1 5674 119 SHARED GENETIC AND EPIGENETIC MECHANISMS BETWEEN CHRONIC PERIODONTITIS AND ORAL SQUAMOUS CELL CARCINOMA. OBJECTIVES: TO ANALYZE BIOINFORMATIC DATASETS FOR DETECTING GENETIC AND EPIGENETIC MECHANISMS SHARED BY CHRONIC PERIODONTITIS (CP) AND ORAL SQUAMOUS CELL CARCINOMA (OSCC). MATERIALS AND METHODS: DATASETS FROM GEO AND TCGA DATABASES REPORTING MRNAS, MIRNAS OR METHYLATION EXPRESSION IN HUMAN CP AND OSCC TISSUES WERE ANALYZED. DIFFERENTIAL EXPRESSION, FUNCTIONAL ENRICHMENT AND PROTEIN-PROTEIN INTERACTION (PPI) NETWORK ANALYSES WERE PERFORMED. DIFFERENTIALLY EXPRESSED MIRNAS (DEMIRNAS) AND GENES (DEG) IN CP AND OSCC WERE DETERMINED. DEMIRNA-TARGET AND DEMIRNA-DEG NETWORKS WERE CONSTRUCTED. DIRECTLY AND INDIRECTLY INTERACTING CROSS-TALK GENES WERE SCREENED, AND THEIR PREDICTION ACCURACY AND ASSOCIATION WITH OSCC PROGNOSIS WAS DETERMINED. RESULTS: 3 DE-MIRNAS (MIR-375, MIR-3609 AND MIR-3652) EXPRESSED IN BOTH CP AND OSCC CRITICALLY REGULATED MOST DEGS. AMONG 12 DIRECTLY INTERACTING CROSS-TALK GENES, NCAPH WAS SIGNIFICANTLY RELATED WITH THE PROGNOSIS OF OSCC. NR2F2 HAD HIGHEST DIFFERENTIAL EXPRESSION IN CP AND OSCC. AMONG 4 CROSS-TALK GENES (FN1, MPPED1, NDEL1, AND NR2F2) DIFFERENTIALLY EXPRESSED IN CP, 3 (FN1, MPPED1, NDEL1) WERE ALSO EXPRESSED IN OSCC. AMONG 12 INDIRECTLY INTERACTING CROSS-TALK GENES DIFFERENTIALLY EXPRESSED IN OSCC, 3 GENES (CDCA8, HIST1H3J, AND RAD51) WERE SIGNIFICANTLY RELATED TO ITS PROGNOSIS. SIGNIFICANT PATHWAYS INVOLVED IN CP AND OSCC INCLUDED: CHEMOKINE RECEPTORS, CLASS I PI3K SIGNALING EVENTS, EPITHELIAL-TO-MESENCHYMAL TRANSITION AND SIGNALING EVENTS BY VEGFR1 AND VEGFR2, EGF RECEPTOR (ERBB1). CONCLUSION: BIOINFORMATIC ANALYSIS OF AVAILABLE DATASETS IMPLICATED 1 DIRECTLY INTERACTING CROSS-TALK GENE (NCAPH), 4 INDIRECTLY INTERACTING CROSS-TALK GENES (NCAPH, NR2F2, FN1, AND MPPED1) AND 3 DE-MIRNAS (HSA-MIR-375, MIR-3609 AND MIR-3652) AS SHARED GENETIC AND EPIGENETIC EXPRESSION PATTERNS BETWEEN CP AND OSCC.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
2 4868  41 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	
                                                                                                                                                                                
3 3296  28 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
