1 3446 106 HYPERMETHYLATION OF MIR21 IN CD4+ T CELLS FROM PATIENTS WITH RELAPSING-REMITTING MULTIPLE SCLEROSIS ASSOCIATES WITH LOWER MIRNA-21 LEVELS AND CONCOMITANT UP-REGULATION OF ITS TARGET GENES. BACKGROUND: MULTIPLE SCLEROSIS (MS) IS A CHRONIC INFLAMMATORY DISEASE OF THE CENTRAL NERVOUS SYSTEM CAUSED BY GENETIC AND ENVIRONMENTAL FACTORS. DNA METHYLATION, AN EPIGENETIC MECHANISM THAT CONTROLS GENOME ACTIVITY, MAY PROVIDE A LINK BETWEEN GENETIC AND ENVIRONMENTAL RISK FACTORS. OBJECTIVE: WE SOUGHT TO IDENTIFY DNA METHYLATION CHANGES IN CD4+ T CELLS IN PATIENTS WITH RELAPSING-REMITTING (RR-MS) AND SECONDARY-PROGRESSIVE (SP-MS) DISEASE AND HEALTHY CONTROLS (HC). METHODS: WE PERFORMED DNA METHYLATION ANALYSIS IN CD4+ T CELLS FROM RR-MS, SP-MS, AND HC AND ASSOCIATED IDENTIFIED CHANGES WITH THE NEARBY RISK ALLELE, SMOKING, AGE, AND GENE EXPRESSION. RESULTS: WE OBSERVED SIGNIFICANT METHYLATION DIFFERENCES IN THE VMP1/MIR21 LOCUS, WITH RR-MS DISPLAYING HIGHER METHYLATION COMPARED TO SP-MS AND HC. VMP1/MIR21 METHYLATION DID NOT CORRELATE WITH A KNOWN MS RISK VARIANT IN VMP1 OR SMOKING BUT DISPLAYED A SIGNIFICANT NEGATIVE CORRELATION WITH AGE AND THE LEVELS OF MATURE MIR-21 IN CD4+ T CELLS. ACCORDINGLY, RR-MS DISPLAYED LOWER LEVELS OF MIR-21 COMPARED TO SP-MS, WHICH MIGHT REFLECT DIFFERENCES IN AGE BETWEEN THE GROUPS, AND HEALTHY INDIVIDUALS AND A SIGNIFICANT ENRICHMENT OF UP-REGULATED MIR-21 TARGET GENES. CONCLUSION: DISEASE-RELATED CHANGES IN EPIGENETIC MARKING OF MIR21 IN RR-MS LEAD TO DIFFERENCES IN MIR-21 EXPRESSION WITH A CONSEQUENCE ON MIR-21 TARGET GENES.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
2  810  47 CHANGES IN DNA METHYLATION IN APOE AND ACKR3 GENES IN MULTIPLE SCLEROSIS PATIENTS AND THE RELATIONSHIP WITH THEIR HEAVY METAL BLOOD LEVELS. MULTIPLE SCLEROSIS (MS) IS A CHRONIC INFLAMMATORY DISEASE WITH DEMYELINATED LESIONS IN THE CENTRAL NERVOUS SYSTEM CAUSED BY GENETIC AND ENVIRONMENTAL FACTORS. DNA METHYLATION AS AN EPIGENETIC CHANGE INFLUENCED BY ENVIRONMENTAL FACTORS, INCLUDING HEAVY METALS HAS BEEN IMPLEMENTED IN MS DISEASE. WE INVESTIGATED THE CORRELATION OF DNA METHYLATION CHANGES IN APOE AND ACKR3 GENES IN MS PATIENTS AND THE POSSIBLE ASSOCIATION WITH BLOOD CONCENTRATION OF ARSENIC (AS), CADMIUM (CD) AND LEAD (PB) AS MAJOR HEAVY METAL POLLUTANTS. THIS STUDY INCLUDED 69 RELAPSING-REMITTING MULTIPLE SCLEROSIS (RR-MS) PATIENTS AND 69 AGE/GENDER-MATCHED HEALTHY SUBJECTS. THE HRM REAL-TIME PCR METHOD WAS USED TO INVESTIGATE THE CHANGES IN DNA METHYLATION AND HEAVY METAL CONCENTRATIONS WERE MEASURED BY ELECTROTHERMAL ATOMIC ABSORPTION SPECTROMETRY. OUR RESULTS SHOWED THAT THE METHYLATION PATTERN IN THE ACKR3 GENE OF THE PATIENT GROUP WAS MORE HYPOMETHYLATED, WHILE IN THE CASE OF THE APOE GENE, THIS PATTERN WAS MORE TOWARDS HYPERMETHYLATION COMPARED TO HEALTHY SUBJECTS. MOREOVER, THE BLOOD LEVELS OF AS AND CD METALS, BUT NOT PB, WERE SIGNIFICANTLY HIGHER IN THE PATIENT GROUP COMPARE TO THE CONTROL GROUP (P </= 0.05). THE DATA INDICATE THAT THE INCREASE IN EXPRESSION OF ACKR3 GENE BY HYPOMETHYLATION AND THE DECREASE IN EXPRESSION OF APOE GENE VIA HYPERMETHYLATION ARE POSSIBLY INVOLVED IN THE ONSET AND PROGRESSION OF INFLAMMATORY PROCESSES IN MS PATIENTS. THE LEVEL OF AS CAN ALSO LEAD TO HYPOMETHYLATION BY DISRUPTING THE METHYLATION PATTERNS OF THE ACKR3 GENE, RESULTING IN INCREASED EXPRESSION IN MS PATIENTS. FINALLY, WE HAVE SHOWN THAT EPIGENETIC CHANGES CAN BE AN IMPORTANT FACTOR IN INCREASING AND DECREASING THE EXPRESSION OF GENES INVOLVED IN THE ONSET AND/OR PROGRESSION OF INFLAMMATORY PROCESSES IN MS. FURTHERMORE, EXPOSURE TO HEAVY METALS, ESPECIALLY AS, BY CHANGING THE NATURAL PATTERNS OF DNA METHYLATION CAN BE EFFECTIVE IN THIS DISEASE.	2021	
                                                                                                                                                                                                                                                                                                  
