1 2768 174 EXPRESSIONS OF SERUM LNCRNAS IN DIABETIC RETINOPATHY - A POTENTIAL DIAGNOSTIC TOOL. WITH INCREASING INCIDENCE OF DIABETES WORLDWIDE, THERE IS AN EVER-EXPANDING NUMBER OF PATIENTS WITH CHRONIC DIABETIC COMPLICATIONS SUCH AS DIABETIC RETINOPATHY (DR), ONE OF THE LEADING CAUSES OF BLINDNESS IN THE WORKING AGE POPULATION. EARLY SCREENING FOR THE ONSET AND SEVERITY OF DR IS ESSENTIAL FOR TIMELY INTERVENTION. WITH RECENT ADVANCEMENTS IN GENOMIC TECHNOLOGIES, EPIGENETIC ALTERATIONS IN DR ARE BEGINNING TO UNRAVEL. LONG NON-CODING RNAS (LNCRNAS), WHICH ARE KEY EPIGENETIC MEDIATORS, HAVE DEMONSTRATED IMPLICATIONS IN SEVERAL (DR) RELATED PROCESSES. BASED ON THE PREVIOUS RESEARCH, WE HAVE DEVELOPED A SERUM-BASED, MULTI-PANEL PCR TEST USING 9 LNCRNAS (ANRIL, MALAT1, WISPER, ZFAS1, H19, HOTAIR, HULC, MEG3, AND MIAT) TO IDENTIFY AND VALIDATE WHETHER THIS PANEL COULD BE USED AS A DIAGNOSTIC AND PROGNOSTIC TOOL FOR DR. WE INITIALLY USED A CELL CULTURE MODEL (HUMAN RETINAL ENDOTHELIAL CELLS) AND CONFIRMED THAT 25 MM GLUCOSE INDUCES UPREGULATIONS OF ANRIL, HOTAIR, HULC, MALAT1, AND ZFAS1, AND DOWNREGULATION OF H19 COMPARED TO 5 MM GLUCOSE CONTROLS. THEN AS AN INITIAL PROOF-OF-CONCEPT, WE TESTED VITREOUS HUMOR AND SERUM SAMPLES FROM A SMALL COHORT OF NON-DIABETIC (N=10) AND DIABETIC PATIENTS WITH PROLIFERATIVE RETINOPATHY (PDR, N=11) AND MEASURED THE LEVELS OF THE 9 LNCRNAS. DIFFERENTIAL EXPRESSIONS OF LNCRNAS WERE FOUND IN THE VITREOUS AND SERUM OF PATIENTS AND SHOWED SIGNIFICANT CORRELATIONS. WE EXPANDED OUR APPROACH AND ASSESSED THE SAME LNCRNAS USING SAMPLES FROM A LARGER COHORT OF DIABETIC (N= 59; M/F:44/15) AND NON-DIABETIC PATIENTS (N= 11; M/F:4/7). SIGNIFICANT INCREASED LNCRNA EXPRESSIONS OF ANRIL, H19, HOTAIR, HULC, MIAT, WISPER AND ZFAS1 WERE OBSERVED IN THE SERUM OF DIABETIC PATIENTS (WITH VARYING STAGES OF DR) COMPARED TO NON-DIABETICS. NO SIGNIFICANT CORRELATIONS WERE DEMONSTRATED BETWEEN LNCRNA EXPRESSIONS AND CREATININE OR GLYCATED HEMOGLOBIN (HBA1C) LEVELS. USING ROC AND FURTHER ANALYSES, WE IDENTIFIED DISTINCT LNCRNA PHENOTYPE COMBINATIONS, WHICH MAY BE USED TO IDENTIFY PATIENTS WITH DR. DATA FROM THIS STUDY INDICATE THAT A PANEL OF SERUM LNCRNAS MAY BE USED FOR A POTENTIAL SCREENING TEST FOR DR. FURTHER LARGE-SCALE STUDIES ARE NEEDED TO VALIDATE THIS NOTION.	2022	
                                         