4 3477  40 IDENTIFICATION OF ABNORMALLY METHYLATED DIFFERENTIALLY EXPRESSED GENES IN CHRONIC PERIODONTITIS BY INTEGRATED BIOINFORMATICS ANALYSIS. BACKGROUND: DNA METHYLATION PLAYS A VITAL ROLE AS AN EPIGENETIC CHANGE THAT CONTRIBUTES TO CHRONIC PERIODONTITIS. OBJECTIVE: THIS STUDY AIMED TO INTEGRATE TWO METHYLATION DATASETS (GSE173081 AND GSE59962) AND TWO GENE EXPRESSION DATASETS (GSE10334 AND GES16134) TO IDENTIFY ABNORMALLY METHYLATED DIFFERENTIALLY EXPRESSED GENES RELATED TO CHRONIC PERIODONTITIS. METHODS: DIFFERENTIALLY METHYLATED GENES WERE OBTAINED. FUNCTIONAL ENRICHMENT ANALYSIS OF DMGS WAS PERFORMED. THE PROTEIN-PROTEIN INTERACTION (PPI) NETWORK WAS CONSTRUCTED USING STRING AND CYTOSCAPE SOFTWARE. FINALLY, THE HUB GENES WERE SELECTED FROM THE PPI NETWORK BY USING CYTOHUBBA. RESULTS: IN TOTAL, 122 HYPOMETHYLATED AND HIGHLY EXPRESSED GENES WERE ENRICHED IN THE BIOLOGICAL MECHANISMS THAT ARE INVOLVED IN THE DIFFERENTIATION OF EXTRACELLULAR MATRIX ORGANIZATION, EXTRACELLULAR STRUCTURE ORGANIZATION, AND CELL CHEMOTAXIS. THE THREE SELECTED HUB GENES OF THE PPI NETWORK WERE IL1B, KDR, AND MMP9. A TOTAL OF 122 HYPERMETHYLATED AND LOWLY EXPRESSED GENES WERE IDENTIFIED, AND BIOLOGICAL PROCESSES, SUCH AS CORNIFICATION, EPIDERMIS DEVELOPMENT, SKIN DEVELOPMENT, AND KERATINOCYTE DIFFERENTIATION WERE ENRICHED. CDSN DSG1, AND KRT2 WERE IDENTIFIED AS THE TOP 3 HUB GENES OF THE PPI NETWORK. CONCLUSION: BASED ON THE COMPREHENSIVE BIOINFORMATICS ANALYSIS, SIX HUB GENES (IL1B, KDR, MMP9, CDSN DSG1, AND KRT2) WERE ASSOCIATED WITH CHRONIC PERIODONTITIS. OUR FINDINGS PROVIDE NOVEL INSIGHTS INTO THE MECHANISMS UNDERLYING EPIGENETIC CHANGES IN CHRONIC PERIODONTITIS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
5   11  37 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                
6 1990  25 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
7 2453  34 EPIGENETIC SUPPRESSION OF THE IMMUNOREGULATOR MZB1 IS ASSOCIATED WITH THE MALIGNANT PHENOTYPE OF GASTRIC CANCER. PREDICTION OF TUMOR RECURRENCE AFTER CURATIVE RESECTION IS CRITICAL FOR DETERMINING THE PROGNOSIS OF PATIENTS WITH GASTRIC CANCER (GC). THE INITIATION AND PROGRESSION OF GC ARE ASSOCIATED WITH INAPPROPRIATE IMMUNE RESPONSES CAUSED BY CHRONIC INFLAMMATION OF THE GASTRIC MUCOSA. TO IDENTIFY IMMUNOREGULATORY MOLECULES INVOLVED IN GC PROGRESSION, GC CELL LINES AND 200 PAIRS OF TUMOR AND NORMAL TISSUES FROM PATIENTS WITH GC WERE ANALYZED FOR GENE EXPRESSION, AMPLIFICATION AND METHYLATION AS WELL AS FUNCTION OF A DIFFERENTIALLY EXPRESSED GENE. THE TRANSCRIPTOME ANALYSIS REVEALED THAT MARGINAL ZONE B AND B1 CELL SPECIFIC PROTEIN (MZB1) WAS EXPRESSED AT SIGNIFICANTLY DECREASED LEVELS IN PRIMARY GC TISSUES WHEN COMPARED WITH THE CORRESPONDING NORMAL GASTRIC MUCOSA. PCR ARRAY ANALYSIS EXPLORING GENES EXPRESSED COOPERATIVELY WITH MZB1 REVEALED THAT DIFFERENTIAL EXPRESSION OF MZB1 MRNA IN GC CELL LINES CORRELATED POSITIVELY WITH THE LEVELS OF THE MRNAS ENCODING ESTROGEN RECEPTOR 1 AND DESUMOYLATING ISOPEPTIDASE 1. HYPERMETHYLATION OF THE MZB1 PROMOTER WAS FREQUENT IN CELL LINES WITH DECREASED LEVELS OF