1  154 85 ABERRANT METHYLATION OF NUCLEOTIDE EXCISION REPAIR GENES IS ASSOCIATED WITH CHRONIC ARSENIC POISONING. OBJECTIVE: TO DEFINE WHETHER ABERRANT METHYLATION OF DNA REPAIR GENES IS ASSOCIATED WITH CHRONIC ARSENIC POISONING. METHODS: HUNDRED AND TWO ENDEMIC ARSENICOSIS PATIENTS AND 36 HEALTHY SUBJECTS WERE RECRUITED. METHYLIGHT AND BISULFITE SEQUENCING (BSP) ASSAYS WERE USED TO EXAMINE THE METHYLATION STATUS OF ERCC1, ERCC2 AND XPC GENES IN PERIPHERAL BLOOD LYMPHOCYTES (PBLS) AND SKIN LESIONS OF ARSENICOSIS PATIENTS AND NAASO(2)-TREATED HACAT CELLS. RESULTS: HYPERMETHYLATION OF ERCC1 AND ERCC2 AND SUPPRESSED GENE EXPRESSION WERE FOUND IN PBLS AND SKIN LESIONS OF ARSENICOSIS PATIENTS AND WAS CORRELATED WITH THE LEVEL OF ARSENIC EXPOSURE. PARTICULARLY, THE EXPRESSION OF ERCC1 AND ERCC2 WAS ASSOCIATED WITH THE SEVERITY OF SKIN LESIONS. IN VITRO STUDIES REVEALED AN INDUCTION OF ERCC2 HYPERMETHYLATION AND DECREASED MRNA EXPRESSION IN RESPONSE TO NAASO(2) TREATMENT. CONCLUSION: HYPERMETHYLATION OF ERCC1 AND ERCC2 AND CONCOMITANT SUPPRESSION OF GENE EXPRESSION MIGHT BE SERVED AS THE EPIGENETIC MARKS ASSOCIATED WITH ARSENIC EXPOSURE AND ADVERSE HEALTH EFFECTS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
2  145 34 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
3 1622 28 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
4 3907 32 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
5 1067 26 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
6 2626 26 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
7 1422 28 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 1187 23 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
9 2763 25 EXPRESSION OF THE LEUKEMIC PROGNOSTIC MARKER CD7 IS LINKED TO EPIGENETIC MODIFICATIONS IN CHRONIC MYELOID LEUKEMIA. BACKGROUND: EXPRESSION LEVELS OF THE CELL SURFACE GLYCOPROTEIN, CD7, AND THE SERINE PROTEASE, ELASTASE 2 (ELA2), IN THE LEUKEMIC CELLS OF PATIENTS WITH CHRONIC MYELOID LEUKEMIA (CML) HAVE BEEN ASSOCIATED WITH CLINICAL OUTCOME. HOWEVER, LITTLE IS KNOWN ABOUT THE MECHANISMS THAT UNDERLIE THE VARIABLE EXPRESSION OF THESE GENES IN THE LEUKEMIC CELLS. RESULTS: TO ADDRESS THIS QUESTION, WE COMPARED THE LEVEL OF THEIR EXPRESSION WITH THE DNA METHYLATION AND HISTONE ACETYLATION STATUS OF 5' SEQUENCES OF BOTH GENES IN LEUKEMIC CELL LINES AND PRIMITIVE (LIN-CD34+) LEUKEMIC CELLS FROM CHRONIC PHASE CML PATIENTS. DNA METHYLATION OF THE ELA2 GENE PROMOTER DID NOT CORRELATE WITH ITS EXPRESSION PATTERN IN LIN-CD34+ CELLS FROM CHRONIC PHASE CML PATIENT SAMPLES EVEN THOUGH THERE WAS CLEAR DIFFERENTIAL DNA