2  423  44 ANRIL REGULATES MULTIPLE MOLECULES OF PATHOGENETIC SIGNIFICANCE IN DIABETIC NEPHROPATHY. BACKGROUND: HYPERGLYCEMIA-INDUCED TRANSCRIPTIONAL ALTERATIONS LEAD TO ABERRANT SYNTHESIS OF A LARGE NUMBER OF PATHOGENETIC MOLECULES LEADING TO FUNCTIONAL AND STRUCTURAL DAMAGE TO MULTIPLE END ORGANS INCLUDING THE KIDNEYS. DIABETIC NEPHROPATHY (DN) REMAINS A MAJOR CAUSE OF END STAGE RENAL DISEASE. MULTIPLE EPIGENETIC MECHANISMS, INCLUDING ALTERATION OF LONG NON-CODING RNAS (LNCRNAS) MAY PLAY A SIGNIFICANT ROLE MEDIATING THE CELLULAR TRANSCRIPTIONAL ACTIVITIES. WE HAVE PREVIOUSLY SHOWN THAT LNCRNA ANRIL MAY MEDIATE DIABETES ASSOCIATED MOLECULAR, FUNCTIONAL AND STRUCTURAL ABNORMALITIES IN DN. HERE WE EXPLORED DOWNSTREAM MECHANISMS OF ANRIL ALTERATION IN DN. METHODS: WE USED RENAL CORTICAL TISSUES FROM ANRIL KNOCKOUT (KO) MICE AND WILD TYPE (WT) MICE, WITH OR WITHOUT STREPTOZOTOCIN (STZ) INDUCED DIABETES FOR RNA SEQUENCING. THE DIFFERENTIALLY EXPRESSED GENES WERE IDENTIFIED USING EDGER AND DESEQ2 COMPUTATIONAL METHODS. KEGG AND REACTOME PATHWAY ANALYSES AND NETWORK ANALYSES USING STRING AND IPA WERE SUBSEQUENTLY PERFORMED. RESULTS: DIABETIC ANIMALS SHOWED HYPERGLYCEMIA, REDUCED BODY WEIGHT GAIN, POLYURIA AND INCREASED URINARY ALBUMIN. BOTH ALBUMINURIA AND POLYURIA WERE CORRECTED IN THE KO DIABETIC MICE. RNA ANALYSES SHOWED DIABETES INDUCED ALTERATIONS OF A LARGE NUMBER OF TRANSCRIPTS IN THE WILD TYPE (WT) ANIMALS. ANRIL KNOCKOUT (KO) PREVENTED A LARGE NUMBER OF SUCH ALTERATIONS. THE ALTERED TRANSCRIPTS INCLUDE METABOLIC PATHWAYS, APOPTOSIS, EXTRACELLULAR MATRIX PROTEIN SYNTHESIS AND DEGRADATION, NFKB RELATED PATHWAYS, AGE-RAGE INTERACTION PATHWAYS ETC. ANRIL KO PREVENTED MAJORITY OF THESE PATHWAYS. CONCLUSION: THESE FINDINGS SUGGEST THAT AS ANRIL REGULATES A LARGE NUMBER OF MOLECULES OF PATHOGENETIC SIGNIFICANCE, IT MAY POTENTIALLY BE A DRUG TARGET FOR DN AND OTHER CHRONIC DIABETIC COMPLICATIONS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                        
3 1727  36 DYSREGULATION OF LONG NON-CODING RNAS IN MOUSE MODELS OF LOCALIZATION-RELATED EPILEPSY. GENOME-WIDE PROFILING HAS REVEALED THAT EUKARYOTIC GENOMES ARE TRANSCRIBED INTO NUMEROUS NON-CODING RNAS. IN PARTICULAR, LONG NON-CODING RNAS (LNCRNAS) HAVE BEEN IMPLICATED IN VARIOUS HUMAN DISEASES DUE TO THEIR BIOCHEMICAL AND FUNCTIONAL DIVERSITY. EPILEPTIC DISORDERS HAVE BEEN CHARACTERIZED BY DYSREGULATION OF EPIGENETIC REGULATORY MECHANISMS, AND RECENT STUDIES HAVE IDENTIFIED SEVERAL LNCRNAS INVOLVED IN NEURAL DEVELOPMENT AND NETWORK FUNCTION. HOWEVER, COMPREHENSIVE PROFILING OF LNCRNAS IMPLICATED IN CHRONIC EPILEPSY HAS BEEN LACKING. IN THIS STUDY, MICROARRAY ANALYSIS WAS PERFORMED TO OBTAIN THE EXPRESSION PROFILE OF LNCRNAS DYSREGULATED IN PILOCARPINE AND KAINATE MODELS, TWO MODELS OF TEMPORAL LOBE