MZB1 MRNA. SIRNA-MEDIATED KNOCKDOWN OF MZB1 SIGNIFICANTLY INCREASED PROLIFERATION, INVASION AND MIGRATION OF GC CELL LINES. LOW MZB1 EXPRESSION WAS AN INDEPENDENT PROGNOSTIC FACTOR FOR RECURRENCE AFTER CURATIVE GASTRECTOMY AND WAS ASSOCIATED SIGNIFICANTLY WITH INCREASED HEMATOGENOUS RECURRENCE. MZB1 ACTS AS A SUPPRESSOR OF GC. LOW MZB1 EXPRESSION IN THE PRIMARY GC TISSUE IS PREDICTIVE OF RECURRENCE AFTER CURATIVE RESECTION.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
8 2767  39 EXPRESSION, PROGNOSTIC VALUE, AND FUNCTIONAL MECHANISM OF THE KDM5 FAMILY IN PANCREATIC CANCER. BACKGROUND: THE HISTONE LYSINE DEMETHYLASE KDM5 FAMILY IS AN IMPORTANT EPIGENETIC STATE-MODIFYING ENZYME FAMILY. INCREASING EVIDENCE SUPPORTS THAT EPIGENETIC ABNORMALITIES IN THE KDM5 FAMILY ARE RELATED TO MULTIPLE CANCERS IN HUMANS. HOWEVER, THE ROLE OF THE KDM5 FAMILY IN PANCREATIC CANCER IS NOT CLEAR, AND RELATED RESEARCH IS VERY SCARCE. METHODS: R SOFTWARE, KAPLAN-MEIER PLOTTER, CBIOPORTAL, TIMER, LINKEDOMICS, STRING, METASCAPE, TISIDB, AND THE GSCA LITE ONLINE TOOL WERE UTILIZED FOR BIOINFORMATICS ANALYSIS. RESULTS: KDM5A/B/C WAS SIGNIFICANTLY OVEREXPRESSED IN MANY KINDS OF TUMOR TISSUES, INCLUDING PANCREATIC ADENOCARCINOMA (PAAD), WHILE THE EXPRESSION OF KDM5D WAS SIGNIFICANTLY DOWNREGULATED. THE HIGH EXPRESSION OF KDM5A/B/C WAS RELATED TO POOR CLINICAL FEATURES, SUCH AS WORSE TREATMENT EFFICACY, HIGHER TUMOR GRADE, AND MORE ADVANCED CLINICAL STAGE. PATIENTS WITH A FAMILY HISTORY OF BREAST CANCER AND MELANOMA, HISTORY OF DRINKING OR HISTORY CHRONIC PANCREATITIS WERE MORE LIKELY TO HAVE KDM5A/B/C GENE ABNORMALITIES, WHICH WERE RELATED TO A VARIETY OF ADVERSE CLINICAL FEATURES. THE RESULTS OF GENE ONTOLOGY (GO) AND KYOTO ENCYCLOPEDIA OF GENES AND GENOMES (KEGG) PATHWAY ANALYSES OF THE KDM5 FAMILY AND ITS 800 CO-EXPRESSED GENES SHOWED THAT MANY GENE TERMS RELATED TO CELL PROLIFERATION, MIGRATION AND MANY CARCINOGENIC PATHWAYS. NOTABLY, WE FOUND THAT THE EXPRESSION LEVEL OF KDM5A/B/C WAS POSITIVELY CORRELATED WITH THE EXPRESSION OF MULTIPLE KEY DRIVER GENES SUCH AS KRAS, BRCA1, AND BRCA2 ETC. IN ADDITION, PPI NETWORK ANALYSIS SHOWED KDM5 FAMILY PROTEINS HAVE STRONG INTERACTIONS WITH HISTONE DEACETYLASE FAMILY 1 (HDAC1), WHICH COULD MODIFY THE LYSINES OF HISTONE H3, AND CO-ACT ON MANY PATHWAYS, INCLUDING THE "LONGEVITY-REGULATING PATHWAY" AND "NOTCH SIGNALING PATHWAY". MOREOVER, THE UPREGULATION OF KDM5A/B/C EXPRESSION WAS ASSOCIATED WITH AN INCREASE IN THE INFILTRATION OF B CELLS, CD8(+) T CELLS AND OTHER INFILTRATING IMMUNE LYMPHOCYTES AND THE EXPRESSION LEVELS OF IMMUNE MOLECULES SUCH AS NT5E AND CD274. INTERESTINGLY, THE OVEREXPRESSION OF KDM5A/C WAS ALSO CORELATED WITH REDUCED SENSITIVITY OF PANCREATIC CANCER CELLS TO MANY KINDS OF PANCREATIC CANCER-TARGETING OR CHEMOTHERAPEUTIC DRUGS, INCLUDING AXITINIB AND GEMCITABINE. CONCLUSION: KDM5 FAMILY MEMBERS MAY BE PROGNOSTIC MARKERS AND NEW THERAPEUTIC TARGETS FOR PATIENTS WITH PANCREATIC CANCER.	2022	