3 3069  44 GENOME-WIDE DNA METHYLATION PROFILING IDENTIFIES EPIGENETIC CHANGES IN CD4+ AND CD14+ CELLS OF MULTIPLE SCLEROSIS PATIENTS. MULTIPLE SCLEROSIS (MS) IS A CHRONIC AUTOIMMUNE AND DEGENERATIVE DISEASE OF THE CENTRAL NERVOUS SYSTEM, WHICH DEVELOPS IN GENETICALLY PREDISPOSED INDIVIDUALS UPON EXPOSURE TO ENVIRONMENTAL INFLUENCES. ENVIRONMENTAL TRIGGERS OF MS, SUCH AS VIRAL INFECTIONS OR SMOKING, WERE DEMONSTRATED TO AFFECT DNA METHYLATION, AND THUS TO INVOLVE THIS IMPORTANT EPIGENETIC MECHANISM IN THE DEVELOPMENT OF PATHOLOGICAL PROCESS. TO IDENTIFY MS-ASSOCIATED DNA METHYLATION HALLMARKS, WE PERFORMED GENOME-WIDE DNA METHYLATION PROFILING OF TWO CELL POPULATIONS (CD4+ T-LYMPHOCYTES AND CD14+ MONOCYTES), COLLECTED FROM THE SAME TREATMENT-NAIVE RELAPSING-REMITTING MS PATIENTS AND HEALTHY SUBJECTS, USING ILLUMINA 450 K METHYLATION ARRAYS. WE REVEALED SIGNIFICANT CHANGES IN DNA METHYLATION FOR BOTH CELL POPULATIONS IN MS. IN CD4+ CELLS OF MS PATIENTS THE MAJORITY OF DIFFERENTIALLY METHYLATED POSITIONS (DMPS) WERE SHOWN TO BE HYPOMETHYLATED, WHILE IN CD14+ CELLS - HYPERMETHYLATED. DIFFERENTIAL METHYLATION OF HLA-DRB1 GENE IN CD4+ AND CD14+ CELLS WAS ASSOCIATED WITH CARRIAGE OF DRB1*15 ALLELE INDEPENDENTLY FROM THE DISEASE STATUS. BESIDES, ABOUT 20% OF IDENTIFIED DMPS WERE SHARED BETWEEN TWO CELL POPULATIONS AND HAD THE SAME DIRECTION OF METHYLATION CHANGES; THEY MAY BE INVOLVED IN BASIC EPIGENETIC PROCESSES OCCURING IN MS. THESE FINDINGS SUGGEST THAT THE EPIGENETIC MECHANISM OF DNA METHYLATION IN IMMUNE CELLS CONTRIBUTES TO MS; FURTHER STUDIES ARE NOW REQUIRED TO VALIDATE THESE RESULTS AND UNDERSTAND THEIR FUNCTIONAL SIGNIFICANCE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
4 1739  39 EARLY DNA METHYLATION CHANGES IN CHILDREN DEVELOPING BETA CELL AUTOIMMUNITY AT A YOUNG AGE. AIMS/HYPOTHESIS: TYPE 1 DIABETES IS A CHRONIC AUTOIMMUNE DISEASE OF COMPLEX AETIOLOGY, INCLUDING A POTENTIAL ROLE FOR EPIGENETIC REGULATION. PREVIOUS EPIGENOMIC STUDIES FOCUSED MAINLY ON CLINICALLY DIAGNOSED INDIVIDUALS. THE AIM OF THE STUDY WAS TO ASSESS EARLY DNA METHYLATION CHANGES ASSOCIATED WITH TYPE 1 DIABETES ALREADY BEFORE THE DIAGNOSIS OR EVEN BEFORE THE APPEARANCE OF AUTOANTIBODIES. METHODS: REDUCED REPRESENTATION BISULPHITE SEQUENCING (RRBS) WAS APPLIED TO STUDY DNA METHYLATION IN PURIFIED CD4(+) T CELL, CD8(+) T CELL AND CD4(-)CD8(-) CELL FRACTIONS OF 226 PERIPHERAL BLOOD MONONUCLEAR CELL SAMPLES LONGITUDINALLY COLLECTED FROM SEVEN TYPE 1 DIABETES-SPECIFIC AUTOANTIBODY-POSITIVE INDIVIDUALS AND CONTROL INDIVIDUALS MATCHED FOR AGE, SEX, HLA RISK AND PLACE OF BIRTH. WE ALSO EXPLORED CORRELATIONS BETWEEN DNA METHYLATION AND GENE EXPRESSION USING RNA SEQUENCING DATA FROM THE SAME SAMPLES. TECHNICAL VALIDATION OF RRBS RESULTS WAS PERFORMED USING PYROSEQUENCING. RESULTS: WE IDENTIFIED 79, 56 AND 45 DIFFERENTIALLY METHYLATED REGIONS IN CD4(+) T CELLS, CD8(+) T CELLS AND CD4(-)CD8(-) CELL FRACTIONS, RESPECTIVELY, BETWEEN TYPE 1 DIABETES-SPECIFIC AUTOANTIBODY-POSITIVE INDIVIDUALS AND CONTROL PARTICIPANTS. THE ANALYSIS OF PRE-SEROCONVERSION SAMPLES IDENTIFIED DNA METHYLATION SIGNATURES AT THE VERY EARLY STAGE OF DISEASE, INCLUDING DIFFERENTIAL METHYLATION AT THE PROMOTER OF IRF5 IN CD4(+) T CELLS. FURTHER, WE VALIDATED RRBS RESULTS USING PYROSEQUENCING AT THE FOLLOWING CPG SITES: CHR19:18118304 IN THE PROMOTER OF ARRDC2; CHR21:47307815 IN THE INTRON OF PCBP3; AND CHR14:81128398 IN THE INTERGENIC REGION NEAR TRAF3 IN CD4(+) T CELLS. CONCLUSIONS/INTERPRETATION: THESE PRELIMINARY RESULTS PROVIDE NOVEL INSIGHTS INTO CELL TYPE-SPECIFIC DIFFERENTIAL EPIGENETIC REGULATION OF GENES, WHICH MAY CONTRIBUTE TO TYPE 1 DIABETES PATHOGENESIS AT THE VERY EARLY STAGE OF DISEASE DEVELOPMENT. SHOULD THESE FINDINGS BE VALIDATED, THEY MAY SERVE AS A POTENTIAL SIGNATURE USEFUL FOR DISEASE PREDICTION AND MANAGEMENT.	2022	
                                                                                                                                                                                                                                                        
