1 1805 85 EFFECT OF SMOKING ON THE DNA METHYLATION PATTERN OF THE SOCS1 PROMOTER IN EPITHELIAL CELLS FROM THE SALIVA OF PATIENTS WITH CHRONIC PERIODONTITIS. BACKGROUND: THE AIM OF THE PRESENT STUDY WAS TO EVALUATE THE METHYLATION PATTERN IN THE SUPPRESSOR OF CYTOKINE SIGNALING 1 (SOCS1) GENE IN SMOKERS AND NON-SMOKERS WITH CHRONIC PERIODONTITIS (CP). METHODS: METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (PCR) WAS PERFORMED TO DETERMINE THE METHYLATION STATUS OF THE SOCS1 PROMOTER IN 45 SALIVA SAMPLES FROM SMOKERS AND NON-SMOKERS WITH CP. RESULTS: CELLS FROM THE SALIVA OF CP PATIENTS WHO SMOKED WERE 7.08 TIMES MORE LIKELY TO HAVE A METHYLATED SOCS1 PROMOTER THAN CELLS FROM THE SALIVA OF NON-SMOKING PATIENTS. CONCLUSIONS: SOCS1 GENE PROMOTER METHYLATION, WITH ITS POTENTIAL EFFECTS ON THE EXPRESSION OF THIS GENE, SEEMS TO BE A CONSEQUENCE OF EXPOSURE TO TOBACCO AND NOT TO PERIODONTAL DISEASE. FURTHER STUDIES ARE NEEDED TO ELUCIDATE THE RELATIONSHIP BETWEEN THE EPIGENETIC CONTROL OF IMMUNE RESPONSE GENE EXPRESSION, EXPOSURE TO ENVIRONMENTAL FACTORS, AND THE DEVELOPMENT, PROGRESSION, AND PROGNOSIS OF CP.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
2 2766 40 EXPRESSION, POLYMORPHISM AND METHYLATION PATTERN OF INTERLEUKIN-6 IN PERIODONTAL TISSUES. PERIODONTITIS IS CONSIDERED AN INFLAMMATORY DISORDER OF BACTERIAL ETIOLOGY THAT RESULTS IN PERIODONTAL TISSUE DESTRUCTION, AS A RESULT OF COMPLEX INTERACTIONS BETWEEN PERIODONTAL PATHOGENS, HOST AND IMMUNE RESPONSE. GENETIC AND EPIGENETIC MECHANISMS MAY MODULATE THE INDIVIDUAL RESPONSE SINCE IT IS ABLE TO INFLUENCE THE GENE EXPRESSION. THE AIM OF THIS STUDY WAS TO EVALUATE THE IMPACT OF -174 G/C POLYMORPHISM AND THE METHYLATION STATUS OF THE PROMOTER REGION OF IL-6 GENE ON THE EXPRESSION OF IL-6 IN GINGIVAL SAMPLES FROM INDIVIDUALS WITH CHRONIC PERIODONTITIS. GINGIVAL BIOPSIES WERE COLLECTED FROM 21 PATIENTS WITH CHRONIC PERIODONTITIS AND 21 CONTROLS. HISTOLOGIC SECTIONS STAINED BY HEMATOXYLIN-EOSIN WERE USED FOR HISTOPATHOLOGICAL EVALUATION. THE IL-6 GENE EXPRESSION WAS ASSESSED BY QUANTITATIVE REAL-TIME PCR. THE POLYMORPHISM IL-6 -174 C/G WAS STUDIED BY POLYMERASE CHAIN REACTION (PCR) AMPLIFICATION AND RESTRICTION ENDONUCLEASE DIGESTION (HSPII). METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION WAS USED TO VERIFY THE DNA METHYLATION PATTERN. THE NUMBER OF INFLAMMATORY CELLS IN TISSUE FRAGMENTS FROM INDIVIDUALS WITH CHRONIC PERIODONTITIS WAS HIGHER THAN IN THE CONTROL GROUP AND THE INFLAMMATORY INFILTRATE WAS PREDOMINANTLY MONONUCLEAR. THE EXPRESSION OF IL-6 WAS HIGHER IN THE GROUP WITH PERIODONTITIS. IN POLYMORPHISM ASSAY, NO STATISTICAL DIFFERENCE IN THE DISTRIBUTION OF GENOTYPES AND ALLELES IN BOTH GROUPS WERE OBSERVED. THE MOST OF SAMPLES WERE PARTIALLY METHYLATED. NO DIFFERENCE WAS OBSERVED IN METHYLATION PATTERN FROM TWO DIFFERENT REGIONS OF THE IL-6 GENE AMONG GROUPS. THE HIGH EXPRESSION OF IL-6 IS AN IMPORTANT FACTOR RELATED TO CHRONIC PERIODONTITIS, BUT WAS NOT ASSOCIATED WITH METHYLATION STATUS OR THE -174 (G/C) GENETIC POLYMORPHISM, SUGGESTING THAT OTHER MECHANISMS ARE INVOLVED IN THIS GENE TRANSCRIPTION REGULATION.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
3 2019 35 EPIGENETIC CHANGE IN E-CADHERIN AND COX-2 TO PREDICT CHRONIC PERIODONTITIS. BACKGROUND: DNA METHYLATION OF CERTAIN GENES FREQUENTLY OCCURS IN NEOPLASTIC CELLS. ALTHOUGH THE CAUSE REMAINS UNKNOWN, MANY GENES HAVE BEEN IDENTIFIED WITH SUCH ATYPICAL METHYLATION IN NEOPLASTIC CELLS. THE HYPERMETHYLATION OF E-CADHERIN AND CYCLOOXYGENASE 2 (COX-2) IN CHRONIC INFLAMMATION SUCH AS CHRONIC PERIODONTITIS MAY DEMONSTRATE MILD LESION/MUTATION EPIGENETIC LEVEL. THIS STUDY COMPARES THE HYPERMETHYLATION STATUS OF E-CADHERIN AND COX-2 GENES WHICH ARE OFTEN FOUND IN BREAST CANCER PATIENTS WITH THAT IN CHRONIC PERIODONTITIS. METHODS: TOTAL DNA WAS EXTRACTED FROM THE BLOOD SAMPLES OF 108 SYSTEMICALLY HEALTHY NON-PERIODONTITIS SUBJECTS, AND THE GINGIVAL TISSUES AND BLOOD SAMPLES OF 110 CHRONIC PERIODONTITIS PATIENT AS WELL AS NEOPLASTIC TISSUES OF 106 BREAST CANCER PATIENTS. METHYLATION-SPECIFIC PCR FOR E-CADHERIN AND COX-2 WAS PERFORMED ON THESE SAMPLES AND THE PCR PRODUCTS WERE ANALYZED ON 2% AGAROSE GEL. RESULTS: HYPERMETHYLATION OF E-CADHERIN AND COX-2 WAS OBSERVED IN 38% AND 35% OF THE BREAST CANCER SAMPLES, RESPECTIVELY. IN CHRONIC PERIODONTITIS PATIENTS THE DETECTION RATE WAS 25% AND 19% RESPECTIVELY, AND NONE WAS FOUND IN THE SYSTEMICALLY HEALTHY NON-PERIODONTITIS CONTROL SUBJECTS. THE HYPERMETHYLATION STATUS WAS SHOWN TO BE CORRELATED AMONG THE