9  145  27 ABERRANT DNA METHYLATION STATUS AND MRNA EXPRESSION LEVEL OF SMG1 GENE IN CHRONIC MYELOID LEUKEMIA: A CASE-CONTROL STUDY. OOBJECTIVE: CHRONIC MYELOID LEUKEMIA (CML) IS A MYELOPROLIFERATIVE MALIGNANCY WITH DIFFERENT STAGES. ABERRANT EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLATION, HAVE BEEN INTRODUCED AS A SIGNATURE FOR DIVERSE CANCERS WHICH ALSO PLAYS A CRUCIAL ROLE IN CML PATHOGENESIS AND DEVELOPMENT. SUPPRESSOR WITH MORPHOGENETIC EFFECT ON GENITALIA (SMG1) GENE RECENTLY HAS BEEN BROUGHT TO THE SPOTLIGHT AS A POTENT TUMOR SUPPRESSOR GENE THAT CAN BE SUPPRESSED BY TUMORS FOR FURTHER PROGRESS. THE PRESENT STUDY AIMS TO INVESTIGATE SMG1 STATUS IN CML PATIENTS. MATERIALS AND METHODS: IN THIS CASE-CONTROL STUDY, PERIPHERAL BLOOD FROM 30 PATIENTS WITH DIFFERENT PHASES OF CML [NEW CASE (N)=10, COMPLETE MOLECULAR REMISSION (CMR)=10, BLASTIC PHASE (BP)=10] AND 10 HEALTHY SUBJECTS WERE COLLECTED. METHYLATION STATUS AND EXPRESSION LEVEL OF SMG1 GENE PROMOTER WAS ASSESSED BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP) AND QUANTITATIVE REVERSE-TRANSCRIPTION PCR, RESPECTIVELY. RESULTS: MSP RESULTS OF SMG1 GENE PROMOTOR IN THE NEW CASE GROUP WERE METHYLATED (60% METHYLATED, 30% HEMIMETHYLATED AND 10% UNMETHYLATED). ALL CMR AND CONTROL GROUP PATIENTS WERE UNMETHYLATED IN THE SMG1 GENE PROMOTER. IN THE BP GROUP, METHYLATED SMG1 PROMOTER WAS SEEN (50% OF PATIENTS HAD A METHYLATED STATUS AND 50% HAD HEMIMETHYLATED STATUS). IN COMPARISON WITH THE HEALTHY SUBJECTS, EXPRESSION LEVEL OF SMG1 IN THE NEW CASE GROUP WAS DECREASED (P<0.01); IN THE CMR GROUP AND BP-CML GROUPS, IT WAS INCREASED (P<0.05). NO SIGNIFICANT CORRELATION BETWEEN PATIENTS' HEMATOLOGICAL FEATURES AND SMG1 METHYLATION WAS SEEN. CONCLUSION: OUR RESULTS DEMONSTRATED THAT ABERRANT METHYLATION OF SMG1 OCCURRED IN CML PATIENTS AND IT HAD A SIGNIFICANT ASSOCIATION WITH SMG1 EXPRESSION. SMG1 GENE PROMOTER SHOWED DIVERSE METHYLATED STATUS AND SUBSEQUENT EXPRESSION LEVELS IN DIFFERENT PHASES OF CML. THESE FINDINGS SUGGESTED POSSIBLE PARTICIPATION OF SMG1 SUPPRESSION IN THE CML PATHOGENESIS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                           
10 2626  31 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                               
11 1187  28 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