5 6083  36 THE EFFECT OF SMOKING ON DNA METHYLATION OF PERIPHERAL BLOOD MONONUCLEAR CELLS FROM AFRICAN AMERICAN WOMEN. BACKGROUND: REGULAR SMOKING IS ASSOCIATED WITH A WIDE VARIETY OF SYNDROMES WITH PROMINENT INFLAMMATORY COMPONENTS SUCH AS CANCER, OBESITY AND TYPE 2 DIABETES. HEAVY REGULAR SMOKING IS ALSO ASSOCIATED WITH CHANGES IN THE DNA METHYLATION OF PERIPHERAL MONONUCLEAR CELLS. HOWEVER, IN YOUNGER SMOKERS, INFLAMMATORY EPIGENETIC FINDINGS ARE LARGELY ABSENT WHICH SUGGESTS THE INFLAMMATORY RESPONSE(S) TO SMOKING MAY BE DOSE DEPENDENT. TO HELP UNDERSTAND WHETHER PERIPHERAL MONONUCLEAR CELLS HAVE A ROLE IN MEDIATING THESE RESPONSES IN OLDER SMOKERS WITH HIGHER CUMULATIVE SMOKE EXPOSURE, WE EXAMINED GENOME-WIDE DNA METHYLATION IN A GROUP OF WELL CHARACTERIZED ADULT AFRICAN AMERICAN SUBJECTS INFORMATIVE FOR SMOKING, AS WELL AS SERUM C-REACTIVE PROTEIN (CRP) AND INTERLEUKIN-6 RECEPTOR (IL6R) LEVELS. IN ADDITION, COMPLEMENTARY BIOINFORMATIC ANALYSES WERE CONDUCTED TO DELINEATE POSSIBLE PATHWAYS AFFECTED BY LONG-TERM SMOKING. RESULTS: GENOME-WIDE DNA METHYLATION ANALYSIS WITH RESPECT TO SMOKING STATUS YIELDED 910 SIGNIFICANT LOCI AFTER BENJAMINI-HOCHBERG CORRECTION. IN PARTICULAR, TWO LOCI FROM THE AHRR GENE (CG05575921 AND CG23576855) AND ONE LOCUS FROM THE GPR15 GENE (CG19859270) WERE IDENTIFIED AS HIGHLY SIGNIFICANTLY DIFFERENTIALLY METHYLATED BETWEEN SMOKERS AND NON-SMOKERS. THE BIOINFORMATIC ANALYSES SHOWED THAT LONG-TERM CHRONIC SMOKING IS ASSOCIATED WITH ALTERED PROMOTER DNA METHYLATION OF GENES CODING FOR PROTEINS MAPPING TO CRITICAL SUB-NETWORKS MODERATING INFLAMMATION, IMMUNE FUNCTION, AND COAGULATION. CONCLUSIONS: WE CONCLUDE THAT CHRONIC REGULAR SMOKING IS ASSOCIATED WITH CHANGES IN PERIPHERAL MONONUCLEAR CELL METHYLATION SIGNATURE WHICH PERTURB INFLAMMATORY AND IMMUNE FUNCTION PATHWAYS AND MAY CONTRIBUTE TO INCREASED VULNERABILITY FOR COMPLEX ILLNESSES WITH INFLAMMATORY COMPONENTS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
6 1607  30 DNA METHYLATION, COLON CANCER AND MEDITERRANEAN DIET: RESULTS FROM THE EPIC-ITALY COHORT. THE BIOLOGICAL MECHANISMS THROUGH WHICH ADHERENCE TO MEDITERRANEAN DIET (MD) PROTECTS AGAINST COLON CANCER (CC) ARE POORLY UNDERSTOOD. EVIDENCE SUGGESTS THAT CHRONIC INFLAMMATION MAY BE IMPLICATED IN THE PATHWAY. BOTH DIET AND CC ARE RELATED TO EPIGENETIC REGULATION. WE PERFORMED A NESTED CASE-CONTROL STUDY ON 161 PAIRS FROM THE ITALIAN COMPONENT OF THE EUROPEAN PROSPECTIVE INVESTIGATION INTO CANCER AND NUTRITION (EPIC) COHORT, IN WHICH WE LOOKED FOR THE METHYLATION SIGNALS IN DNA EXTRACTED FROM LEUCOCYTES ASSOCIATED WITH BOTH CC AND MD IN 995 CPGS LOCATED IN 48 INFLAMMATION GENES. THE DNA METHYLATION SIGNALS DETECTED IN THIS ANALYSIS WERE VALIDATED IN A SUBGROUP OF 47 CASE-CONTROL PAIRS AND FURTHER REPLICATED (WHERE VALIDATED) IN 95 NEW PAIRS BY MEANS OF PYROSEQUENCING. AMONG THE CPG SITES SELECTED A-PRIORI IN INFLAMMATION-RELATED GENES, SEVEN CPG SITES WERE FOUND TO BE ASSOCIATED WITH CC STATUS AND WITH MD, IN LINE WITH ITS PROTECTIVE EFFECT. ONLY TWO CPG SITES (CG17968347-SERPINE1 AND CG20674490-RUNX3) WERE VALIDATED USING BISULPHITE PYROSEQUENCING AND, AFTER REPLICATION, WE FOUND THAT DNA METHYLATION OF CG20674490-RUNX3 MAY BE A POTENTIAL MOLECULAR MEDIATOR EXPLAINING THE PROTECTIVE EFFECT OF MD ON CC ONSET. THE USE OF A 'MEET-IN-THE-MIDDLE' APPROACH TO IDENTIFY THE OVERLAP BETWEEN EXPOSURE AND PREDICTIVE MARKERS OF DISEASE IS INNOVATIVE IN STUDIES ON THE RELATIONSHIP BETWEEN DIET AND CANCER, IN WHICH EXPOSURE ASSESSMENT IS DIFFICULT AND THE MECHANISMS THROUGH WHICH THE NUTRIENTS EXERT THEIR PROTECTIVE EFFECT IS LARGELY UNKNOWN.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