METHYLATION OF THIS LOCUS IN ELA2-EXPRESSING AND NON-EXPRESSING CELL LINES. IN CONTRAST, WE FOUND A STRONG RELATION BETWEEN CD7 EXPRESSION AND TRANSCRIPTION-PERMISSIVE CHROMATIN MODIFICATIONS, BOTH AT THE LEVEL OF DNA METHYLATION AND HISTONE ACETYLATION WITH EVIDENCE OF HYPOMETHYLATION OF THE CD7 PROMOTER REGION IN THE LIN-CD34+ CELLS FROM CML PATIENTS WITH HIGH CD7 EXPRESSION. CONCLUSION: THESE FINDINGS INDICATE A LINK BETWEEN EPIGENETIC MODIFICATIONS AND CD7 EXPRESSION IN PRIMITIVE CML CELLS.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
10 1950 17 EPIGENETIC ACTIVATION OF TENSIN 4 PROMOTES GASTRIC CANCER PROGRESSION. GASTRIC CANCER (GC) IS A COMPLEX DISEASE INFLUENCED BY MULTIPLE GENETIC AND EPIGENETIC FACTORS. CHRONIC INFLAMMATION CAUSED BY HELICOBACTER PYLORI INFECTION AND DIETARY RISK FACTORS CAN RESULT IN THE ACCUMULATION OF ABERRANT DNA METHYLATION IN GASTRIC MUCOSA, WHICH PROMOTES GC DEVELOPMENT. TENSIN 4 (TNS4), A MEMBER OF THE TENSIN FAMILY OF PROTEINS, IS LOCALIZED TO FOCAL ADHESION SITES, WHICH CONNECT THE EXTRACELLULAR MATRIX AND CYTOSKELETAL NETWORK. WE IDENTIFIED UPREGULATION OF TNS4 IN GC USING QUANTITATIVE REVERSE TRANSCRIPTION PCR WITH 174 PAIRED SAMPLES OF GC TUMORS AND ADJACENT NORMAL TISSUES. TRANSCRIPTIONAL ACTIVATION OF TNS4 OCCURRED EVEN DURING THE EARLY STAGE OF TUMOR DEVELOPMENT. TNS4 DEPLETION IN GC CELL LINES THAT EXPRESSED HIGH TO MODERATE LEVELS OF TNS4, I.E., SNU-601, KATO III, AND MKN74, REDUCED CELL PROLIFERATION AND MIGRATION, WHEREAS ECTOPIC EXPRESSION OF TNS4 IN THOSE LINES THAT EXPRESSED LOWER LEVELS OF TNS4, I.E., SNU-638, MKN1, AND MKN45 INCREASED COLONY FORMATION AND CELL MIGRATION. THE PROMOTER REGION OF TNS4 WAS HYPOMETHYLATED IN GC CELL LINES THAT SHOWED UPREGULATION OF TNS4. WE ALSO FOUND A SIGNIFICANT NEGATIVE CORRELATION BETWEEN TNS4 EXPRESSION AND CPG METHYLATION IN 250 GC TUMORS BASED ON THE CANCER GENOME ATLAS (TCGA) DATA. THIS STUDY ELUCIDATES THE EPIGENETIC MECHANISM OF TNS4 ACTIVATION AND FUNCTIONAL ROLES OF TNS4 IN GC DEVELOPMENT AND PROGRESSION AND SUGGESTS A POSSIBLE APPROACH FOR FUTURE GC TREATMENTS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
11 5621 21 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