EPILEPSY COMMONLY USED FOR STUDYING EPILEPTIC MECHANISMS. TOTAL OF 4622 LNCRNAS WERE ANALYZED: 384 LNCRNAS WERE SIGNIFICANTLY DYSREGULATED IN PILOCARPINE MODEL, AND 279 LNCRNAS WERE SIGNIFICANTLY DYSREGULATED IN KAINATE MODEL COMPARED WITH CONTROL MICE (>/=3.0-FOLD, P < 0.05). AMONG THESE, 54 AND 14 LNCRNAS, RESPECTIVELY, HAD ADJACENT PROTEIN-CODING GENES WHOSE EXPRESSIONS WERE ALSO SIGNIFICANTLY DYSREGULATED (>/=2.0-FOLD, P < 0.05). MAJORITY OF THESE PAIRS OF LNCRNAS AND ADJACENT GENES SHARED THE SAME DIRECTION OF DYSREGULATION. FOR THE SELECTED ADJACENT GENE-LNCRNA PAIRS, SIGNIFICANT GENE ONTOLOGY TERMS WERE EMBRYONIC APPENDAGE MORPHOGENESIS AND NEURON DIFFERENTIATION. THIS WAS THE FIRST STUDY TO COMPREHENSIVELY IDENTIFY DYSREGULATED LNCRNAS IN TWO DIFFERENT MODELS OF CHRONIC EPILEPSY AND WILL LIKELY PROVIDE A NOVEL INSIGHT INTO DEVELOPING LNCRNA THERAPEUTICS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
4 1897  51 ENDOTHELIN-1 REGULATION IS ENTANGLED IN A COMPLEX WEB OF EPIGENETIC MECHANISMS IN DIABETES. ENDOTHELIAL CELLS (ECS) ARE PRIMARY TARGETS OF GLUCOSE-INDUCED TISSUE DAMAGE. AS A RESULT OF HYPERGLYCEMIA, ENDOTHELIN-1 (ET-1) IS UPREGULATED IN ORGANS AFFECTED BY CHRONIC DIABETIC COMPLICATIONS. THE OBJECTIVE OF THE PRESENT STUDY WAS TO IDENTIFY NOVEL TRANSCRIPTIONAL MECHANISMS THAT INFLUENCE ET-1 REGULATION IN DIABETES. WE CARRIED OUT THE INVESTIGATION IN MICROVASCULAR ECS USING MULTIPLE APPROACHES. ECS WERE INCUBATED WITH 5 MM GLUCOSE (NG) OR 25 MM GLUCOSE (HG) AND ANALYSES FOR DNA METHYLATION, HISTONE METHYLATION, OR LONG NON-CODING RNA- MEDIATED REGULATION OF ET-1 MRNA WERE THEN PERFORMED. DNA METHYLATION ARRAY ANALYSES DEMONSTRATED THE PRESENCE OF HYPOMETHYLATION IN THE PROXIMAL PROMOTER AND 5' UTR/FIRST EXON REGIONS OF EDN1 FOLLOWING HG CULTURE. FURTHER, GLOBALLY BLOCKING DNA METHYLATION OR HISTONE METHYLATION SIGNIFICANTLY INCREASED ET-1 MRNA EXPRESSIONS IN BOTH NG AND HG-TREATED HRECS. WHILE, KNOCKING DOWN THE PATHOGENETIC LNCRNAS ANRIL, MALAT1, AND ZFAS1 SUBSEQUENTLY PREVENTED THE GLUCOSE-INDUCED UPREGULATION OF ET-1 TRANSCRIPTS. BASED ON OUR PAST AND PRESENT FINDINGS, WE PRESENT A NOVEL PARADIGM THAT REVEALS A COMPLEX WEB OF EPIGENETIC MECHANISMS REGULATING GLUCOSE-INDUCED TRANSCRIPTION OF ET-1. IMPROVING OUR UNDERSTANDING OF SUCH PROCESSES MAY LEAD TO BETTER TARGETED THERAPIES.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
