARMING EAST ASIANS. METHODS: GENOME-WIDE DNA METHYLATION STATUS OF PERIPHERAL BLOOD CELLS (PBCS) FROM 23 MONGOLIAN ADULTS AND 24 THAI ADULTS WAS DETERMINED USING THE INFINIUM HUMAN METHYLATION 450K ARRAYS AND ANALYZED IN COMBINATION WITH PREVIOUSLY PUBLISHED 450K DATA OF 20 JAPANESE AND 8 CHINESE ADULTS. CPG SITES/REGIONS DIFFERENTIALLY METHYLATED BETWEEN MONGOLIANS AND CROP-FARMING EAST ASIANS WERE DETECTED USING A LINEAR MODEL ADJUSTED FOR SEX, AGE, ETHNICITY, AND IMMUNE CELL HETEROGENEITY ON RNBEADS SOFTWARE. RESULTS: OF THE QUALITY-CONTROLLED 389,454 AUTOSOMAL CPG SITES, 223 CPG SITES WERE SIGNIFICANTLY DIFFERENTIALLY METHYLATED AMONG MONGOLIANS AND THE FOUR CROP FARMING EAST ASIAN POPULATIONS (FALSE DISCOVERY RATE < 0.05). ANALYSES FOCUSED ON GENE PROMOTER REGIONS REVEALED THAT PM20D1 (PEPTIDASE M20 DOMAIN CONTAINING 1), WHICH IS INVOLVED IN MITOCHONDRIAL UNCOUPLING AND VARIOUS PROCESSES, INCLUDING CELLULAR PROTECTION FROM REACTIVE OXYGEN SPECIES (ROS) AND THERMOGENESIS, WAS THE TOP DIFFERENTIALLY METHYLATED GENE. MOREOVER, GENE ONTOLOGY ENRICHMENT ANALYSIS REVEALED THAT BIOLOGICAL PROCESSES RELATED TO ROS METABOLISM WERE OVERREPRESENTED AMONG THE TOP 1% DIFFERENTIALLY METHYLATED GENES. THE PROMOTER REGIONS OF THESE GENES WERE GENERALLY HYPERMETHYLATED IN MONGOLIANS, SUGGESTING THAT THE METABOLIC PATHWAY DETOXIFYING ROS MIGHT BE GLOBALLY SUPPRESSED IN MONGOLIANS, RESULTING IN THE HIGH SUSCEPTIBILITY OF THIS POPULATION TO VARIOUS CHRONIC DISEASES. CONCLUSIONS: THIS STUDY SHOWED A SIGNIFICANTLY DIVERSE DNA METHYLATION STATUS AMONG MONGOLIANS AND CROP-FARMING EAST ASIANS. FURTHER, WE FOUND AN ASSOCIATION BETWEEN THE DIFFERENTIALLY METHYLATED GENES AND VARIOUS METABOLIC AND NEURODEGENERATIVE DISEASES. KNOWLEDGE OF THE EPIGENETIC REGULATORS MIGHT HELP IN PROPER UNDERSTANDING, TREATMENT, AND CONTROL OF SUCH DISORDERS, AND PHYSIOLOGICAL ADAPTATION IN THE FUTURE.	2022	

19 3907  37 LEUCOCYTIC DNA METHYLATION OF INTERLEUKIN-6 PROMOTER REDUCTION IN PRE-HYPERTENSIVE YOUNG ADULTS. BACKGROUND: PRE-HYPERTENSION IS ASSOCIATED WITH INCREASED RISK OF CARDIOVASCULAR DISEASE. CHRONIC INFLAMMATION PLAYS AN IMPORTANT ROLE IN THE PATHOPHYSIOLOGY OF ESSENTIAL HYPERTENSION, WITH EPIGENETIC DYSREGULATION INVOLVEMENT. NEVERTHELESS, THE ROLE OF DNA METHYLATION IN PREHYPERTENSIVE STATE IS UNKNOWN. THE AIM OF THIS STUDY WAS TO INVESTIGATE THE ASSOCIATION BETWEEN DNA METHYLATION LEVEL OF INTERLEUKIN-6 (IL-6) PROMOTER IN PRE-HYPERTENSIVE (PREHT) AND NORMOTENSIVE (NT) YOUNG ADULTS. METHODS: A TOTAL OF 80 NT AND 80 PREHT HEALTHY SUBJECTS AGED BETWEEN 18-45 YEARS WERE RECRUITED IN KUANTAN, PAHANG, MALAYSIA USING AN OBSERVATIONAL CROSS-SECTIONAL STUDY APPROACH. DNA METHYLATION LEVEL OF IL-6 PROMOTER IN PERIPHERAL LEUKOCYTES WERE MEASURED USING BISULPHITE CONVERSION AND METHYLIGHT ASSAY. RESULTS: THERE WAS NO SIGNIFICANT DIFFERENCE IN AGE BETWEEN NT AND PREHT (P = 0.655). THE MEAN BLOOD PRESSURE WAS 110(8)/73(5) MMHG