12 2974 28 GENETIC AND METHYLATION STATUS OF CDKN2A (P14(ARF)/P16(INK4A)) AND TP53 GENES IN RECURRENT RESPIRATORY PAPILLOMATOSIS. RECURRENT RESPIRATORY PAPILLOMATOSIS (RRP) IS A RARE AND CHRONIC DISEASE AFFECTING THE UPPER AIRWAY WITH PAPILLOMATOUS LESIONS CAUSED BY THE HUMAN PAPILLOMAVIRUS (HPV) INFECTION, ESPECIALLY HPV-6 AND/OR HPV-11 TYPES. LITTLE IS KNOWN ABOUT THE GENETIC AND EPIGENETIC DRIVERS IN RRP PATHOPHYSIOLOGY. FOR THIS PURPOSE, WE ANALYZED 27 PAPILLOMATOUS LESIONS FROM PATIENTS WITH RRP TO EVALUATE SOMATIC MUTATIONS AND METHYLATION STATUS IN CDKN2A (P14(ARF)/P16(INK4A)) AND TP53, WHICH ARE KEY TUMOR SUPPRESSOR GENES FOR THE CELL CYCLE CONTROL. SANGER SEQUENCING ANALYSIS REVEALED ONE SOMATIC MUTATION IN TP53 (C.733_734INSA) AND FOUR MUTATIONS IN CDKN2A (C.-30G > T, C.29_30INSA, C.69DELT, AND C.300C > A). THESE MUTATIONS WERE OBSERVED IN 10 PATIENTS, 6 OF WHICH CARRIED DOUBLE MUTATION. FURTHERMORE, 50% (5/10) OF THESE PATIENTS CARRYING SOMATIC MUTATIONS HAD RRP SEVERITY, REPRESENTING 62.5% (5/8) OF THE SEVERITY CASES IN THIS STUDY, ALBEIT NO SIGNIFICANT ASSOCIATION WAS FOUND BETWEEN SOMATIC MUTATIONS AND DISEASE SEVERITY. METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION ASSAYS REVEALED P14(ARF) PROMOTER HYPERMETHYLATION IN 100% OF CASES, FOLLOWED BY TP53 (96.3%) AND P16(INK4A) (55.6%), SUGGESTING THE INFLUENCE OF HPV IN THE DNA METHYLATION MACHINERY. IN CONCLUSION, SOMATIC MUTATIONS WERE NOT COMMON EVENTS IDENTIFIED IN PATIENTS WITH RRP. HOWEVER, EPIGENETIC MODULATION BY HIGH METHYLATION RATES, PARTICULARLY FOR THE P14(ARF)/TP53 PATHWAY, SEEMS TO BE IN THE COURSE OF RRP DEVELOPMENT.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
13 6632 21 UNDERSTANDING THE ROLE OF THE CHROMOSOME 15Q25.1 IN COPD THROUGH EPIGENETICS AND TRANSCRIPTOMICS. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A MAJOR HEALTH BURDEN IN ADULTS AND CIGARETTE SMOKING IS CONSIDERED THE MOST IMPORTANT ENVIRONMENTAL RISK FACTOR OF COPD. CHROMOSOME 15Q25.1 LOCUS IS ASSOCIATED WITH BOTH COPD AND SMOKING. OUR STUDY AIMS AT UNDERSTANDING THE MECHANISM UNDERLYING THE ASSOCIATION OF CHROMOSOME 15Q25.1 WITH COPD THROUGH EPIGENETIC AND TRANSCRIPTIONAL VARIATION IN A POPULATION-BASED SETTING. TO ASSESS IF COPD-ASSOCIATED VARIANTS IN 15Q25.1 ARE METHYLATION QUANTITATIVE TRAIT LOCI, EPIGENOME-WIDE ASSOCIATION ANALYSIS OF FOUR GENETIC VARIANTS, PREVIOUSLY ASSOCIATED WITH COPD (P < 5 X 10(-8)) IN THE 15Q25.1 LOCUS (RS12914385:C>T-CHRNA3, RS8034191:T>C-HYKK, RS13180:C>T-IREB2 AND RS8042238:C>T-IREB2), WAS PERFORMED IN THE ROTTERDAM STUDY (N = 1489). ALL FOUR VARIANTS WERE SIGNIFICANTLY ASSOCIATED (P < 1.4 X 10(-6)) WITH BLOOD DNA METHYLATION OF IREB2, CHRNA3 AND PSMA4, OF WHICH TWO, INCLUDING IREB2 AND PSMA4, WERE ALSO DIFFERENTIALLY METHYLATED IN COPD CASES AND CONTROLS (P < 0.04). FURTHER ADDITIVE AND MULTIPLICATIVE EFFECTS OF SMOKING WERE EVALUATED AND NO SIGNIFICANT EFFECT WAS OBSERVED. TO EVALUATE IF THESE FOUR GENETIC VARIANTS ARE