12 1067  29 CLINICAL UTILITY OF PDSS2 EXPRESSION TO STRATIFY PATIENTS AT RISK FOR RECURRENCE OF HEPATOCELLULAR CARCINOMA. IDENTIFICATION OF NOVEL GENETIC AND EPIGENETIC ALTERATIONS IS REQUIRED FOR OPTIMAL STRATIFICATION OF PATIENTS WITH HEPATOCELLULAR CARCINOMA (HCC) AT RISK FOR RECURRENCE AND ADVERSE PROGNOSIS. COENZYME Q10 (COQ10), WHICH MEDIATES APOPTOSIS, IS SYNTHESIZED BY PRENYL DIPHOSPHATE SYNTHASE SUBUNIT 2 (PDSS2). IN THE PRESENT STUDY WE EVALUATED THE CLINICAL SIGNIFICANCE AND REGULATORY MECHANISMS OF PDSS2 EXPRESSION IN HCC. PDSS2 EXPRESSION LEVELS AND THOSE OF GENES ENCODING POTENTIALLY INTERACTING PROTEINS AS WELL AS THE METHYLATION STATUS OF THE PDSS2 PROMOTER REGION WERE ANALYZED IN HCC CELL LINES. PDSS2 MRNA LEVELS IN 151 PAIRS OF RESECTED SPECIMENS WERE DETERMINED TO EVALUATE THE ASSOCIATION OF PDSS2 EXPRESSION AND CLINICOPATHOLOGICAL FACTORS. THE EXPRESSION AND DISTRIBUTION OF PDSS2 WERE DETERMINED USING IMMUNOHISTOCHEMISTRY. PDSS2 MRNA EXPRESSION WAS DECREASED IN SIX OF NINE HCC CELL LINES AND SIGNIFICANTLY CORRELATED WITH THOSE OF HEPATOCYTE NUCLEAR FACTOR 4ALPHA. PDSS2 TRANSCRIPTION IN HCC CELLS WITH DECREASED PDSS2 EXPRESSION ACCOMPANYING HYPERMETHYLATION WAS REACTIVATED AFTER TREATING THESE CELLS WITH A METHYLATION INHIBITOR. MEAN EXPRESSION LEVELS OF PDSS2 MRNA RELATIVE TO THAT OF UNINVOLVED LIVER DIMINISHED GRADUALLY IN THE ORDER OF CHRONIC HEPATITIS TO CIRRHOSIS, AND EACH WAS SIGNIFICANTLY HIGHER THAN THOSE OF HCCS. PDSS2 AND PDSS2 MRNA LEVELS WERE CONSISTENT. DECREASED PDSS2 MRNA LEVELS WERE DETECTED IN HCC TISSUES OF 56 PATIENTS, CORRELATED WITH SHORTER DISEASE-SPECIFIC SURVIVAL, AND WAS IDENTIFIED AS AN INDEPENDENT PROGNOSTIC FACTOR. PDSS2 IS A PUTATIVE TUMOR SUPPRESSOR, AND PROMOTER HYPERMETHYLATION IS A KEY REGULATORY MECHANISM IN HCC. DECREASED LEVELS OF PDSS2 MRNA EXPRESSION MAY REPRESENT A NOVEL BIOMARKER OF HCC.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
13 1742  29 EARLY EPIGENETIC DOWNREGULATION OF WNK2 KINASE DURING PANCREATIC DUCTAL ADENOCARCINOMA DEVELOPMENT. PANCREATIC DUCTAL ADENOCARCINOMA (PDAC) IS USUALLY INCURABLE. CONTRARY TO GENETIC MECHANISMS INVOLVED IN PDAC PATHOGENESIS, EPIGENETIC ALTERATIONS ARE ILL DEFINED. HERE, WE DETERMINE THE CONTRIBUTION OF EPIGENETICALLY SILENCED GENES TO THE DEVELOPMENT OF PDAC. WE ANALYZED ENRICHED, HIGHLY METHYLATED DNAS FROM PDACS, CHRONIC PANCREATITIS (CP) AND NORMAL TISSUES USING CPG ISLAND MICROARRAYS AND IDENTIFIED WNK2 AS A PROMINENT CANDIDATE TUMOR SUPPRESSOR GENE BEING DOWNREGULATED EARLY IN PDAC DEVELOPMENT. WNK2 WAS FURTHER INVESTIGATED IN TISSUE MICROARRAYS, METHYLATION ANALYSIS OF EARLY PANCREATIC INTRAEPITHELIAL NEOPLASIA (PANIN), MOUSE MODELS FOR PDAC AND PANCREATITIS, RE-EXPRESSION STUDIES AFTER DEMETHYLATION, AND CELL GROWTH ASSAYS USING WNK2 OVEREXPRESSION. DEMETHYLATION ASSAYS