7 5638  39 SERUM METABOLOMICS REVEALS PATHWAYS AND BIOMARKERS ASSOCIATED WITH ASTHMA PATHOGENESIS. BACKGROUND: ASTHMA IS A CHRONIC INFLAMMATORY DISEASE CAUSED BY COMPLEX INTERACTIONS OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. FOR THIS REASON, NEW APPROACHES ARE REQUIRED TO CLARIFY THE PATHOGENESIS OF ASTHMA BY SYSTEMIC REVIEW. OBJECTIVE: WE APPLIED A (1)H-NMR METABOLOMICS APPROACH TO INVESTIGATE THE ALTERED METABOLIC PATTERN IN SERA FROM PATIENTS WITH ASTHMA AND SOUGHT TO IDENTIFY THE MECHANISM UNDERLYING ASTHMA AND POTENTIAL BIOMARKERS. METHOD: A GLOBAL PROFILE OF SERA FROM PATIENTS WITH ASTHMA (N = 39) AND CONTROLS (N = 26) WAS GENERATED USING (1)H-NMR SPECTROSCOPY COUPLED WITH MULTIVARIATE STATISTICAL ANALYSIS. ENDOGENOUS METABOLITES IN SERUM WERE RAPIDLY MEASURED USING THE TARGET-PROFILING PROCEDURE. RESULTS: MULTIVARIATE STATISTICAL ANALYSIS SHOWED A CLEAR DISTINCTION BETWEEN PATIENTS WITH ASTHMA AND HEALTHY SUBJECTS. SERA OF ASTHMA PATIENTS WERE CHARACTERIZED BY INCREASED LEVELS OF METHIONINE, GLUTAMINE, AND HISTIDINE AND BY DECREASED LEVELS OF FORMATE, METHANOL, ACETATE, CHOLINE, O-PHOSPHOCHOLINE, ARGININE, AND GLUCOSE. THE METABOLITES DETECTED IN THE SERA OF PATIENTS WITH ASTHMA ARE INVOLVED IN HYPERMETHYLATION, RESPONSE TO HYPOXIA, AND IMMUNE REACTION. FURTHERMORE, THE LEVELS OF SERUM METABOLITES FROM PATIENTS WITH ASTHMA CORRELATED WITH ASTHMA SEVERITY; IN PARTICULAR, LIPID METABOLISM WAS ALTERED IN PATIENTS WITH LOWER FORCED EXPIRATORY VOLUME IN 1 S PERCENTAGE (FEV(1)%) PREDICTED VALUES. IN ADDITION, POTENTIAL BIOMARKERS SHOWED STRONG PREDICTIVE POWER IN ROC ANALYSIS, AND THE PRESENCE OF ASTHMA IN EXTERNAL VALIDATION MODELS WAS PREDICTED WITH HIGH ACCURACY (90.9% FOR ASTHMA AND 100% FOR CONTROL SUBJECTS). CONCLUSION & CLINICAL RELEVANCE: THESE DATA SHOWED THAT (1)H-NMR-BASED METABOLITE PROFILING OF SERUM MAY BE USEFUL FOR THE EFFECTIVE DIAGNOSIS OF ASTHMA AND A FURTHER UNDERSTANDING OF ITS PATHOGENESIS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                         
8 1297  45 DECREASED MRNA EXPRESSION LEVELS OF DNA METHYLTRANSFERASES TYPE 1 AND 3A IN SYSTEMIC LUPUS ERYTHEMATOSUS. OBJECTIVES: SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC RELAPSING AUTOIMMUNE DISEASE CHARACTERIZED BY THE PRESENCE OF AUTOANTIBODIES DIRECTED AGAINST NUCLEAR ANTIGENS AND BY CHRONIC INFLAMMATION. ALTHOUGH THE ETIOLOGY OF SLE REMAINS UNCLEAR, THE INFLUENCE OF ENVIRONMENT FACTORS, WHICH IS LARGELY REFLECTED BY THE EPIGENETIC MECHANISMS, WITH DNA METHYLATION CHANGES IN PARTICULAR, IS GENERALLY CONSIDERED AS MAIN PLAYERS IN THE PATHOGENESIS OF SLE. WE STUDIED DNA METHYLTRANSFERASES' (DNMTS) TYPE 1, 3A AND 3B TRANSCRIPT LEVELS IN PERIPHERAL BLOOD MONONUCLEAR CELLS FROM PATIENTS DIAGNOSED WITH SYSTEMIC LUPUS ERYTHEMATOSUS AND FROM THE HEALTHY CONTROL SUBJECTS. FURTHERMORE, THE ASSOCIATION OF DNMT1, DNMT3A, AND DNMT3B MRNA LEVELS WITH GENDER, AGE, AND MAJOR CLINICAL MANIFESTATIONS WAS ANALYZED. METHODS: PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) WERE ISOLATED FROM 32 SLE PATIENTS AND 40 HEALTHY CONTROLS. REVERSE TRANSCRIPTION AND REAL-TIME QUANTITATIVE POLYMERASE CHAIN REACTION (RT-QPCR) ANALYSES WERE USED TO DETERMINE DNMT1, DNMT3A, AND DNMT3B MRNA EXPRESSION LEVELS. RESULTS: SIGNIFICANTLY LOWER DNMT1 (P = 0.015543) AND DNMT3A (P = 0.003652) TRANSCRIPT LEVELS IN SLE PATIENTS WERE OBSERVED COMPARED WITH HEALTHY CONTROLS. NEVERTHELESS, THE DNMT3B MRNA EXPRESSION LEVELS WERE MARKEDLY LOWER COMPARED WITH DNMT1 AND DNMT3A, BOTH IN PBMCS FROM AFFECTED PATIENTS AND THOSE FROM CONTROL SUBJECTS. FURTHERMORE, THE DNMT1 TRANSCRIPT LEVELS WERE POSITIVELY CORRELATED WITH SLE DISEASE ACTIVITY INDEX (SLEDAI) (R (S) = 0.4087, P = 0.020224), WHILE THE DNMT3A TRANSCRIPT LEVELS WERE NEGATIVELY CORRELATED WITH PATIENTS AGE (R (S) = -0.3765, P = 0.03369). CONCLUSIONS: OUR ANALYSES CONFIRMED THE IMPORTANCE OF EPIGENETIC ALTERATIONS IN SLE ETIOLOGY. MOREOVER, OUR RESULTS SUGGEST THAT THE PRESENCE OF SOME CLINICAL MANIFESTATIONS, SUCH AS PHOTOTOSENSITIVITY AND ARTHRITIS, MIGHT BE ASSOCIATED WITH THE DYSREGULATION OF DNA METHYLTRANSFERASES' MRNA EXPRESSION LEVELS.	2017	
                                                                                                                                                                                                                                                                                                    