THREE GROUPS WITH STATISTICAL SIGNIFICANCE (P < 0.0001). THE METHYLATION OF CPG ISLANDS IN E-CADHERIN AND COX-2 GENES IN PERIODONTITIS PATIENTS OCCURS MORE FREQUENTLY IN PERIODONTITIS PATIENTS THAN IN THE CONTROL SUBJECTS, BUT OCCURS LESS FREQUENTLY THAN IN THE BREAST CANCER PATIENTS. CONCLUSIONS: THIS SET OF DATA SHOWS THAT THE EPIGENETIC CHANGE IN E-CADHERIN AND CYCLOOXYGENASE-2 IS ASSOCIATED WITH CHRONIC PERIODONTITIS. THE EPIGENETIC CHANGES PRESENTED IN CHRONIC INFLAMMATION PATIENTS MIGHT DEMONSTRATE AN IRREVERSIBLE DESTRUCTION IN THE TISSUES OR ORGANS SIMILAR TO THE EFFECTS OF CANCER. CHRONIC PERIODONTITIS TO SOME EXTENT MIGHT BE ASSOCIATED WITH DNA HYPERMETHYLATION WHICH IS RELATED TO CANCER RISK FACTORS.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                            
4 3588 33 IMPACT OF TP53 GENE PROMOTER METHYLATION ON CHRONIC LYMPHOCYTIC LEUKEMIA PATHOGENESIS AND PROGRESSION. BACKGROUND: CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS A MALIGNANT LYMPHOID DISORDER THAT RESULTS FROM THE OVERGROWTH OF MATURE-LOOKING LYMPHOID CELLS IN THE BLOOD AND LYMPHATIC TISSUE. VARIOUS CLINICAL PRESENTATIONS HAVE BEEN ATTRIBUTED TO THE DISEASE AS A RESULT OF THE DIFFERENT UNDERLYING GENETIC AND EPIGENETIC ALTERATIONS. THE CURRENT STUDY HAS BEEN INITIATED TO STUDY THE ROLE OF AN EPIGENETIC ALTERATION AFFECTING THE PROMOTER OF THE TP53GENE ON CLL PATHOGENESIS AND PROGRESSION. METHODS: THE CURRENT STUDY INVOLVED 54 NEWLY DIAGNOSED PATIENTS PRESENTING WITH CLL AS WELL AS 30 NORMAL INDIVIDUALS AS CONTROLS. AFTER OBTAINING VERBAL CONSENT, DATA COLLECTION WAS DONE AND THE BLOOD COLLECTED FROM ALL ENROLLED INDIVIDUALS FOR HEMATOLOGICAL INVESTIGATIONS AS WELL AS FOR MOLECULAR CATEGORIZATION OF TP53 METHYLATION STATUS. METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MS-PCR) TECHNIQUE WAS USED TO DEFINE THE METHYLATION STATUS OF THE TP53 GENE PROMOTER THAT ENCOMPASSES DNA EXTRACTION, BISULFITE CONVERSION, CONVENTIONAL PCR AMPLIFICATION, RUNNING ON AGAROSE GEL AND DOCUMENTATION. FINALLY, STATISTICAL ANALYSIS WAS DONE TO ASSESS ANY CORRELATION OF THE TP53 EPIGENETIC ALTERATION TO THE DISEASE ETIOLOGY AND THE PROGRESSION. RESULTS: IN THE CURRENT STUDY, ALL CONTROLS AND 42 OF 54 PATIENTS SHOW UNMETHYLATED TP53 GENE PROMOTER; ON THE OTHER HAND, THE METHYLATED PROMOTER WAS DETECTED AMONG 12 PATIENTS WITH A P-VALUE OF 0.001. TP53 GENE PROMOTER METHYLATION SIGNIFICANTLY LINKED TO REDUCED PLATELET COUNT (P-VALUE OF 0.047) AND ADVANCED STAGE AT PRESENTATION (P-VALUE OF 0.076). NO SIGNIFICANT DIFFERENCES WERE SEEN AMONG BOTH METHYLATED AND UNMETHYLATED TP53 PROMOTERS IN RELATION TO THE AGE OF THE AFFECTED INDIVIDUALS, TOTAL WHITE BLOOD CELL COUNTS AND HEMOGLOBIN LEVEL OF THE AFFECTED INDIVIDUALS. CONCLUSION: THE CURRENT STUDY REVEALED A SIGNIFICANT CORRELATION OF TP53 GENE PROMOTER METHYLATION TO CHRONIC LYMPHOCYTIC LEUKEMIA PATHOGENESIS AND LOWER PLATELET COUNTS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                     
5 3440 31 HYPERMETHYLATION AND LOW TRANSCRIPTION OF TLR2 GENE IN CHRONIC PERIODONTITIS. PERIODONTITIS IS AN INFLAMMATORY DISORDER CHARACTERIZED BY INTERACTIONS BETWEEN PERIODONTAL PATHOGENS AND HOST'S IMMUNE RESPONSE. EPIGENETIC MAY CONTRIBUTE TO DISEASE DEVELOPMENT AND OUTCOME BY INFLUENCING THE EXPRESSION OF GENES INVOLVED IN THE IMMUNE RESPONSE. IT HAS BEEN SHOWN THAT TOLL-LIKE RECEPTORS (TLR) PLAY AN IMPORTANT ROLE IN THE RESPONSE TO PERIODONTOPATHIC BACTERIA. THE AIM OF STUDY WAS TO EVALUATE THE METHYLATION STATUS AND THE EXPRESSION OF TLR2 GENE IN GINGIVAL SAMPLES FROM INDIVIDUALS WITH AND WITHOUT PERIODONTITIS. DNA WAS ANALYZED USING THE METHYL PROFILER DNA METHYLATION QPCR ASSAY. DNA METHYLATION AND TRANSCRIPT LEVELS WERE EVALUATED BY REAL-TIME POLYMERASE CHAIN REACTION. THE PERIODONTITIS GROUP SHOWED A HYPERMETHYLATED PROFILE AND A LOW EXPRESSION OF GENE. POSITIVE CORRELATION BETWEEN THE TLR2 METHYLATION FREQUENCY AND PROBING DEPTH WAS OBSERVED. THIS STUDY GIVES THE FIRST EVIDENCE OF METHYLATION FREQUENCY IN INFLAMED PERIODONTAL TISSUES AND OF THE POSSIBLE PARTICIPATION OF METHYLATION IN THE DEVELOPMENT OF PERIODONTITIS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