CONFIRMED THE LINK BETWEEN METHYLATION AND EXPRESSION. WNK2 HYPERMETHYLATION WAS HIGHER IN TUMOR THAN IN SURROUNDING INFLAMED TISSUES AND WAS OBSERVED IN PANIN LESIONS AS WELL AS IN A PDAC MOUSE MODEL. WNK2 MRNA AND PROTEIN EXPRESSIONS WERE LOWER IN PDAC AND CP COMPARED WITH NORMAL TISSUES BOTH IN PATIENTS AND MOUSE MODELS. OVEREXPRESSION OF WNK2 LED TO REDUCED CELL GROWTH, AND WNK2 EXPRESSION IN TISSUES CORRELATED NEGATIVELY WITH PERK1/2 EXPRESSION, A DOWNSTREAM TARGET OF WNK2 RESPONSIBLE FOR CELL PROLIFERATION. DOWNREGULATION OF WNK2 BY PROMOTER HYPERMETHYLATION OCCURS EARLY IN PDAC PATHOGENESIS AND MAY SUPPORT TUMOR CELL GROWTH VIA THE ERK-MAPK PATHWAY.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
14 2761  26 EXPRESSION OF TESTIS-SPECIFIC GENES, TEX101 AND ODF4, IN CHRONIC MYELOID LEUKEMIA AND EVALUATION OF TEX101 IMMUNOGENICITY. BACKGROUND AND OBJECTIVES: CANCER-TESTIS (CT) ANTIGENS ARE A GROUP OF ANTIGENS WITH A RESTRICTED EXPRESSION IN NORMAL TISSUES, EXCEPT TESTIS, AND THEY HAVE ABERRANT EXPRESSION IN DIFFERENT TUMORS. THIS PATTERN OF EXPRESSION HAS MADE THEM PROMISING TARGETS FOR IMMUNOTHERAPY AND CANCER DETECTION. OUR AIM WAS TO FIND NEW MEMBERS OF THIS GROUP THAT MIGHT BE USEFUL AS MARKERS IN THE DETECTION OF CANCER AND IMMUNOTHERAPY. DESIGN AND SETTING: A DESCRIPTIVE STUDY CONDUCTED IN REFERRAL CENTERS OF TEHRAN UNIVERSITY OF MEDICAL SCIENCE FROM JANUARY 2008 TO JANUARY 2009. PATIENTS AND METHODS: WE ANALYZED THE EXPRESSION OF TWO TESTIS-SPECIFIC GENES NAMED ODF4 (OUTER DENSE FIBER OF SPERM TAILS 4) AND TEX101 (TESTIS EXPRESSED 101) IN 20 CHRONIC MYELOID LEUKEMIA (CML) AND 20 NORMAL SAMPLES BY REVERSE TRANSCRIPTION-POLYMERASE CHAIN REACTION AND SEQUENCING. IMMUNOGENICITY OF TEX101 WAS EVALUATED BY MEANS OF ENZYME-LINKED IMMUNOSORBENT ASSAY. RESULTS: THESE TWO GENES WERE EXPRESSED IN 30% OF CML PATIENTS BUT NOT IN ANY OF THE HEALTHY DONORS. HUMORAL RESPONSE AGAINST TEX101 WAS NOT DETECTED IN ANY SAMPLES. CONCLUSIONS: TEX101 AND ODF4 ARE CT GENES USEFUL FOR DETECTION OF CML. UNLIKE MANY CT GENES, OVEREXPRESSION OF TEX101 WAS NOT SHOWN TO INDUCE IMMUNOLOGIC RESPONSES IN THESE SAMPLES. ACCORDING TO THE PREVIOUS STUDIES, OVEREXPRESSION OF TEX101 LEADS TO SUPPRESSION OF CANCER INVASION AND METASTASIS; THUS, THE INDUCTION OF THE EXPRESSION OF TEX101 IN CANCER BY EPIGENETIC MECHANISMS MAY BE A TREATMENT STRATEGY.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
15 2946  23 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
16 4516  22 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