9 4350  36 MIR-181A-5P IS A POTENTIAL CANDIDATE EPIGENETIC BIOMARKER IN MULTIPLE SCLEROSIS. MULTIPLE SCLEROSIS (MS) IS A CHRONIC INFLAMMATORY DISEASE OF THE CENTRAL NERVOUS SYSTEM (CNS) CHARACTERIZED BY DEMYELINATION AND AXONAL DEGENERATION. ABNORMAL EXPRESSION OF MICRORNAS (MIRNAS) PLAYS AN IMPORTANT ROLE IN MS PATHOLOGY. IN THIS COHORT STUDY, DIFFERENTIAL EXPRESSION OF THE FOUR MIRNAS (HSA-MIR-155-5P, HSA-MIR-9-5P, HSA-MIR-181A-5P, AND HSA-MIR-125B-5P) WAS INVESTIGATED IN 69 INDIVIDUALS, INCLUDING 39 MS PATIENTS (RELAPSING-REMITTING MS (RRMS), N = 27; SECONDARY PROGRESSIVE MS (SPMS), N = 12) AND 30 HEALTHY CONTROLS. IN SILICO ANALYSES REVEALED POSSIBLE GENES AND PATHWAYS SPECIFIC TO MIRNAS. PERIPHERAL BLOOD MIRNA EXPRESSIONS WERE DETECTED BY QUANTITATIVE REAL-TIME PCR (QPCR). HSA-MIR-181A-5P WAS DOWNREGULATED AND ASSOCIATED WITH INCREASED MS RISK (P = 0.012). THE OTHER THREE MIRNAS WERE UPREGULATED AND NOT ASSOCIATED WITH MS (P < 0.05). THE AREA UNDER THE CURVE (AUC) IS 0.779. IN SILICO ANALYSES SHOWED THAT HSA-MIR-181A-5P MAY PARTICIPATE IN MS PATHOLOGY BY TARGETING MAP2K1, CREB1, ATXN1, AND ATXN3 GENES IN INFLAMMATION AND NEURODEGENERATION PATHWAYS. THE CIRCULATORY HSA-MIR-181A-5P CAN REGULATE TARGET GENES, REVERSING THE MECHANISMS INVOLVED IN MS PATHOLOGIES SUCH AS PROTEIN UPTAKE AND PROCESSING, CELL PROLIFERATION AND SURVIVAL, INFLAMMATION, AND NEURODEGENERATION. THUS, THIS MIRNA COULD BE USED AS AN EPIGENOMIC-GUIDED DIAGNOSTIC TOOL AND FOR THERAPEUTIC PURPOSE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
10 1587  32 DNA METHYLATION PROFILING IDENTIFIES NOVEL MARKERS OF PROGRESSION IN HEPATITIS B-RELATED CHRONIC LIVER DISEASE. BACKGROUND: CHRONIC HEPATITIS B INFECTION IS CHARACTERIZED BY HEPATIC IMMUNE AND INFLAMMATORY RESPONSE WITH CONSIDERABLE VARIATION IN THE RATES OF PROGRESSION TO CIRRHOSIS. GENETIC VARIANTS AND ENVIRONMENTAL CUES INFLUENCE PREDISPOSITION TO THE DEVELOPMENT OF CHRONIC LIVER DISEASE; HOWEVER, IT REMAINS UNKNOWN IF ABERRANT DNA METHYLATION IS ASSOCIATED WITH FIBROSIS PROGRESSION IN CHRONIC HEPATITIS B. RESULTS: TO IDENTIFY EPIGENETIC MARKS ASSOCIATED WITH INFLAMMATORY AND FIBROTIC PROCESSES OF THE HEPATITIS B-INDUCED CHRONIC LIVER DISEASE, WE CARRIED OUT HEPATIC GENOME-WIDE METHYLATION PROFILING USING ILLUMINA INFINIUM BEADARRAYS COMPARING MILD AND SEVERE FIBROTIC DISEASE IN A DISCOVERY COHORT OF 29 PATIENTS. WE OBTAINED 310 DIFFERENTIALLY METHYLATED REGIONS AND SELECTED FOUR LOCI COMPRISING THREE GENES FROM THE TOP DIFFERENTIALLY METHYLATED REGIONS: HYPERMETHYLATION OF HOXA2 AND HDAC4 ALONG WITH HYPOMETHYLATION OF PPP1R18 WERE SIGNIFICANTLY LINKED TO SEVERE FIBROSIS. WE REPLICATED THE PROMINENT METHYLATION MARKS IN AN INDEPENDENT COHORT OF 102 PATIENTS BY BISULFITE MODIFICATION AND PYROSEQUENCING. THE TIMING AND CAUSAL RELATIONSHIP OF EPIGENETIC MODIFICATIONS WITH DISEASE SEVERITY WAS FURTHER INVESTIGATED USING A COHORT OF PATIENTS WITH SERIAL BIOPSIES. CONCLUSIONS: OUR FINDINGS SUGGEST A LINKAGE OF WIDESPREAD EPIGENETIC DYSREGULATION WITH DISEASE PROGRESSION IN CHRONIC HEPATITIS B INFECTION. CPG METHYLATION AT NOVEL GENES SHEDS LIGHT ON NEW MOLECULAR PATHWAYS, WHICH CAN BE POTENTIALLY EXPLOITED AS A BIOMARKER OR TARGETED TO ATTENUATE INFLAMMATION AND FIBROSIS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
11 1345  38 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