EXPRESSION QUANTITATIVE TRAIT LOCI, TRANSCRIPTOME-WIDE ASSOCIATION ANALYSIS WAS PERFORMED IN 1087 LUNG SAMPLES. ALL FOUR VARIANTS WERE ALSO SIGNIFICANTLY ASSOCIATED WITH DIFFERENTIAL EXPRESSION OF THE IREB2 3'UTR IN LUNG TISSUES (P < 5.4 X 10(-95)). WE CONCLUDE THAT REGULATORY MECHANISMS AFFECTING THE EXPRESSION OF IREB2 GENE, SUCH AS DNA METHYLATION, MAY EXPLAIN THE ASSOCIATION BETWEEN GENETIC VARIANTS IN CHROMOSOME 15Q25.1 AND COPD, LARGELY INDEPENDENT OF SMOKING.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14 2761 29 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 3657 29 INDUCTION AND RECOVERY OF CPG SITE SPECIFIC METHYLATION CHANGES IN HUMAN BRONCHIAL CELLS AFTER LONG-TERM EXPOSURE TO CARBON NANOTUBES AND ASBESTOS. INTRODUCTION: INHALATION OF ASBESTOS INDUCES LUNG CANCER VIA DIFFERENT CELLULAR MECHANISMS. TOGETHER WITH THE INCREASED PRODUCTION OF CARBON NANOTUBES (CNTS) GROWS THE CONCERN ABOUT ADVERSE EFFECTS ON THE LUNGS GIVEN THE SIMILARITIES WITH ASBESTOS. WHILE IT HAS BEEN ESTABLISHED THAT CNT AND ASBESTOS INDUCE EPIGENETIC ALTERATIONS, IT IS CURRENTLY NOT KNOWN WHETHER ALTERATIONS AT EPIGENETIC LEVEL REMAIN STABLE AFTER WITHDRAWAL OF THE EXPOSURE. IDENTIFICATION OF DNA METHYLATION CHANGES AFTER A LOW DOSE OF CNT AND ASBESTOS EXPOSURE AND RECOVERY CAN BE USEFUL TO DETERMINE THE FIBRE/PARTICLE TOXICITY AND ADVERSE OUTCOME. METHODS: HUMAN BRONCHIAL EPITHELIAL CELLS (16HBE) WERE TREATED WITH A LOW AND NON-CYTOTOXIC DOSE (0.25 MICROG/ML) OF MULTI-WALLED CARBON NANOTUBES (MWCNTS-NM400) OR SINGLE-WALLED CARBON NANOTUBES (SWCNTS-SRM2483) AND 0.05 MICROG/ML AMOSITE (BROWN) ASBESTOS FOR THE COURSE OF FOUR WEEKS (SUB-CHRONIC EXPOSURE). AFTER THIS TREATMENT, THE CELLS WERE FURTHER INCUBATED (WITHOUT PARTICLE/FIBRE) FOR TWO WEEKS, ALLOWING RECOVERY FROM THE EXPOSURE (RECOVERY PERIOD). NUCLEAR DEPOSITIONS OF THE CNTS WERE ASSESSED USING FEMTOSECOND PULSED LASER MICROSCOPY IN A LABEL-FREE MANNER. DNA METHYLATION ALTERATIONS WERE ANALYSED USING MICROARRAYS THAT ASSESS MORE THAN 850 THOUSAND CPG SITES IN THE WHOLE GENOME. RESULTS: AT NON-CYTOTOXIC DOSES, CNTS WERE NOTED TO BE INCORPORATED WITH IN THE NUCLEUS AFTER A FOUR WEEKS PERIOD. EXPOSURE TO MWCNTS INDUCED A SINGLE HYPOMETHYLATION AT A CPG SITE AND GENE PROMOTER REGION. NO CHANGE IN DNA METHYLATION WAS OBSERVED AFTER THE RECOVERY PERIOD FOR MWCNTS. EXPOSURE TO SWCNTS OR AMOSITE INDUCED HYPERMETHYLATION AT CPG SITES AFTER SUB-CHRONIC EXPOSURE WHICH MAY INVOLVE IN 'TRANSCRIPTION FACTOR ACTIVITY' AND 'SEQUENCE-SPECIFIC DNA BINDING' GENE ONTOLOGIES. AFTER THE RECOVERY PERIOD, HYPERMETHYLATION AND