6   59 26 A GENOME-WIDE SCREEN IDENTIFIES FREQUENTLY METHYLATED GENES IN HAEMATOLOGICAL AND EPITHELIAL CANCERS. BACKGROUND: GENETIC AS WELL AS EPIGENETIC ALTERATIONS ARE A HALLMARK OF BOTH EPITHELIAL AND HAEMATOLOGICAL MALIGNANCIES. HIGH THROUGHPUT SCREENS ARE REQUIRED TO IDENTIFY EPIGENETIC MARKERS THAT CAN BE USEFUL FOR DIAGNOSTIC AND PROGNOSTIC PURPOSES ACROSS MALIGNANCIES. RESULTS: HERE WE REPORT FOR THE FIRST TIME THE USE OF THE MIRA ASSAY (METHYLATED CPG ISLAND RECOVERY ASSAY) IN COMBINATION WITH GENOME-WIDE CPG ISLAND ARRAYS TO IDENTIFY EPIGENETIC MOLECULAR MARKERS IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) ON A GENOME-WIDE SCALE. WE IDENTIFIED 30 GENES DEMONSTRATING METHYLATION FREQUENCIES OF > OR =25% IN CHILDHOOD ALL, NINE GENES SHOWED SIGNIFICANTLY DIFFERENT METHYLATION FREQUENCIES IN B VS T-ALL. FOR MAJORITY OF THE GENES EXPRESSION COULD BE RESTORED IN METHYLATED LEUKEMIA LINES AFTER TREATMENT WITH 5-AZADC. FORTY-FOUR PERCENT OF THE GENES REPRESENT TARGETS OF THE POLYCOMB COMPLEX. IN CHRONIC MYELOID LEUKEMIA (CML) TWO OF THE GENES, (TFAP2A AND EBF2), DEMONSTRATED INCREASED METHYLATION IN BLAST CRISIS COMPARED TO CHRONIC PHASE (P < 0.05). FURTHERMORE HYPERMETHYLATION OF AN AUTOPHAGY RELATED GENE ATG16L2 WAS ASSOCIATED WITH POORER PROGNOSIS IN TERMS OF MOLECULAR RESPONSE TO IMATINIB TREATMENT. LASTLY WE DEMONSTRATED THAT TEN OF THESE GENES WERE ALSO FREQUENTLY METHYLATED IN COMMON EPITHELIAL CANCERS. CONCLUSION: IN SUMMARY WE HAVE IDENTIFIED A LARGE NUMBER OF GENES SHOWING FREQUENT METHYLATION IN CHILDHOOD ALL, METHYLATION STATUS OF TWO OF THESE GENES IS ASSOCIATED WITH ADVANCED DISEASE IN CML AND METHYLATION STATUS OF ANOTHER GENE IS ASSOCIATED WITH PROGNOSIS. IN ADDITION A SUBSET OF THESE GENES MAY ACT AS EPIGENETIC MARKERS ACROSS HEMATOLOGICAL MALIGNANCIES AS WELL AS COMMON EPITHELIAL CANCERS.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
7 1345 29 DETECTION OF DIFFERENTIALLY METHYLATED REGIONS USING BAYES FACTOR FOR ORDINAL GROUP RESPONSES. RESEARCHERS IN GENOMICS ARE INCREASINGLY INTERESTED IN EPIGENETIC FACTORS SUCH AS DNA METHYLATION, BECAUSE THEY PLAY AN IMPORTANT ROLE IN REGULATING GENE EXPRESSION WITHOUT CHANGES IN THE DNA SEQUENCE. THERE HAVE BEEN SIGNIFICANT ADVANCES IN DEVELOPING STATISTICAL METHODS TO DETECT DIFFERENTIALLY METHYLATED REGIONS (DMRS) ASSOCIATED WITH BINARY DISEASE STATUS. MOST OF THESE METHODS ARE BEING DEVELOPED FOR DETECTING DIFFERENTIAL METHYLATION RATES BETWEEN CASES AND CONTROLS. WE CONSIDER MULTIPLE SEVERITY LEVELS OF DISEASE, AND DEVELOP A BAYESIAN STATISTICAL METHOD TO DETECT THE REGION WITH INCREASING (OR DECREASING) METHYLATION RATES AS THE DISEASE SEVERITY INCREASES. PATIENTS ARE CLASSIFIED INTO MORE THAN TWO GROUPS, BASED ON THE DISEASE SEVERITY (E.G., STAGES OF CANCER), AND DMRS ARE DETECTED BY USING MOVING WINDOWS ALONG THE GENOME. WITHIN EACH WINDOW, THE BAYES FACTOR IS CALCULATED TO TEST THE HYPOTHESIS OF MONOTONIC INCREASE IN METHYLATION RATES CORRESPONDING TO SEVERITY OF THE DISEASE VERSUS NO DIFFERENCE. A MIXED-EFFECT MODEL IS USED TO INCORPORATE THE CORRELATION OF METHYLATION RATES OF NEARBY CPG SITES IN THE REGION. RESULTS FROM EXTENSIVE SIMULATION INDICATE THAT OUR PROPOSED METHOD IS STATISTICALLY VALID AND REASONABLY POWERFUL. WE DEMONSTRATE OUR APPROACH ON A BISULFITE SEQUENCING DATASET FROM A CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) STUDY.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
8 1185 31 COORDINATED CHANGES IN AHRR METHYLATION IN LYMPHOBLASTS AND PULMONARY MACROPHAGES FROM SMOKERS. SMOKING IS ASSOCIATED WITH A WIDE VARIETY OF ADVERSE HEALTH OUTCOMES INCLUDING CANCER, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, DIABETES, DEPRESSION, AND HEART DISEASE. UNFORTUNATELY, THE MOLECULAR MECHANISMS THROUGH WHICH THESE EFFECTS ARE CONVEYED ARE NOT CLEARLY UNDERSTOOD. TO EXAMINE THE POTENTIAL ROLE OF EPIGENETIC FACTORS IN THESE PROCESSES, WE EXAMINED THE RELATIONSHIP OF SMOKING TO GENOME WIDE METHYLATION AND GENE EXPRESSION USING BIOMATERIAL FROM TWO INDEPENDENT SAMPLES, LYMPHOBLAST DNA AND RNA (N = 119) AND LUNG ALVEOLAR MACROPHAGE DNA (N = 19). WE FOUND THAT IN BOTH SAMPLES CURRENT SMOKING STATUS WAS ASSOCIATED WITH SIGNIFICANT CHANGES IN DNA METHYLATION, IN PARTICULAR AT THE ARYL HYDROCARBON RECEPTOR REPRESSOR (AHRR), A KNOWN TUMOR SUPPRESSOR. BOTH BASELINE DNA METHYLATION AND SMOKER ASSOCIATED DNA METHYLATION SIGNATURES AT AHRR WERE HIGHLY CORRELATED (R = 0.94 AND 0.45, RESPECTIVELY). DNA METHYLATION AT THE MOST DIFFERENTIALLY METHYLATED AHRR CPG RESIDUE IN BOTH SAMPLES, CG0557592, WAS SIGNIFICANTLY ASSOCIATED WITH AHRR GENE EXPRESSION. PATHWAY ANALYSIS OF LYMPHOBLAST DATA (GENES WITH MOST SIGNIFICANT METHYLATION CHANGES) DEMONSTRATED ENRICHMENT IN PROTEIN KINASE C PATHWAYS AND IN TGF BETA SIGNALING PATHWAYS. FOR ALVEOLAR MACROPHAGES, PATHWAY ANALYSIS DEMONSTRATED ALTERATIONS IN INFLAMMATION-RELATED PROCESSES. WE CONCLUDE THAT SMOKING IS ASSOCIATED WITH FUNCTIONALLY SIGNIFICANT GENOME WIDE CHANGES IN DNA METHYLATION IN BOTH LYMPHOBLASTS AND PULMONARY MACROPHAGES AND THAT FURTHER INTEGRATED INVESTIGATIONS OF THESE EPIGENETIC EFFECTS OF SMOKING ON CARCINOGENESIS AND OTHER RELATED CO-MORBIDITIES ARE INDICATED.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