12 3135  39 GLOBAL DNA METHYLATION AND HYDROXYMETHYLATION LEVELS IN PBMCS ARE ALTERED IN RRMS PATIENTS TREATED WITH IFN-BETA AND GA-A PRELIMINARY STUDY. MULTIPLE SCLEROSIS (MS) IS A CHRONIC DISEASE AFFECTING THE CENTRAL NERVOUS SYSTEM (CNS) DUE TO AN AUTOIMMUNE ATTACK ON AXONAL MYELIN SHEATHS. EPIGENETICS IS AN OPEN RESEARCH TOPIC ON MS, WHICH HAS BEEN INVESTIGATED IN SEARCH OF BIOMARKERS AND TREATMENT TARGETS FOR THIS HETEROGENEOUS DISEASE. IN THIS STUDY, WE QUANTIFIED GLOBAL LEVELS OF EPIGENETIC MARKS USING AN ELISA-LIKE APPROACH IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM 52 PATIENTS WITH MS, TREATED WITH INTERFERON BETA (IFN-BETA) AND GLATIRAMER ACETATE (GA) OR UNTREATED, AND 30 HEALTHY CONTROLS. WE PERFORMED MEDIA COMPARISONS AND CORRELATION ANALYSES OF THESE EPIGENETIC MARKERS WITH CLINICAL VARIABLES IN SUBGROUPS OF PATIENTS AND CONTROLS. WE OBSERVED THAT DNA METHYLATION (5-MC) DECREASED IN TREATED PATIENTS COMPARED WITH UNTREATED AND HEALTHY CONTROLS. MOREOVER, 5-MC AND HYDROXYMETHYLATION (5-HMC) CORRELATED WITH CLINICAL VARIABLES. IN CONTRAST, HISTONE H3 AND H4 ACETYLATION DID NOT CORRELATE WITH THE DISEASE VARIABLES CONSIDERED. GLOBALLY QUANTIFIED EPIGENETIC DNA MARKS 5-MC AND 5-HMC CORRELATE WITH DISEASE AND WERE ALTERED WITH TREATMENT. HOWEVER, TO DATE, NO BIOMARKER HAS BEEN IDENTIFIED THAT CAN PREDICT THE POTENTIAL RESPONSE TO THERAPY BEFORE TREATMENT INITIATION.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
13 1500  41 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 5741  42 SMOKING INDUCES DNA METHYLATION CHANGES IN MULTIPLE SCLEROSIS PATIENTS WITH EXPOSURE-RESPONSE RELATIONSHIP. CIGARETTE SMOKING IS AN ESTABLISHED ENVIRONMENTAL RISK FACTOR FOR MULTIPLE SCLEROSIS (MS), A CHRONIC INFLAMMATORY AND NEURODEGENERATIVE DISEASE, ALTHOUGH A MECHANISTIC BASIS REMAINS LARGELY UNKNOWN. WE AIMED AT INVESTIGATING HOW SMOKING AFFECTS BLOOD DNA METHYLATION IN MS PATIENTS, BY ASSAYING GENOME-WIDE DNA METHYLATION AND COMPARING SMOKERS, FORMER SMOKERS AND NEVER SMOKERS IN TWO SWEDISH COHORTS, DIFFERING FOR KNOWN MS RISK FACTORS. SMOKING AFFECTS DNA METHYLATION GENOME-WIDE SIGNIFICANTLY, AN EXPOSURE-RESPONSE RELATIONSHIP EXISTS AND THE TIME SINCE SMOKING CESSATION AFFECTS METHYLATION LEVELS. THE RESULTS ALSO SHOW THAT THE CHANGES WERE LARGER IN THE COHORT BEARING THE MAJOR GENETIC RISK FACTORS FOR MS (FEMALE SEX AND HLA RISK HAPLOTYPES). FURTHERMORE, CPG SITES MAPPING TO GENES WITH KNOWN GENETIC OR FUNCTIONAL ROLE IN THE DISEASE ARE DIFFERENTIALLY METHYLATED BY SMOKING. MODELING OF THE METHYLATION LEVELS FOR A CPG SITE IN THE AHRR GENE INDICATES THAT MS MODIFIES THE EFFECT OF SMOKING ON METHYLATION CHANGES, BY SIGNIFICANTLY INTERACTING WITH THE EFFECT OF SMOKING LOAD. ALONGSIDE, WE REPORT THAT THE GENE EXPRESSION OF AHRR INCREASED IN MS PATIENTS AFTER SMOKING. OUR RESULTS SUGGEST THAT EPIGENETIC MODIFICATIONS MAY REVEAL THE LINK BETWEEN A MODIFIABLE RISK FACTOR AND THE PATHOGENETIC MECHANISMS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
15 3954  29 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
16 1526  37 DNA METHYLATION CHANGES IN GLIAL CELLS OF THE NORMAL-APPEARING WHITE MATTER IN MULTIPLE SCLEROSIS PATIENTS. MULTIPLE SCLEROSIS (MS), THE LEADING CAUSE OF NON-TRAUMATIC NEUROLOGICAL DISABILITY IN YOUNG ADULTS, IS A CHRONIC INFLAMMATORY AND NEURODEGENERATIVE DISEASE OF THE CENTRAL NERVOUS SYSTEM (CNS). DUE TO THE POOR ACCESSIBILITY TO THE TARGET ORGAN, CNS-CONFINED PROCESSES UNDERPINNING THE LATER PROGRESSIVE FORM OF MS REMAIN ELUSIVE THEREBY LIMITING TREATMENT OPTIONS. WE AIMED TO EXAMINE DNA METHYLATION, A STABLE EPIGENETIC MARK OF GENOME ACTIVITY, IN GLIAL CELLS TO CAPTURE RELEVANT MOLECULAR CHANGES UNDERLYING MS NEUROPATHOLOGY. WE PROFILED DNA METHYLATION IN NUCLEI OF NON-NEURONAL CELLS, ISOLATED FROM 38 POST-MORTEM NORMAL-APPEARING WHITE MATTER (NAWM) SPECIMENS OF MS PATIENTS (N = 8) IN COMPARISON TO WHITE MATTER OF CONTROL INDIVIDUALS (N = 14), USING INFINIUM METHYLATIONEPIC BEADCHIP. WE IDENTIFIED 1,226 SIGNIFICANT (GENOME-WIDE ADJUSTED P-VALUE < 0.05) DIFFERENTIALLY METHYLATED POSITIONS (DMPS) BETWEEN MS PATIENTS AND CONTROLS. FUNCTIONAL ANNOTATION OF THE ALTERED DMP-GENES UNCOVERED ALTERATIONS OF PROCESSES RELATED TO CELLULAR