HYPOMETHYLATION WERE NOTED FOR BOTH SWCNTS AND AMOSITE. HIPPOCALCINLIKE 1 (HPCAL1), PROTEASE SERINE 3 (PRSS3), KALLIKREIN-RELATED PEPTIDASE 3 (KLK3), KRUPPEL LIKE FACTOR 3 (KLF3) GENES WERE HYPERMETHYLATED AT DIFFERENT TIME POINTS IN EITHER SWCNT-EXPOSED OR AMOSITE-EXPOSED CELLS. CONCLUSION: THESE RESULTS SUGGEST THAT THE SPECIFIC SWCNT (SRM2483) AND AMOSITE FIBRES STUDIED INDUCE HYPO- OR HYPERMETHYLATION ON CPG SITES IN DNA AFTER VERY LOW-DOSE EXPOSURE AND RECOVERY PERIOD. THIS EFFECT WAS NOT SEEN FOR THE STUDIED MWCNT (NM400).	2020	

16 1843 17 EFFECTS OF TELOMERASE INHIBITOR ON EPIGENETIC CHROMATIN MODIFICATION ENZYMES IN MALIGNANCIES. TELOMERASE HAS A CRITICAL ROLE IN CELL PROLIFERATION, TUMOR MAINTAINING, AND THERAPY RESISTANCE, WHICH ACT BY MODIFYING MANY SIGNALING PATHWAYS. 2-[(E)-3-NAPHTALEN-2-YL-BUT-2-ENOYLAMINO]-BENZOIC ACID (BIBR1532) IS ONE OF THE MOST STUDIED TELOMERASE INHIBITORS, AND IT TARGETS TELOMERASE COMPONENTS TERC AND TERT. IN THIS NOVEL STUDY, WE AIMED TO INVESTIGATE THE EPIGENETIC EFFECTS OF BIBR1532 ON BOTH HEMATOLOGIC MALIGNANCIES AND SOLID TUMORS. K-562 HUMAN CHRONIC MYELOID LEUKEMIA CELL LINE AND U87MG GLIOBLASTOMA CELL LINE WERE COMPARED WITH CONTROL GROUPS WITHOUT BIBR1532 TREATMENT. CYTOTOXIC EFFECTS OF BIBR1532 WERE DETERMINED BY USING WST-1 ASSAY. APOPTOTIC EFFECTS OF BIBR1532 WERE DETECTED BY USING ANNEXIN V METHOD. TO ASSESS EXPRESSION CHANGES IN THE HUMAN EPIGENETIC CHROMATIN MODIFICATION ENZYME GENES, TOTAL RNA WAS ISOLATED FROM K-562 AND U87MG CELLS TREATED WITH BIBR1532 AND UNTREATED CONTROL CELLS. BIBR1532 INDUCED 2.41-FOLD APOPTOTIC CELL DEATH IN U87MG CELL LINES COMPARED WITH CONTROL GROUPS. APOPTOSIS WAS SLIGHTLY INDUCED IN K-562 CELLS WITH BIBR1532 TREATMENT COMPARED WITH CONTROL CELLS. WE OBSERVED THAT BIBR1532 ALSO REGULATES SIMILAR GENES IN BOTH CELL LINES, AND IT IS USEFUL ON EPIGENETIC MECHANISMS. AS A RESULT, TELOMERASE INHIBITOR BIBR1532 HAS A SIGNIFICANT EFFECT ON BOTH HEMATOLOGICAL MALIGNANCIES AND SOLID TUMORS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
17  136 24 ABERRANT DNA HYPERMETHYLATION PATTERNS LEAD TO TRANSCRIPTIONAL SILENCING OF TUMOR SUPPRESSOR GENES IN UVB-EXPOSED SKIN AND UVB-INDUCED SKIN TUMORS OF MICE. OVEREXPOSURE OF THE HUMAN SKIN TO SOLAR ULTRAVIOLET (UV) RADIATION IS THE MAJOR ETIOLOGIC FACTOR FOR DEVELOPMENT OF SKIN CANCERS. HERE, WE REPORT THE RESULTS OF EPIGENETIC MODIFICATIONS IN UV-EXPOSED SKIN AND SKIN TUMORS IN A SYSTEMATIC MANNER. THE SKIN AND TUMOR SAMPLES WERE COLLECTED AFTER CHRONIC EXPOSURE OF THE SKIN OF SKH-1 HAIRLESS MICE TO UVB RADIATION USING A WELL-ESTABLISHED