17 3049  26 GENOME-WIDE ANALYSIS REVEALS ZINC TRANSPORTER ZIP9 REGULATED BY DNA METHYLATION PROMOTES RADIATION-INDUCED SKIN FIBROSIS VIA THE TGF-BETA SIGNALING PATHWAY. RADIATION-INDUCED SKIN FIBROSIS IS A DETRIMENTAL AND CHRONIC DISORDER THAT OCCURS AFTER RADIATION EXPOSURE. DNA METHYLATION HAS BEEN CHARACTERIZED AS AN IMPORTANT REGULATORY MECHANISM OF MULTIPLE PATHOLOGICAL PROCESSES. IN THIS STUDY, WE COMPARED THE GENOME-WIDE DNA METHYLATION STATUS IN RADIATION-INDUCED FIBROTIC SKIN AND ADJACENT NORMAL TISSUES OF RATS BY METHYLATED DNA IMMUNOPRECIPITATION SEQUENCING. RADIATION-INDUCED FIBROTIC SKIN SHOWED DIFFERENTIALLY METHYLATED REGIONS ASSOCIATED WITH 3,650 PROTEIN-CODING GENES, 72 MICRORNAS, 5,836 LONG NONCODING RNAS AND 3 PIWI-INTERACTING RNAS. BY INTEGRATING THE MRNA AND METHYLATION PROFILES, THE ZINC TRANSPORTER SLC39A9/ZIP9 WAS INVESTIGATED IN GREATER DETAIL. THE PROTEIN LEVEL OF ZIP9 WAS INCREASED IN IRRADIATED SKIN TISSUES OF HUMANS, MONKEYS, AND RATS, ESPECIALLY IN RADIOGENIC FIBROTIC SKIN TISSUES. RADIATION INDUCED THE DEMETHYLATION OF A CPG DINUCLEOTIDE IN EXON 1 OF ZIP9 THAT RESULTED IN RECRUITMENT OF THE TRANSCRIPTIONAL FACTOR SP1 AND INCREASED ZIP9 EXPRESSION. OVEREXPRESSION OF ZIP9 RESULTED IN ACTIVATION OF THE PROFIBROTIC TRANSFORMING GROWTH FACTOR-BETA SIGNALING PATHWAY THROUGH PROTEIN KINASE B IN HUMAN FIBROBLASTS. IN ADDITION, RADIATION-INDUCED SKIN FIBROSIS WAS ASSOCIATED WITH INCREASED ZINC ACCUMULATION. THE ZINC CHELATOR N,N,N',N'-TETRAKIS(2-PYRIDYLMETHYL)-1,2-ETHYLENEDIAMINE ABROGATED ZIP9-INDUCED ACTIVATION OF THE TRANSFORMING GROWTH FACTOR-BETA SIGNALING PATHWAY AND ATTENUATED RADIATION-INDUCED SKIN FIBROSIS IN A RAT MODEL. IN SUMMARY, OUR FINDINGS ILLUSTRATE EPIGENETIC REGULATION OF ZIP9 AND ITS CRITICAL ROLE IN PROMOTING RADIATION-INDUCED SKIN FIBROSIS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
18 1622  29 DNA METHYLTRANSFERASES IN MALAR MELASMA AND THEIR MODIFICATION BY SUNSCREEN IN COMBINATION WITH 4% NIACINAMIDE, 0.05% RETINOIC ACID, OR PLACEBO. BACKGROUND: MALAR MELASMA HAS A CHRONIC AND RECURRENT CHARACTER THAT MAY BE RELATED TO EPIGENETIC CHANGES. OBJECTIVE: TO RECOGNIZE THE EXPRESSION AND DNA METHYLATION OF DNA METHYLTRANSFERASES (DNMTS) IN MALAR MELASMA AND PERILESIONAL SKIN, AS WELL AS THE CHANGES IN DNMTS AFTER THEIR TREATMENT WITH SUNSCREEN IN COMBINATION WITH 4% NIACINAMIDE, 0.05% RETINOIC ACID, OR PLACEBO. METHODS: THIRTY FEMALE PATIENTS WERE CLINICALLY EVALUATED FOR THE EXPRESSION OF DNMT1 AND DNMT3B USING REAL-TIME PCR AND IMMUNOFLUORESCENCE. THESE INITIAL RESULTS WERE COMPARED TO RESULTS AFTER EIGHT WEEKS OF TREATMENT WITH SUNSCREEN IN COMBINATION WITH NIACINAMIDE, RETINOIC ACID, OR PLACEBO. RESULTS: THE RELATIVE EXPRESSION OF DNMT1 WAS SIGNIFICANTLY ELEVATED IN MELASMA COMPARED WITH UNAFFECTED SKIN IN ALL SUBJECTS, INDICATING DNA HYPERMETHYLATION. AFTER TREATMENT, IT WAS DECREASED IN