MOTILITY, CYTOSKELETON DYNAMICS, METABOLIC PROCESSES, SYNAPTIC SUPPORT, NEUROINFLAMMATION AND SIGNALING, SUCH AS WNT AND TGF-BETA PATHWAYS. A FRACTION OF THE AFFECTED GENES DISPLAYED TRANSCRIPTIONAL DIFFERENCES IN THE BRAIN OF MS PATIENTS, AS REPORTED BY PUBLICALLY AVAILABLE TRANSCRIPTOMIC DATA. CELL TYPE-RESTRICTED ANNOTATION OF DMP-GENES ATTRIBUTED ALTERATIONS OF CYTOSKELETON REARRANGEMENT AND EXTRACELLULAR MATRIX REMODELLING TO ALL GLIAL CELL TYPES, WHILE SOME PROCESSES, INCLUDING ION TRANSPORT, WNT/TGF-BETA SIGNALING AND IMMUNE PROCESSES WERE MORE SPECIFICALLY LINKED TO OLIGODENDROCYTES, ASTROCYTES AND MICROGLIAL CELLS, RESPECTIVELY. OUR FINDINGS STRONGLY SUGGEST THAT NAWM GLIAL CELLS ARE HIGHLY ALTERED, EVEN IN THE ABSENCE OF LESIONAL INSULT, COLLECTIVELY EXHIBITING A MULTICELLULAR REACTION IN RESPONSE TO DIFFUSE INFLAMMATION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                      
17 1508  45 DNA METHYLATION AND MRNA AND MICRORNA EXPRESSION OF SLE CD4+ T CELLS CORRELATE WITH DISEASE PHENOTYPE. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS AN AUTOIMMUNE DISEASE WELL KNOWN FOR ITS CLINICAL HETEROGENEITY, AND ITS ETIOLOGY SECONDARY TO A CROSS-TALK INVOLVING GENETIC PREDISPOSITION AND ENVIRONMENTAL STIMULI. ALTHOUGH GENOME-WIDE ANALYSIS HAS CONTRIBUTED GREATLY TO OUR UNDERSTANDING OF THE GENETIC BASIS OF SLE, THERE IS INCREASING EVIDENCE FOR A ROLE OF EPIGENETICS. INDEED, RECENT DATA HAVE DEMONSTRATED THAT IN PATIENTS WITH SLE, THERE ARE STRIKING ALTERATIONS OF DNA METHYLATION, HISTONE MODIFICATIONS, AND DEREGULATED MICRORNA EXPRESSION, THE SUM OF WHICH CONTRIBUTE TO OVER-EXPRESSION OF SELECT AUTOIMMUNE-RELATED GENES AND LOSS OF TOLERANCE. TO ADDRESS THIS ISSUE AT THE LEVEL OF CLINICAL PHENOTYPE, WE PERFORMED DNA METHYLATION, MRNA AND MICRORNA EXPRESSION SCREENING USING HIGH-THROUGHPUT SEQUENCING OF PURIFIED CD4+ T CELLS FROM PATIENTS WITH SLE, COMPARED TO AGE AND SEX MATCHED CONTROLS. IN PARTICULAR, WE STUDIED 42 PATIENTS WITH SLE AND DIVIDED THIS GROUP INTO THREE CLINICAL PHENOTYPES: A) THE PRESENCE OF SKIN LESIONS WITHOUT SIGNS OF SYSTEMIC PATHOLOGY; B) SKIN LESIONS BUT ALSO CHRONIC RENAL PATHOLOGY; AND C) SKIN LESIONS, CHRONIC RENAL PATHOLOGY AND POLYARTICULAR DISEASE. INTERESTINGLY, AND AS EXPECTED, SEQUENCING DATA REVEALED CHANGES IN DNA METHYLATION IN SLE COMPARED TO CONTROLS. HOWEVER, AND MORE IMPORTANTLY, ALTHOUGH THERE WERE COMMON METHYLATION CHANGES FOUND IN ALL GROUPS OF SLE COMPARED TO CONTROLS, THERE WAS SPECIFIC DNA METHYLATION CHANGES THAT CORRELATED WITH CLINICAL PHENOTYPE. THESE INCLUDED CHANGES IN THE NOVEL KEY TARGET GENES NLRP2, CD300LB AND S1PR3, AS WELL AS CHANGES IN THE CRITICAL PATHWAYS, INCLUDING THE ADHERENS JUNCTION AND LEUKOCYTE TRANSENDOTHELIAL MIGRATION. WE ALSO NOTED THAT A SIGNIFICANT PROPORTION OF GENES UNDERGOING DNA METHYLATION CHANGES WERE INVERSELY CORRELATED WITH GENE EXPRESSION AND THAT MIRNA SCREENING REVEALED THE EXISTENCE OF SUBSETS WITH CHANGES IN EXPRESSION. INTEGRATED ANALYSIS OF THIS DATA HIGHLIGHTS SPECIFIC SETS OF MIRNAS CONTROLLED BY DNA METHYLATION, AND GENES THAT ARE ALTERED BY METHYLATION AND TARGETED BY MIRNAS. IN CONCLUSION, OUR FINDINGS SUGGEST SELECT EPIGENETIC MECHANISMS THAT CONTRIBUTE TO CLINICAL PHENOTYPES AND FURTHER SHED LIGHT ON A NEW VENUE FOR BASIC SLE RESEARCH.	2014	

18 2046  40 EPIGENETIC CLOCK INDICATES ACCELERATED AGING IN GLIAL CELLS OF PROGRESSIVE MULTIPLE SCLEROSIS PATIENTS. BACKGROUND: MULTIPLE SCLEROSIS (MS) IS A CHRONIC INFLAMMATORY NEURODEGENERATIVE DISEASE OF THE CENTRAL NERVOUS SYSTEM (CNS) CHARACTERIZED BY IRREVERSIBLE DISABILITY AT LATER PROGRESSIVE STAGES. A GROWING BODY OF EVIDENCE SUGGESTS THAT DISEASE PROGRESSION DEPENDS ON AGE AND INFLAMMATION WITHIN THE CNS. WE AIMED TO INVESTIGATE EPIGENETIC AGING IN BULK BRAIN TISSUE AND SORTED NUCLEI FROM MS PATIENTS USING DNA METHYLATION-BASED EPIGENETIC CLOCKS. METHODS: WE APPLIED HORVATH'S MULTI-TISSUE AND SHIREBY'S BRAIN-SPECIFIC CORTICAL CLOCK ON BULK BRAIN