PHOTOCARCINOGENESIS PROTOCOL. WE FOUND A DISTINCT DNA HYPERMETHYLATION PATTERN IN THE UVB-EXPOSED EPIDERMAL SKIN AND UVB-INDUCED SKIN TUMORS THAT WAS ASSOCIATED WITH THE ELEVATED EXPRESSION AND ACTIVITY OF THE DNA METHYLTRANSFERASES (DNMT) 1, DNMT3A AND DNMT3B. TO EXPLORE THE ROLE OF HYPERMETHYLATION IN SKIN PHOTOCARCINOGENESIS, WE FOCUSED ON THE P16(INK4A) AND RASSF1A TUMOR SUPPRESSOR GENES, WHICH ARE TRANSCRIPTIONALLY SILENCED ON METHYLATION. WE ESTABLISHED THAT THE SILENCING OF THESE GENES IN UVB-EXPOSED EPIDERMIS AND UVB-INDUCED SKIN TUMORS IS ASSOCIATED WITH A NETWORK OF EPIGENETIC MODIFICATIONS, INCLUDING HYPOACETYLATION OF HISTONE H3 AND H4 AND INCREASED HISTONE DEACETYLATION, AS WELL AS RECRUITMENT OF METHYL-BINDING PROTEINS, INCLUDING MECP2 AND MBD1, TO THE METHYLATED CPGS. HIGHER LEVELS OF DNA METHYLATION AND DNMT ACTIVITY IN HUMAN SQUAMOUS CELL CARCINOMA SPECIMENS THAN IN NORMAL HUMAN SKIN SUGGEST THAT THE DATA ARE RELEVANT CLINICALLY. OUR DATA INDICATE FOR THE FIRST TIME THAT UVB-INDUCED DNA HYPERMETHYLATION, ENHANCED DNMT ACTIVITY AND HISTONE MODIFICATIONS OCCUR IN UVB-EXPOSED SKIN AND UVB-INDUCED SKIN TUMORS AND SUGGEST THAT THESE EVENTS ARE INVOLVED IN THE SILENCING OF TUMOR SUPPRESSOR GENES AND IN SKIN TUMOR DEVELOPMENT.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
18 2946 20 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
19 4740 27 NOVEL GENETIC VARIANTS ASSOCIATED WITH CHRONIC KIDNEY DISEASE PROGRESSION. SIGNIFICANCE STATEMENT: EGFR SLOPE HAS BEEN USED AS A SURROGATE OUTCOME FOR PROGRESSION OF CKD. HOWEVER, GENETIC MARKERS ASSOCIATED WITH EGFR SLOPE AMONG PATIENTS WITH CKD WERE UNKNOWN. WE AIMED TO IDENTIFY GENETIC SUSCEPTIBILITY LOCI ASSOCIATED WITH EGFR SLOPE. A TWO-PHASE GENOME-WIDE ASSOCIATION STUDY IDENTIFIED SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) IN TPPP AND FAT1-LINC02374 , AND 22 OF THEM WERE USED TO DERIVE POLYGENIC RISK SCORES THAT MARK THE DECLINE OF EGFR BY DISRUPTING BINDING OF NEARBY TRANSCRIPTION FACTORS. THIS WORK IS THE FIRST TO IDENTIFY THE IMPACT OF TPPP AND FAT1-LINC02374 ON CKD PROGRESSION, PROVIDING PREDICTIVE MARKERS FOR THE DECLINE OF EGFR IN PATIENTS WITH CKD. BACKGROUND: THE INCIDENCE OF CKD IS ASSOCIATED WITH GENETIC FACTORS. HOWEVER, GENETIC MARKERS ASSOCIATED WITH THE PROGRESSION OF CKD HAVE NOT BEEN FULLY ELUCIDATED. METHODS: WE CONDUCTED A GENOME-WIDE ASSOCIATION STUDY AMONG 1738 PATIENTS WITH CKD, MAINLY FROM THE KOREAN COHORT STUDY FOR OUTCOMES IN PATIENTS WITH CKD. THE OUTCOME WAS EGFR SLOPE. WE PERFORMED A REPLICATION STUDY FOR DISCOVERED SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) WITH P <10 -6 IN 2498 PATIENTS WITH CKD FROM THE CHRONIC RENAL INSUFFICIENCY COHORT STUDY. SEVERAL EXPRESSION QUANTITATIVE TRAIT LOCI (EQTL) STUDIES, PATHWAY ENRICHMENT ANALYSES, EXPLORATION OF EPIGENETIC ARCHITECTURE, AND PREDICTING DISRUPTION OF TRANSCRIPTION FACTOR (TF) BINDING SITES EXPLORED POTENTIAL BIOLOGICAL IMPLICATIONS OF THE LOCI. WE DEVELOPED AND EVALUATED THE EFFECT OF POLYGENIC RISK SCORES (PRS) ON INCIDENT CKD OUTCOMES. RESULTS: SNPS IN TWO NOVEL LOCI, TPPP AND FAT1-LINC02374 , WERE REPLICATED (RS59402340 IN TPPP , PDISCOVERY =7.11X10 -7 , PCRIC =8.13X10 -4 , PMETA =7.23X10 -8 ; RS28629773 IN FAT1-LINC02374 , PDISCOVERY =6.08X10 -7 , PCRIC =4.33X10 -2 , PMETA =1.87X10 -7 ). THE EQTL STUDIES REVEALED THAT THE REPLICATED SNPS REGULATED THE EXPRESSION LEVEL OF NEARBY GENES ASSOCIATED WITH KIDNEY FUNCTION. FURTHERMORE, THESE SNPS WERE NEAR GENE ENHANCER REGIONS AND PREDICTED TO DISRUPT THE BINDING OF TFS. PRS BASED ON THE INDEPENDENTLY SIGNIFICANT TOP 22 SNPS WERE SIGNIFICANTLY ASSOCIATED WITH CKD OUTCOMES. CONCLUSIONS: THIS STUDY DEMONSTRATES THAT SNP MARKERS IN THE TPPP AND FAT1-LINC02374 LOCI COULD BE PREDICTIVE MARKERS FOR THE DECLINE OF EGFR IN PATIENTS WITH CKD.	2023	
                                                                                                                                          
20 6835 18 [INFLUENCE OF AGE OF PATIENTS WITH BRONCHOPULMONARY PATHOLOGY ON LOW-MOLECULAR DNA CONCENTRATION IN BLOOD PLASMA.]. THE AIM OF THE WORK WAS TO DETERMINE THE CONCENTRATION OF LOW-MOLECULAR-WEIGHT PLASMA DNA (LMDNA) IN PATIENTS WITH COPD AND CHRONIC NON-OBSTRUCTIVE BRONCHITIS (CNONB) OF TWO AGE GROUPS - 34-59 AND 60-80 YEARS. THE LEVELS OF LMDNA IN HEALTHY DONORS, PATIENTS WITH CNONB, HEALTHY RELATIVES OF PATIENTS WITH COPD DID NOT DIFFER, WHILE THE CONCENTRATION OF LMDNA IN PATIENTS WITH COPD WAS SIGNIFICANTLY LOWER. IN COPD PATIENTS AGED 34-59 YEARS, THE LEVEL OF LMDNA WAS REDUCED BY MORE THAN 7 TIMES, AND IN COPD PATIENTS WHO SURVIVED TO 60-80 YEARS, IT WAS 3 TIMES LOWER COMPARED TO THE VALUE OF THIS BIOCHEMICAL INDICATOR IN HEALTHY DONORS OF THE SAME AGE. THE REDUCTION OF LMDNA REFLECTED A REDUCED SYSTEMIC APOPTOTIC ACTIVITY IN THE BODY OF PATIENTS WITH COPD. A SIGNIFICANT DIFFERENCE IN THE CONCENTRATION OF LMDNA IN PATIENTS WITH COPD AND CNONB IN REMISSION CAN BE USED FOR DIFFERENTIAL DIAGNOSIS OF THE DEVELOPMENT OF THESE PATHOLOGICAL PROCESSES. AN INCREASE IN THE LOW LEVEL OF LMDNA IN COPD PATIENTS DURING AGING MAY INDICATE THE INVOLVEMENT OF EPIGENETIC MECHANISMS IN LIFE EXTENSION.	2022