9 6311 29 THE RELATION BETWEEN DNA METHYLATION PATTERNS AND SERUM CYTOKINE LEVELS IN COMMUNITY-DWELLING ADULTS: A PRELIMINARY STUDY. BACKGROUND: THE LEVELS OF CIRCULATING CYTOKINES FLUCTUATE WITH AGE, ACUTE ILLNESS, AND CHRONIC DISEASE, AND ARE PREDICTIVE OF MORTALITY; THIS IS ALSO TRUE FOR PATTERNS OF DNA (CPG) METHYLATION. GIVEN THAT IMMUNE CELLS ARE PARTICULARLY SENSITIVE TO CHANGES IN THE CONCENTRATION OF CYTOKINES IN THEIR MICROENVIRONMENT, WE HYPOTHESIZED THAT SERUM LEVELS OF TNF, IL-6, IL-8 AND IL-10 WOULD CORRELATE WITH GENOME-WIDE ALTERATIONS IN THE DNA METHYLATION LEVELS OF BLOOD LEUKOCYTES. TO TEST THIS, WE EVALUATED COMMUNITY-DWELLING ADULTS (N = 14; 48-78 YEARS OLD) RECRUITED TO A PILOT STUDY FOR THE CANADIAN LONGITUDINAL STUDY ON AGING (CLSA), EXAMINING DNA METHYLATION PATTERNS IN PERIPHERAL BLOOD MONONUCLEAR CELLS USING THE ILLUMINA HUMANMETHYLATION 450 K BEADCHIP. RESULTS: WE SHOW THAT, APART FROM AGE, SERUM IL-10 LEVELS EXHIBITED THE MOST SUBSTANTIAL ASSOCIATION TO DNA METHYLATION PATTERNS, FOLLOWED BY TNF, IL-6 AND IL-8. FURTHERMORE, WHILE THE LEVELS OF THESE CYTOKINES WERE HIGHER IN ELDERLY ADULTS, NO ASSOCIATIONS WITH EPIGENETIC ACCELERATED AGING, DERIVED USING THE EPIGENETIC CLOCK, WERE OBSERVED. CONCLUSIONS: AS A PRELIMINARY STUDY WITH A SMALL SAMPLE SIZE, THE CONCLUSIONS DRAWN FROM THIS WORK MUST BE VIEWED WITH CAUTION; HOWEVER, OUR OBSERVATIONS ARE ENCOURAGING AND CERTAINLY WARRANT MORE SUITABLY POWERED STUDIES OF THIS RELATIONSHIP.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
10  507 28 ASSOCIATION OF INCREASED DNA METHYLTRANSFERASE EXPRESSION WITH CARCINOGENESIS AND POOR PROGNOSIS IN PANCREATIC DUCTAL ADENOCARCINOMA. INTRODUCTION: EPIGENETIC MODIFICATIONS PLAY AN IMPORTANT ROLE IN MULTISTAGE CARCINOGENESIS. THE ROLE OF THE THREE FUNCTIONAL DNA METHYLTRANSFERASES (DNMTS) IN PANCREATIC CARCINOGENESIS HAS NOT BEEN FULLY UNDERSTOOD. THE MAIN GOAL OF THIS STUDY WAS TO EXAMINE DNMT EXPRESSION IN DIFFERENT STAGES OF PANCREATIC DUCTAL ADENOCARCINOMA (PDAC), AND EVALUATE THEIR PROGNOSTIC SIGNIFICANCE IN PDAC. MATERIALS AND METHODS: A LARGE NUMBER OF PREMALIGNANT AND MALIGNANT PANCREATIC LESIONS WERE OBTAINED BY MANUAL MICRODISSECTION. QUANTITATIVE REAL-TIME RT-PCR WAS USED TO DETECT DNMTS MRNA EXPRESSION. NONPARAMETRIC TEST, LOGRANK TEST AND COX REGRESSION ANALYSIS WERE USED TO EVALUATE THE CLINICAL SIGNIFICANCE OF DNMT EXPRESSION. RESULTS: THE MRNA EXPRESSION OF THE THREE DNMTS INCREASED WITH THE DEVELOPMENT OF PANCREATIC CANCER FROM NORMAL DUCT TO PANCREATIC INTRADUCTAL NEOPLASIA AND FURTHER TO PDAC, AND WERE STATISTICALLY CORRELATED WITH EACH OTHER. EXPRESSION OF THE THREE DNMTS WAS STATISTICALLY CORRELATED WITH TNM STAGING AND HISTORY OF CHRONIC PANCREATITIS. DNMT3A AND DNMT3B, BUT NOT DNMT1 EXPRESSION, WAS STATISTICALLY CORRELATED WITH TUMOUR SIZE. PATIENTS WITH HIGHER LEVELS OF DNMT1, DNMT3A AND/OR DNMT3B EXPRESSION HAD AN OVERALL LOWER SURVIVAL THAN THOSE WITH LOWER LEVELS OF EXPRESSION. UNIVARIATE ANALYSIS SHOWED THAT HIGH EXPRESSION LEVELS OF DNMTS, ALCOHOL CONSUMPTION, TUMOUR DIFFERENTIATION AND TNM STAGING WERE STATISTICALLY SIGNIFICANT RISK FACTORS. MULTIVARIATE ANALYSIS SHOWED THAT HIGH LEVEL OF DNMT3B EXPRESSION AND TUMOUR DIFFERENTIATION WERE STATISTICALLY SIGNIFICANT INDEPENDENT POOR PROGNOSTIC FACTORS. CONCLUSIONS: THESE RESULTS SUGGESTED THAT PANCREATIC CARCINOGENESIS INVOLVES AN INCREASED MRNA EXPRESSION OF THREE DNMTS, AND THEY MAY BECOME VALUABLE DIAGNOSTIC AND PROGNOSTIC MARKERS AS WELL AS POTENTIAL THERAPEUTIC TARGETS FOR PANCREATIC CANCER.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