TISSUE (N = 46), SORTED NEURONAL (N = 54), AND GLIAL NUCLEI (N = 66) FROM POST-MORTEM BRAIN TISSUE OF PROGRESSIVE MS PATIENTS AND CONTROLS. RESULTS: WE FOUND A SIGNIFICANT INCREASE IN AGE ACCELERATION RESIDUALS, CORRESPONDING TO 3.6 YEARS, IN GLIAL CELLS OF MS PATIENTS COMPARED TO CONTROLS (P = 0.0024) USING THE CORTICAL CLOCK, WHICH HELD AFTER ADJUSTMENT FOR COVARIATES (P (ADJ) = 0.0263). THE 4.8-YEAR AGE ACCELERATION FOUND IN MS NEURONS (P = 0.0054) DID NOT WITHSTAND ADJUSTMENT FOR COVARIATES AND NO SIGNIFICANT DIFFERENCE IN AGE ACCELERATION RESIDUALS WAS OBSERVED IN BULK BRAIN TISSUE BETWEEN MS PATIENTS AND CONTROLS. CONCLUSION: WHILE THE FINDINGS WARRANT REPLICATION IN LARGER COHORTS, OUR STUDY SUGGESTS THAT GLIAL CELLS OF PROGRESSIVE MS PATIENTS EXHIBIT ACCELERATED BIOLOGICAL AGING.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
19 1909  32 ENRICHMENT OF GENOMIC PATHWAYS BASED ON DIFFERENTIAL DNA METHYLATION PROFILES ASSOCIATED WITH CHRONIC MUSCULOSKELETAL PAIN IN OLDER ADULTS: AN EXPLORATORY STUDY. OUR STUDY AIMED TO IDENTIFY DIFFERENTIALLY METHYLATED CPGS/REGIONS AND THEIR ENRICHED GENOMIC PATHWAYS ASSOCIATED WITH UNDERLYING CHRONIC MUSCULOSKELETAL PAIN IN OLDER INDIVIDUALS. WE RECRUITED COGNITIVELY HEALTHY OLDER ADULTS WITH (N = 20) AND WITHOUT (N = 9) SELF-REPORTED MUSCULOSKELETAL PAIN AND COLLECTED DNA FROM PERIPHERAL BLOOD THAT WAS ANALYZED USING METHYLATIONEPIC ARRAYS. WE IDENTIFIED 31,739 HYPERMETHYLATED CPG AND 10,811 HYPOMETHYLATED CPG PROBES (PS </= 0.05). ALL CPG PROBES WERE CLUSTERED INTO 5966 REGIONS, AMONG WHICH 600 REGIONS WERE DIFFERENTIALLY METHYLATED AT P </= 0.05 LEVEL, INCLUDING 294 HYPERMETHYLATED REGIONS AND 306 HYPOMETHYLATED REGIONS (DIFFERENTIALLY METHYLATED REGIONS). INGENUITY PATHWAY ENRICHMENT ANALYSIS REVEALED THAT THE PAIN-RELATED DIFFERENTIALLY METHYLATED REGIONS WERE ENRICHED ACROSS MULTIPLE PATHWAYS. THE TOP 10 CANONICAL PATHWAYS WERE LINKED TO CELLULAR SIGNALING PROCESSES RELATED TO IMMUNE RESPONSES (I.E. ANTIGEN PRESENTATION, PROGRAMED CELL DEATH 1 RECEPTOR/PD-1 LIGAND 1, INTERLEUKIN-4, OX40 SIGNALING, T CELL EXHAUSTION, AND APOPTOSIS) AND GAMMA-AMINOBUTYRIC ACID RECEPTOR SIGNALING. FURTHER, WEIGHTED GENE CORRELATION NETWORK ANALYSIS REVEALED A COMETHYLATION NETWORK MODULE IN THE PAIN GROUP THAT WAS NOT PRESERVED IN THE CONTROL GROUP, WHERE THE HUB GENE WAS THE CYCLIC ADENOSINE MONOPHOSPHATE-DEPENDENT TRANSCRIPTION FACTOR ATF-2. OUR PRELIMINARY FINDINGS PROVIDE NEW EPIGENETIC INSIGHTS INTO THE ROLE OF ABERRANT IMMUNE SIGNALING IN MUSCULOSKELETAL PAIN IN OLDER ADULTS WHILE FURTHER SUPPORTING INVOLVEMENT OF DYSFUNCTIONAL GABAERGIC SIGNALING MECHANISMS IN CHRONIC PAIN. OUR FINDINGS NEED TO BE URGENTLY REPLICATED IN LARGER COHORTS AS THEY MAY SERVE AS A BASIS FOR DEVELOPING AND TARGETING FUTURE INTERVENTIONS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                               
20 6684  24 VALIDATION OF AN LC-MS BASED APPROACH FOR PROFILING HISTONES IN CHRONIC LYMPHOCYTIC LEUKEMIA. THE IN VITRO EVALUATION OF HISTONES AND THEIR PTMS HAS DRAWN SUBSTANTIAL INTEREST IN THE DEVELOPMENT OF EPIGENETIC THERAPIES. THE DIFFERENTIAL EXPRESSION OF HISTONE ISOFORMS MAY SERVE AS A POTENTIAL MARKER IN THE CLASSIFICATION OF DISEASES AFFECTED BY CHROMATIN ABNORMALITIES. IN THIS STUDY, PROTEIN PROFILING BY LC AND MS WAS USED TO EXPLORE DIFFERENCES IN HISTONE COMPOSITION IN PRIMARY CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) CELLS. EXTENSIVE METHOD VALIDATIONS WERE PERFORMED TO DETERMINE THE EXPERIMENTAL VARIANCES THAT WOULD IMPACT HISTONE RELATIVE ABUNDANCE. THE RESULTING DATA DEMONSTRATED THAT THE PROPOSED METHODOLOGY WAS SUITABLE FOR THE ANALYSIS OF HISTONE PROFILES. IN 4 NORMAL INDIVIDUALS AND 40 CLL PATIENTS, A SIGNIFICANT DECREASE IN THE RELATIVE ABUNDANCE OF HISTONE H2A VARIANTS (H2AFL AND H2AFA/M*) WAS OBSERVED IN PRIMARY CLL CELLS AS COMPARED TO NORMAL B CELLS. PROTEIN IDENTITIES WERE DETERMINED USING HIGH MASS ACCURACY MS AND SHOTGUN PROTEOMICS.	2009