ALL GROUPS: NIACINAMIDE (7 VERSUS 1; P<0.01), RETINOIC ACID (7 VERSUS 2; P<0.05), AND PLACEBO (7 VERSUS 3; P<0.05), WHICH CORRELATES WITH CLINICAL IMPROVEMENT. DNMT3B WAS NOT OVEREXPRESSED IN LESIONAL SKIN BUT REDUCED IN ALL GROUPS. CONCLUSIONS: WE FOUND DNA HYPERMETHYLATION IN MELASMA LESIONS. ENVIRONMENTAL FACTORS SUCH AS SOLAR RADIATION MAY INDUCE CELLULAR CHANGES THAT TRIGGER HYPERPIGMENTATION THROUGH THE ACTIVATION OF PATHWAYS REGULATED BY EPIGENETIC MODIFICATIONS. HOWEVER, LIMITING OR DECREASING DNA METHYLATION THROUGH SUNSCREEN, NIACINAMIDE, AND RETINOIC ACID TREATMENTS THAT PROVIDE PHOTOPROTECTION AND GENETIC TRANSCRIPTION CAN COUNTERACT THIS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
19 3198  28 HDAC-LINKED "PROLIFERATIVE" MIRNA EXPRESSION PATTERN IN PANCREATIC NEUROENDOCRINE TUMORS. EPIGENETIC FACTORS ARE ESSENTIALLY INVOLVED IN CARCINOGENESIS, TUMOR PROMOTION, AND CHEMORESISTANCE. TWO EPIGENETIC KEY PLAYERS ARE MIRNAS AND HISTONE DEACETYLASES (HDACS). AS PREVIOUSLY SHOWN BY OWN THEORETICAL DATABANK ANALYSIS, THE CROSSTALK BETWEEN MIRNAS AND HDACS IS RELEVANT IN DIFFERENT HUMAN CHRONIC DISEASES AND CANCEROGENIC PATHWAYS. WE AIMED TO INVESTIGATE A POTENTIAL CONNECTION BETWEEN THE EXPRESSION OF A WELL-DEFINED SUBSET OF "PROLIFERATION-ASSOCIATED" MIRNAS AND THE EXPRESSION OF HDACS AS WELL AS CLINICAL PARAMETERS IN PANCREATIC NEUROENDOCRINE TUMORS (PNETS). MATERIALS AND METHODS: EXPRESSION LEVELS OF MIRNA132-3P, MIRNA145-5P, MIRNA183-5P, MIRNA34A-5P, AND MIRNA449A IN 57 PNETS RESECTED BETWEEN 1997 AND 2015 WERE MEASURED AND LINKED TO THE IMMUNOHISTOCHEMICAL EXPRESSION PATTERN OF MEMBERS OF THE FOUR HDAC CLASSES ON HUMAN TISSUE MICROARRAYS. ALL PNET CASES WERE CLINICALLY AND PATHOLOGICALLY CHARACTERIZED ACCORDING TO PUBLISHED GUIDELINES. CORRELATION ANALYSIS REVEALED A SIGNIFICANT ASSOCIATION BETWEEN EXPRESSION OF SPECIFIC MIRNAS AND TWO MEMBERS OF THE HDAC FAMILY (HDAC3 AND HDAC4). ADDITIONALLY, A LINKAGE BETWEEN MIRNA EXPRESSION AND CLINICO-PATHOLOGICAL PARAMETERS LIKE GRADING, TNM-STAGING, AND HORMONE ACTIVITY WAS FOUND. MOREOVER, OVERALL AND DISEASE-FREE SURVIVAL IS STATISTICALLY CORRELATED WITH THE EXPRESSION OF THE INVESTIGATED MIRNAS. OVERALL, WE DEMONSTRATED THAT SPECIFIC MIRNAS COULD BE LINKED TO HDAC EXPRESSION IN PNETS. ESPECIALLY MIRNA449A (ASSOCIATED WITH HDAC3/4) SEEMS TO PLAY AN IMPORTANT ROLE IN PNET PROLIFERATION AND COULD BE A POTENTIAL PROGNOSTIC FACTOR FOR POOR SURVIVAL. THESE FIRST DATA COULD HELP, TO IMPROVE OUR KNOWLEDGE OF THE COMPLEX INTERACTIONS OF THE EPIGENETIC DRIVERS IN PNETS FOR FURTHER THERAPEUTIC APPROACHES.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
20 5621  27 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