11 2400 28 EPIGENETIC REPROGRAMMING OF IMMUNE CELLS IN WOMEN WITH PCOS IMPACT GENES CONTROLLING REPRODUCTIVE FUNCTION. CONTEXT: POLYCYSTIC OVARY SYNDROME (PCOS) IS A CHRONIC DISEASE AFFECTING REPRODUCTIVE FUNCTION AND WHOLE-BODY METABOLISM. ALTHOUGH THE ETIOLOGY IS UNCLEAR, EMERGING EVIDENCE INDICATES THAT THE EPIGENETICS MAY BE A CONTRIBUTING FACTOR. OBJECTIVE: TO DETERMINE THE ROLE OF GLOBAL AND GENOME-WIDE EPIGENETIC MODIFICATIONS IN SPECIFIC IMMUNE CELLS IN PCOS COMPARED WITH CONTROLS AND WHETHER THESE COULD BE RELATED TO CLINICAL FEATURES OF PCOS. DESIGN: CROSS-SECTIONAL STUDY. PARTICIPANTS: WOMEN WITH (N = 17) OR WITHOUT PCOS (N = 17). SETTING: RECRUITED FROM THE GENERAL COMMUNITY. MAIN OUTCOME MEASURES: ISOLATED PERIPHERAL BLOOD MONONUCLEAR CELLS WERE ANALYZED USING MULTICOLOR FLOW CYTOMETRY METHODS TO DETERMINE GLOBAL DNA METHYLATION LEVELS IN A CELL-SPECIFIC FASHION. TRANSCRIPTOMIC AND GENOME-WIDE DNA METHYLATION ANALYSES WERE PERFORMED ON T HELPER CELLS USING RNA SEQUENCING AND REDUCED REPRESENTATION BISULFITE SEQUENCING. RESULTS: WOMEN WITH PCOS HAD LOWER GLOBAL DNA METHYLATION IN MONOCYTES (P = 0.006) AND IN T HELPER (P = 0.004), T CYTOTOXIC (P = 0.004), AND B CELLS (P = 0.03). SPECIFIC GENOME-WIDE DNA METHYLATION ANALYSIS OF T HELPER CELLS FROM WOMEN WITH PCOS IDENTIFIED 5581 DIFFERENTIALLY METHYLATED CPG SITES. FUNCTIONAL GENE ONTOLOGY ENRICHMENT ANALYSIS SHOWED THAT GENES LOCATED AT THE PROXIMITY OF DIFFERENTIALLY METHYLATED CPG SITES BELONG TO PATHWAYS RELATED TO REPRODUCTIVE FUNCTION AND IMMUNE CELL FUNCTION. HOWEVER, THESE GENES WERE NOT ALTERED AT THE TRANSCRIPTOMIC LEVEL. CONCLUSIONS: IT WAS SHOWN THAT PCOS IS ASSOCIATED WITH GLOBAL AND GENE-SPECIFIC DNA METHYLATION REMODELING IN A CELL TYPE-SPECIFIC MANNER. FURTHER INVESTIGATION IS WARRANTED TO DETERMINE WHETHER EPIGENETIC REPROGRAMMING OF IMMUNE CELLS IS IMPORTANT IN DETERMINING THE DIFFERENT PHENOTYPES OF PCOS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
12 2771 26 EXTENSIVE PROMOTER DNA HYPERMETHYLATION AND HYPOMETHYLATION IS ASSOCIATED WITH ABERRANT MICRORNA EXPRESSION IN CHRONIC LYMPHOCYTIC LEUKEMIA. DYSREGULATED MICRORNA (MIRNA) EXPRESSION CONTRIBUTES TO THE PATHOGENESIS OF HEMATOPOIETIC MALIGNANCIES, INCLUDING CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). HOWEVER, AN UNDERSTANDING OF THE MECHANISMS THAT CAUSE ABERRANT MIRNA TRANSCRIPTIONAL CONTROL IS LACKING. IN THIS STUDY, WE COMPREHENSIVELY INVESTIGATED THE ROLE AND EXTENT OF MIRNA EPIGENETIC REGULATION IN CLL. GENOME-WIDE PROFILING CONDUCTED ON 24 CLL AND 10 HEALTHY B CELL SAMPLES REVEALED GLOBAL DNA METHYLATION PATTERNS UPSTREAM OF MIRNA SEQUENCES THAT DISTINGUISHED MALIGNANT FROM HEALTHY CELLS AND IDENTIFIED PUTATIVE MIRNA PROMOTERS. INTEGRATION OF DNA METHYLATION AND MIRNA PROMOTER DATA LED TO THE IDENTIFICATION OF 128 RECURRENT MIRNA TARGETS FOR ABERRANT PROMOTER DNA METHYLATION. DNA HYPOMETHYLATION ACCOUNTED FOR MORE THAN 60% OF ALL ABERRANT PROMOTER-ASSOCIATED DNA METHYLATION IN CLL, AND PROMOTER DNA HYPOMETHYLATION WAS RESTRICTED TO WELL-DEFINED REGIONS. INDIVIDUAL HYPER- AND HYPOMETHYLATED PROMOTERS ALLOWED DISCRIMINATION OF CLL SAMPLES FROM HEALTHY CONTROLS. PROMOTER DNA METHYLATION PATTERNS WERE CONFIRMED IN AN INDEPENDENT PATIENT COHORT, WITH 11 MIRNAS CONSISTENTLY SHOWING AN INVERSE CORRELATION BETWEEN DNA METHYLATION STATUS AND EXPRESSION LEVEL. TOGETHER, OUR FINDINGS CHARACTERIZE THE ROLE OF EPIGENETIC CHANGES IN THE REGULATION OF MIRNA TRANSCRIPTION AND CREATE A REPOSITORY OF DISEASE-SPECIFIC PROMOTER REGIONS THAT MAY PROVIDE ADDITIONAL INSIGHTS INTO THE PATHOGENESIS OF CLL.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
13 1500 30 DNA METHYLATION ANALYSIS OF CD4+ T CELLS IN PATIENTS WITH PSORIASIS. PSORIASIS IS A CHRONIC INFLAMMATORY SKIN DISEASE THAT IS CHARACTERIZED BY ABERRANT CROSS-TALK BETWEEN KERATINOCYTES AND IMMUNE CELLS SUCH AS CD4+ T CELLS, RESULTING IN KERATINOCYTE HYPERPROLIFERATION IN THE EPIDERMIS. DNA METHYLATION, ONE OF SEVERAL EPIGENETIC MECHANISMS, PLAYS AN IMPORTANT ROLE IN GENE EXPRESSION WITHOUT CHANGING THE DNA SEQUENCE. SEVERAL STUDIES HAVE SUGGESTED THE INVOLVEMENT OF EPIGENETIC REGULATION IN SKIN LESIONS FROM PATIENTS WITH PSORIASIS. IN THIS STUDY, WE INVESTIGATED THE GENOME-WIDE DNA METHYLATION STATUS OF CD4+ T CELLS IN PATIENTS WITH PSORIASIS COMPARED WITH HEALTHY SUBJECTS USING METHYLATED DNA IMMUNOPRECIPITATION SEQUENCING (MEDIP-SEQ). THE RESULTS OF MEDIP-SEQ SHOWED THAT THE GLOBAL METHYLATION VALUES OF CD4+ T CELLS ARE HIGHER IN PATIENTS WITH PSORIASIS THAN IN HEALTHY CONTROLS, PARTICULARLY IN THE PROMOTER REGIONS. AMONG THE MOST HYPERMETHYLATED GENES IN THE PROMOTER REGIONS, WE SELECTED THE GENES WHOSE EXPRESSION IS SIGNIFICANTLY REDUCED IN THE CD4+ T CELLS OF PSORIASIS PATIENTS. STUDIES USING THE METHYLATION INHIBITOR 5-AZACYTIDINE IN VITRO METHYLATION ASSAYS HAVE SHOWN THAT THE DIFFERENTIAL EXPRESSION LEVELS WERE ASSOCIATED WITH THE METHYLATION STATUS OF EACH GENE. BISULFITE SEQUENCING OF THE TRANSCRIPTION START REGION OF PHOSPHATIDIC ACID PHOSPHATASE TYPE 2 DOMAIN CONTAINING 3 (PPAPDC3), ONE OF THE SELECTED GENES, SHOWED HYPERMETHYLATION IN THE CD4+ T CELLS OF PSORIASIS PATIENTS. THESE RESULTS SUGGESTED THAT THE METHYLATION STATUS, WHICH IS IDENTIFIED BY MEDIP-SEQ OF THE GENES, WAS CORRELATED WITH THE MRNA EXPRESSION LEVEL OF THE GENES. COLLECTIVELY, THE DNA METHYLATION STATUS IN CD4+ T CELLS MIGHT BE ASSOCIATED WITH THE PATHOGENESIS OF PSORIASIS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