IN NT AND 125(7)/82(5) MMHG IN PREHT SUBJECTS. THE IL-6 PROMOTER METHYLATION LEVEL WAS SIGNIFICANTLY LOWER IN PREHT COMPARED TO NT SUBJECTS (P < 0.001). CONCLUSION: THE CURRENT STUDY DEMONSTRATES THAT HYPOMETHYLATION OF IL-6 PROMOTER WAS ASSOCIATED WITH PRE-HYPERTENSION IN YOUNG ADULTS. THUS, IL-6 METHYLATION COULD BE USED AS AN EARLY INDICATOR FOR PREDICTING HYPERTENSION AND RELATED RISK OF CARDIOVASCULAR DISEASES IN PREHYPERTENSIVE SUBJECTS. GENE EXPRESSION AND LONGITUDINAL STUDIES ARE WARRANTED TO EXAMINE THE METHYLATION EFFECT ON IL-6 EXPRESSION OVER TIME.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
20 6036  54 THE CHARACTERISTICS OF EXTRACHROMOSOMAL CIRCULAR DNA IN PATIENTS WITH END-STAGE RENAL DISEASE. BACKGROUND: END-STAGE RENAL DISEASE (ESRD) IS THE FINAL STAGE OF CHRONIC KIDNEY DISEASE (CKD). IN ADDITION TO THE STRUCTURALLY INTACT CHROMOSOME GENOMIC DNA, THERE IS A DOUBLE-STRANDED CIRCULAR DNA CALLED EXTRACHROMOSOMAL CIRCULAR DNA (ECCDNA), WHICH IS THOUGHT TO BE INVOLVED IN THE EPIGENETIC REGULATION OF HUMAN DISEASE. HOWEVER, THE FEATURES OF ECCDNA IN ESRD PATIENTS ARE BARELY KNOWN. IN THIS STUDY, WE IDENTIFIED ECCDNA FROM ESRD PATIENTS AND HEALTHY PEOPLE, AS WELL AS REVEALED THE CHARACTERISTICS OF ECCDNA IN PATIENTS WITH ESRD. METHODS: USING THE HIGH-THROUGHPUT CIRCLE-SEQUENCING TECHNIQUE, WE EXAMINED THE ECCDNA IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM HEALTHY PEOPLE (NC) (N = 12) AND ESRD PATIENTS (N = 16). WE ANALYZED THE LENGTH DISTRIBUTION, GENOME ELEMENTS, AND MOTIFS FEATURE OF ECCDNA IN ESRD PATIENTS. THEN, AFTER IDENTIFYING THE SPECIFIC ECCDNA IN ESRD PATIENTS, WE EXPLORED THE POTENTIAL FUNCTIONS OF THE TARGET GENES OF THE SPECIFIC ECCDNA. FINALLY, WE INVESTIGATED THE PROBABLE HUB ECCDNA USING ALGORITHMS. RESULTS: IN TOTAL, 14,431 AND 11,324 ECCDNAS WERE FOUND IN THE ESRD AND NC GROUPS, RESPECTIVELY, WITH SIZES RANGING FROM 0.01 KB TO 60 KB AT MOST. ADDITIONALLY, THE ESRD GROUP HAD A GREATER DISTRIBUTION OF ECCDNA ON CHROMOSOMES 4, 11, 13, AND 20. IN TWO GROUPS, WE ALSO DISCOVERED SEVERAL MOTIFS OF SPECIFIC ECCDNAS. FURTHERMORE, WE IDENTIFIED 13,715 SPECIFIC ECCDNAS IN THE ESRD GROUP AND 10,585 SPECIFIC ECCDNAS IN THE NC GROUP, BOTH OF WHICH WERE LARGELY ANNOTATED AS MRNA CATALOG. PATHWAY STUDIES USING GENE ONTOLOGY (GO) AND THE KYOTO ENCYCLOPEDIA OF GENES AND GENOMES (KEGG) SHOWED THAT THE SPECIFIC ECCDNA IN ESRD WAS MARKEDLY ENRICHED IN CELL JUNCTION AND COMMUNICATION PATHWAYS. FURTHERMORE, WE IDENTIFIED POTENTIALLY 20 HUB ECCDNA-TARGETING GENES FROM ALL ESRD-SPECIFIC ECCDNA-TARGETING GENES. ALSO, WE FOUND THAT 39 ECCDNA-TARGETING GENES WERE ASSOCIATED WITH ESRD, AND SOME OF THESE ECCDNAS MAY BE RELATED TO THE PATHOGENESIS OF ESRD. CONCLUSIONS: OUR FINDINGS REVEALED THE CHARACTERISTICS OF ECCDNA IN ESRD PATIENTS AND DISCOVERED POTENTIALLY HUB AND ESRD-RELEVANT ECCDNA-TARGETING GENES, SUGGESTING A NOVEL PROBABLE MECHANISM OF ESRD.	2023