14 6083 32 THE EFFECT OF SMOKING ON DNA METHYLATION OF PERIPHERAL BLOOD MONONUCLEAR CELLS FROM AFRICAN AMERICAN WOMEN. BACKGROUND: REGULAR SMOKING IS ASSOCIATED WITH A WIDE VARIETY OF SYNDROMES WITH PROMINENT INFLAMMATORY COMPONENTS SUCH AS CANCER, OBESITY AND TYPE 2 DIABETES. HEAVY REGULAR SMOKING IS ALSO ASSOCIATED WITH CHANGES IN THE DNA METHYLATION OF PERIPHERAL MONONUCLEAR CELLS. HOWEVER, IN YOUNGER SMOKERS, INFLAMMATORY EPIGENETIC FINDINGS ARE LARGELY ABSENT WHICH SUGGESTS THE INFLAMMATORY RESPONSE(S) TO SMOKING MAY BE DOSE DEPENDENT. TO HELP UNDERSTAND WHETHER PERIPHERAL MONONUCLEAR CELLS HAVE A ROLE IN MEDIATING THESE RESPONSES IN OLDER SMOKERS WITH HIGHER CUMULATIVE SMOKE EXPOSURE, WE EXAMINED GENOME-WIDE DNA METHYLATION IN A GROUP OF WELL CHARACTERIZED ADULT AFRICAN AMERICAN SUBJECTS INFORMATIVE FOR SMOKING, AS WELL AS SERUM C-REACTIVE PROTEIN (CRP) AND INTERLEUKIN-6 RECEPTOR (IL6R) LEVELS. IN ADDITION, COMPLEMENTARY BIOINFORMATIC ANALYSES WERE CONDUCTED TO DELINEATE POSSIBLE PATHWAYS AFFECTED BY LONG-TERM SMOKING. RESULTS: GENOME-WIDE DNA METHYLATION ANALYSIS WITH RESPECT TO SMOKING STATUS YIELDED 910 SIGNIFICANT LOCI AFTER BENJAMINI-HOCHBERG CORRECTION. IN PARTICULAR, TWO LOCI FROM THE AHRR GENE (CG05575921 AND CG23576855) AND ONE LOCUS FROM THE GPR15 GENE (CG19859270) WERE IDENTIFIED AS HIGHLY SIGNIFICANTLY DIFFERENTIALLY METHYLATED BETWEEN SMOKERS AND NON-SMOKERS. THE BIOINFORMATIC ANALYSES SHOWED THAT LONG-TERM CHRONIC SMOKING IS ASSOCIATED WITH ALTERED PROMOTER DNA METHYLATION OF GENES CODING FOR PROTEINS MAPPING TO CRITICAL SUB-NETWORKS MODERATING INFLAMMATION, IMMUNE FUNCTION, AND COAGULATION. CONCLUSIONS: WE CONCLUDE THAT CHRONIC REGULAR SMOKING IS ASSOCIATED WITH CHANGES IN PERIPHERAL MONONUCLEAR CELL METHYLATION SIGNATURE WHICH PERTURB INFLAMMATORY AND IMMUNE FUNCTION PATHWAYS AND MAY CONTRIBUTE TO INCREASED VULNERABILITY FOR COMPLEX ILLNESSES WITH INFLAMMATORY COMPONENTS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
15 1968 27 EPIGENETIC ALTERATION OF THE SOCS1 GENE IN CHRONIC MYELOID LEUKAEMIA. THE EXPRESSION OF THE SUPPRESSOR OF CYTOKINE SIGNALLING-1 (SOCS1) PROTEIN IS INDUCED IN RESPONSE TO STIMULATION BY SEVERAL CYTOKINES. THE INDUCED SOCS1 INHIBITS THE SIGNALLING PATHWAY THROUGH THE ASSOCIATION WITH A VARIETY OF TYROSINE KINASE PROTEINS. IN THIS STUDY, THE MUTATION ANALYSES, CPG ISLAND METHYLATION STATUS, AND THE EXPRESSION OF THE SOCS1 GENE IN 112 CHRONIC MYELOID LEUKAEMIA (CML) SAMPLES, FIVE LEUKAEMIA CELL LINES, AND 30 NORMAL CONTROLS WERE ANALYSED. NO GENETIC MUTATIONS OF SOCS1 GENE WERE NOTED IN THE CML SAMPLES. THE SOCS1 GENE WAS HYPERMETHYLATED IN 67% AND 46% OF THE BLASTIC AND CHRONIC PHASE CML SAMPLES RESPECTIVELY (P < 0.0001). HOWEVER, THERE WAS NO METHYLATION OF THE SOCS1 GENE IN NORMAL CONTROLS OR CML IN MOLECULAR REMISSION. THE METHYLATION STATUS OF THE SOCS1 GENE IS CONSISTENT WITH THE RESULTS OF THE REAL-TIME QUANTITATIVE REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION AND IMMUNOCYTOCHEMISTRY STAINING. OUR RESULTS DEMONSTRATE THAT THE SOCS1 GENE SILENCING IS CAUSED BY THE METHYLATION OF CPG ISLANDS IN CML AND IS REVERSED TO AN UNMETHYLATED STATUS IN MOLECULAR REMISSION. AS SOCS1 HAS UNIVERSAL ACTIVITY TO NEGATIVELY REGULATE SEVERAL CYTOKINE SIGNALLING PATHWAYS, THE LOSS OF THE NEGATIVE REGULATION OF CYTOKINE SIGNALLING BY THE SOCS1 MAY PLAY A ROLE IN THE PATHOGENESIS OF CML PROGRESSION.	2003	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
16 2682 26 EVALUATION OF SERUM LINE-1 HYPOMETHYLATION AS A PROGNOSTIC MARKER FOR HEPATOCELLULAR CARCINOMA. BACKGROUND AND STUDY AIMS: GLOBAL HYPOMETHYLATION IS ONE OF THE MOST CONSISTENT EPIGENETIC CHANGES IN CANCER. DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC) MUST BE UNDERSTOOD AS A MULTISTEP PROCESS WITH ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS. IN THE LAST DECADES, IN ADDITION TO GENETIC ALTERATIONS, EPIGENETIC CHANGES HAVE BEEN RECOGNIZED AS AN IMPORTANT AND ALTERNATIVE MECHANISM IN TUMOURIGENESIS. WE INVESTIGATED THE CLINICAL IMPLICATIONS OF GLOBAL HYPOMETHYLATION IN THE SERA OF PATIENTS WITH HEPATOCELLULAR CARCINOMA (HCC). PATIENTS AND METHODS: PCR WAS USED TO ASSESS THE METHYLATION STATUS OF LONG INTERSPERSED NUCLEAR ELEMENT TYPE 1 (LINE-1) REPETITIVE SEQUENCES IN GENOMIC DNA DERIVED FROM SERA OF 50 PATIENTS WITH HCC, 20 PATIENTS WITH CIRRHOSIS, 20 PATIENTS WITH CHRONIC HEPATITIS C AND 10 HEALTHY SUBJECTS. RESULTS: SERUM GENOME HYPOMETHYLATION WAS SIGNIFICANTLY INCREASED IN PATIENTS WITH HCC (P<0.001). THE LEVELS OF SERUM LINE-1 HYPOMETHYLATION AT INITIAL PRESENTATION CORRELATED SIGNIFICANTLY WITH TUMOUR SIZE, TUMOUR NUMBER AND ALPHA-FOETOPROTEIN LEVEL. MOREOVER HIGH SERUM LINE-1 HYPOMETHYLATION CORRELATES SIGNIFICANTLY WITH POOR SURVIVAL. CONCLUSION: SERUM LINE-1 HYPOMETHYLATION MAY SERVE AS A PROGNOSTIC MARKER FOR PATIENTS WITH HCC.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
17 3954 22 LONG INTERSPERSED NUCLEAR ELEMENT-1 METHYLATION STATUS IN THE CIRCULATING DNA FROM BLOOD OF PATIENTS WITH MALIGNANT AND CHRONIC INFLAMMATORY LUNG DISEASES. ALONG WITH OTHER MALIGNANT DISEASES, LUNG CANCER ARISES FROM THE PRECANCEROUS LUNG TISSUE STATE. ABERRANT DNA METHYLATION (HYPERMETHYLATION OF CERTAIN GENES AND HYPOMETHYLATION OF RETROTRANSPOSONS) IS KNOWN AS ONE OF THE DRIVING FORCES OF MALIGNANT CELL TRANSFORMATION. EPIGENETIC CHANGES WERE SHOWN TO BE DETECTABLE IN DNA, CIRCULATING IN THE BLOOD (CIRDNA) OF CANCER PATIENTS, INDICATING THE POSSIBILITY TO USE THEM AS CANCER MARKERS. THE CURRENT STUDY IS THE FIRST TO COMPARE THE LONG INTERSPERSED NUCLEAR ELEMENT-1 (LINE-1) METHYLATION LEVEL IN THE BLOOD FROM LUNG CANCER PATIENTS BEFORE TREATMENT VERSUS DIFFERENT CONTROL GROUPS AS HEALTHY SUBJECTS, PATIENTS WITH BRONCHITIS AND PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). THE CONCENTRATION OF LINE-1 METHYLATED FRAGMENTS, REGION 1 (LINE-1 METHYLATED, LINE-1-MET) WAS ESTIMATED BY QUANTITATIVE METHYL-SPECIFIC PCR. THE TOTAL CONCENTRATION OF THE CIRCULATING LINE-1 COPIES WAS MEASURED BY QPCR SPECIFIC FOR LINE-1 REGION 2, WHICH WAS SELECTED DUE TO ITS CPG METHYLATION-INDEPENDENT SEQUENCE (LINE-1-IND). BOTH LINE-1 METHYLATION LEVEL AND LINE-1 METHYLATION INDEX (LINE-1-MET/LINE-1-IND RATIO) WAS DECREASED IN LUNG CANCER PATIENTS COMPARED WITH THE JOINT CONTROL GROUP (HEALTHY SUBJECTS + PATIENTS WITH BRONCHITIS + COPD PATIENTS) (MANN-WHITNEY U-TEST, P = 0.016). WE ALSO FOUND THAT THE TENDENCY OF LINE-1 METHYLATION INDEX DECREASES IN THE CIRDNA FROM LUNG CANCER PATIENTS VERSUS COPD PATIENTS (MANN-WHITNEY U-TEST, P = 0.07). OUR DATA INDICATE THAT THE QUANTITATIVE ANALYSIS OF THE LINE-1 METHYLATION LEVEL IN THE CIRDNA IS VALUABLE FOR DISCRIMINATION OF LUNG CANCER PATIENTS FROM PATIENTS WITH CHRONIC INFLAMMATORY LUNG DISEASES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
18 6845 28 [METHYLATION STATUS OF APOPTOSIS GENES AND INTENSITY OF APOPTOTIC DEATH OF PERIPHERAL BLOOD LYMPHOCYTES IN PERSONS CHRONICALLY EXPOSED TO RADIATION]. METHYLATION OF THE CPG ISLANDS OF GENE PROMOTER REGIONS IS THE MOST COMMON EPIGENETIC MODIFICATION INVOLVED IN THE REGULATION OF GENE EXPRESSION. A NUMBER OF STUDIES HAVE SHOWN THAT IONIZING RADIATION CAN CAUSE BOTH HYPER- AND HYPOMETHYLATION OF DNA. ABERRANT METHYLATION AFFECTS CELLULAR PROCESSES AND CAN LEAD TO THE DEVELOPMENT OF VARIOUS PATHOLOGICAL STATES. IN THE LITERATURE, THERE ARE FEW STUDIES ON THE METHYLATION STATUS OF HUMAN DNA A LONG TIME AFTER RADIATION EXPOSURE. HERE, THE METHYLATION LEVEL OF CPG ISLANDS OF THE PROMOTER REGIONS OF APOPTOSIS GENES (BCL2, ATM, MDM2, CDKN1A, STAT3, AND NFKB1), AND ALSO ITS INFLUENCE ON APOPTOSIS OF PERIPHERAL BLOOD LYMPHOCYTES IN CHRONICALLY EXPOSED PERSONS WERE STUDIED. RESIDENTS OF THE SOUTH URAL REGION WHO WERE CHRONICALLY EXPOSED TO RADIATION (AFTER DISCHARGES OF RADIOACTIVE WASTES INTO THE TECHA RIVER BY THE "MAYAK PRODUCTION ASSOCIATION" IN 1949-1956) WERE INCLUDED IN THE STUDY. IT WAS ESTABLISHED THAT THE PROPORTION OF INDIVIDUALS WITH HYPERMETHYLATED BCL2 GENE PROMOTER AMONG THE EXPOSED PEOPLE WAS STATISTICALLY SIGNIFICANTLY HIGHER THAN IN THE CONTROL GROUP. THE PERCENTAGE OF METHYLATION OF THE ATM GENE PROMOTER WEAKLY POSITIVELY CORRELATED WITH DOSE AND AGE CHARACTERISTICS. DIFFERENCES IN THE FREQUENCY OF LYMPHOCYTE APOPTOSIS IN EXPOSED INDIVIDUALS WITH A HYPO- OR HYPERMETHYLATED ATM GENE PROMOTER WERE ALSO ESTABLISHED. THE DATA INDICATE THAT, IN THE LONG-TERM, AFTER CHRONIC LOW INTENSITY RADIATION EXPOSURE AT LOW AND MEDIUM DOSES, EPIGENETIC MODIFICATIONS OF THE GENOME OCCUR, WHICH ARE MANIFESTED AS CHANGES IN METHYLATION OF PROMOTER REGIONS OF BCL2 AND ATM GENES.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
19  344 37 ALTERED BDNF METHYLATION IN PATIENTS WITH CHRONIC MUSCULOSKELETAL PAIN AND HIGH BIOPSYCHOSOCIAL COMPLEXITY. PURPOSE: THE INTERMED INSTRUMENT, WHICH WAS DEVELOPED TO MEASURE PATIENT'S BIOPSYCHOSOCIAL (BPS) COMPLEXITY, REPRESENTS A POWERFUL DIAGNOSTIC AND THERAPEUTIC TOOL. EPIGENETIC CHANGES ARE THE INTERFACE BETWEEN SIGNALS FROM THE ENVIRONMENT AND GENETIC MODIFICATIONS, AFFECTING GENE EXPRESSION, IN PARTICULAR, BY DNA METHYLATION OF CPG DINUCLEOTIDES IN PROMOTOR REGIONS OF THE CORRESPONDING GENES. THE BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) GENE PLAYS A CRUCIAL ROLE IN THE CENTRAL SENSITIZATION (CS) OF PAIN. IN THIS STUDY, WE HYPOTHESIZED THAT CHRONIC PAIN MODIFIES THE METHYLATION LEVELS OF THE BDNF GENE IN A MANNER THAT IS INTERCONNECTED WITH THE BPS STATUS. PATIENTS AND METHODS: FIFTY-EIGHT CHRONIC MUSCULOSKELETAL PAIN PATIENTS (CMSP) WERE ENROLLED IN THE STUDY. DNA WAS EXTRACTED FROM BLOOD SAMPLES, THE METHYLATION LEVELS OF 13 CPG SITES IN THE BDNF PROMOTER WERE MEASURED BY PYROSEQUENCING, AND ASSOCIATION STUDIES WITH VARIOUS PATIENT PARAMETERS AND THE INTERMED SCORES WERE PERFORMED. RESULTS: INTERESTINGLY, A NEGATIVE CORRELATION (-0.40) WAS FOUND BETWEEN THE TOTAL INTERMED SCORES AND THE AVERAGE CPG METHYLATION VALUES OF THE BDNF GENE, BUT NO CORRELATION WAS OBSERVED WITH THE SEVERITY OF PAIN, DEGREE OF ANXIETY, DEPRESSION, OR KINESIOPHOBIA AND CATASTROPHISM. MOREOVER, THE ASSOCIATION WAS INDEPENDENT OF AGE, SEX AND LEVEL OF COMORBIDITIES. CONCLUSION: THIS RESULT SHOWS THAT CMSP, IN ASSOCIATION WITH ITS BIOPSYCHOSOCIAL CONTEXT, EPIGENETICALLY DECREASES THE DEGREE OF METHYLATION OF THE BDNF PROMOTER AND SHOULD THEREFORE INCREASE THE LEVEL OF BDNF TRANSCRIPTION. IT ALSO SUGGESTS A ROLE OF THE INTERMED TOOL TO DETECT A RELATIONSHIP BETWEEN THE BPS COMPLEXITY AND THE EPIGENETIC CONTROL OF A TARGET GENE. THE POSSIBLE UPREGULATION OF BDNF EXPRESSION MIGHT BE, AT LEAST IN PART, THE SIGNAL FOR CHRONIC PAIN-INDUCED CENTRAL SENSITIZATION (CS). THIS COULD PARTLY EXPLAIN WHY PATIENTS WITH A HIGHER LEVEL OF COMPLEXITY FEEL MORE PAIN THAN THOSE WITH LOWER COMPLEXITY.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                         
20 3079 38 GENOME-WIDE METHYLATION AND EXPRESSION ANALYSES REVEAL THE EPIGENETIC LANDSCAPE OF IMMUNE-RELATED DISEASES FOR TOBACCO SMOKING. BACKGROUND: SMOKING IS A MAJOR CAUSAL RISK FACTOR FOR LUNG CANCER, CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), CARDIOVASCULAR DISEASE (CVD), AND IS THE MAIN PREVENTABLE CAUSE OF DEATHS IN THE WORLD. THE COMPONENTS OF CIGARETTE SMOKE ARE INVOLVED IN IMMUNE AND INFLAMMATORY PROCESSES, WHICH MAY INCREASE THE PREVALENCE OF CIGARETTE SMOKE-RELATED DISEASES. HOWEVER, THE UNDERLYING MOLECULAR MECHANISMS LINKING SMOKING AND DISEASES HAVE NOT BEEN WELL EXPLORED. THIS STUDY WAS AIMED TO DEPICT A GLOBAL MAP OF DNA METHYLATION AND GENE EXPRESSION CHANGES INDUCED BY TOBACCO SMOKING AND TO EXPLORE THE MOLECULAR MECHANISMS BETWEEN SMOKING AND HUMAN DISEASES THROUGH WHOLE-GENOME BISULFITE SEQUENCING (WGBS) AND RNA-SEQUENCING (RNA-SEQ). RESULTS: WE PERFORMED WGBS ON 72 SAMPLES (36 SMOKERS AND 36 NONSMOKERS) AND RNA-SEQ ON 75 SAMPLES (38 SMOKERS AND 37 NONSMOKERS), AND CYTOKINE IMMUNOASSAY ON PLASMA FROM 22 MALES (9 SMOKERS AND 13 NONSMOKERS) WHO WERE RECRUITED FROM THE CITY OF JINCHENG IN CHINA. BY COMPARING THE DATA OF THE TWO GROUPS, WE DISCOVERED A GENOME-WIDE METHYLATION LANDSCAPE OF DIFFERENTIALLY METHYLATED REGIONS (DMRS) ASSOCIATED WITH SMOKING. FUNCTIONAL ENRICHMENT ANALYSES REVEALED THAT BOTH SMOKING-RELATED HYPER-DMR GENES (DMGS) AND HYPO-DMGS WERE RELATED TO SYNAPSE-RELATED PATHWAYS, WHEREAS THE HYPO-DMGS WERE SPECIFICALLY RELATED TO CANCER AND ADDICTION. THE DIFFERENTIALLY EXPRESSED GENES (DEGS) REVEALED BY RNA-SEQ ANALYSIS WERE SIGNIFICANTLY ENRICHED IN THE "IMMUNOSUPPRESSION" PATHWAY. CORRELATION ANALYSIS OF DMRS WITH THEIR CORRESPONDING GENE EXPRESSION SHOWED THAT GENES AFFECTED BY TOBACCO SMOKING WERE MOSTLY RELATED TO IMMUNE SYSTEM DISEASES. FINALLY, BY COMPARING CYTOKINE CONCENTRATIONS BETWEEN SMOKERS AND NONSMOKERS, WE FOUND THAT VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) WAS SIGNIFICANTLY UPREGULATED IN SMOKERS. CONCLUSIONS: IN SUM, WE FOUND THAT SMOKING-INDUCED DMRS HAVE DIFFERENT DISTRIBUTION PATTERNS IN HYPERMETHYLATED AND HYPOMETHYLATED AREAS BETWEEN SMOKERS AND NONSMOKERS. WE FURTHER IDENTIFIED AND VERIFIED SMOKING-RELATED DMGS AND DEGS THROUGH MULTI-OMICS INTEGRATION ANALYSIS OF DNA METHYLOME AND TRANSCRIPTOME DATA. THESE FINDINGS PROVIDE US A COMPREHENSIVE GENOMIC MAP OF THE MOLECULAR CHANGES INDUCED BY SMOKING WHICH WOULD ENHANCE OUR UNDERSTANDING OF THE HARMS OF SMOKING AND ITS RELATIONSHIP WITH DISEASES.	2021