5 5638  42 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	
                                                                                                                                                                                                                                                                                                                                                                                                         
6 5567  55 ROLE OF LNCRNAS IN REMODELING OF THE CORONARY ARTERY PLAQUES IN PATIENTS WITH ATHEROSCLEROSIS. INTRODUCTION: CARDIOVASCULAR DISEASES (CVDS) ARE THE LEADING CAUSE OF DEATH WORLDWIDE ACCORDING TO WORLD HEALTH ORGANIZATION (WHO) DATA. ATHEROSCLEROSIS IS CONSIDERED AS A CHRONIC INFLAMMATORY DISEASE THAT DEVELOPS IN RESPONSE TO DAMAGE TO THE VASCULAR INTIMA-MEDIA LAYER IN MOST CASES. IN RECENT YEARS, EPIGENETIC EVENTS HAVE EMERGED AS IMPORTANT PLAYERS IN THE DEVELOPMENT AND PROGRESSION OF CVDS. SINCE NONCODING RNA (NCRNAS) ARE IMPORTANT REGULATORS IN THE ORGANIZATION OF THE PATHOPHYSIOLOGICAL PROCESSES OF THE CARDIOVASCULAR SYSTEM, THEY HAVE THE POTENTIAL TO BE USED AS THERAPEUTIC TARGETS, DIAGNOSTIC AND PROGNOSTIC BIOMARKERS. IN THIS STUDY LONG NONCODING RNA (LNCRNA) AND MRNA GENE EXPRESSION WERE COMPARED BETWEEN CORONARY ATHEROSCLEROTIC PLAQUES (CAP) AND THE INTERNAL MAMMARY ARTERY (IMA) WHICH HAS THE SAME GENETIC MAKEUP AND IS EXPOSED TO THE SAME ENVIRONMENTAL STRESS CONDITIONS WITH CAP IN THE SAME INDIVIDUAL. METHODS: LNCRNA AND MRNA GENE EXPRESSIONS WERE DETERMINED USING THE MICROARRAY IN THE SAMPLES. MICROARRAY RESULTS WERE VALIDATED BY RT-QPCR. DIFFERENTIALLY EXPRESSED GENES (DEGS; LNCRNAS AND MRNAS) WERE DETERMINED BY GENESPRING (VER 3.0) [P VALUES < 0.05 AND FOLD CHANGE (FC) > 2]. DAVID BIOINFORMATICS PROGRAM WAS USED FOR GENE ONTOLOGY (GO) ANNOTATION AND ENRICHMENT ANALYSES OF STATISTICALLY SIGNIFICANT GENES BETWEEN CAP AND IMA TISSUE. RESULTS AND CONCLUSIONS: IN OUR STUDY, 345 DEGS WERE FOUND TO BE STATISTICALLY SIGNIFICANT (P < 0.05; FC > 2) BETWEEN CAP AND IMA. OF THESE, 65 WERE LNCRNA AND 280 WERE MRNA. THIRTY-THREE LNCRNAS WERE UPREGULATED, WHILE 32 LNCRNAS WERE DOWNREGULATED. SOME OF THE IMPORTANT MRNAS ARE SPP1, CYP4B1, CHRDL1, MYOC, AND ALKAL2, WHILE SOME OF THE LNCRNAS ARE LOC105377123, LINC01857, DIO3OS, LOC101928134, AND KCNA3 BETWEEN CAP AND IMA TISSUE. WE ALSO IDENTIFIED GENES THAT CORRELATED WITH STATISTICALLY SIGNIFICANT LNCRNAS. THE RESULTS OF THIS STUDY ARE EXPECTED TO BE AN IMPORTANT SOURCE OF DATA IN THE DEVELOPMENT OF NEW GENETICALLY BASED DRUGS TO PREVENT ATHEROSCLEROTIC PLAQUE. IN ADDITION, THE DATA OBTAINED MAY CONTRIBUTE TO THE EXPLANATION OF THE EPIGENETIC MECHANISMS THAT PLAY A ROLE IN THE PATHOLOGICAL BASIS OF THE PROCESS THAT PROTECTS THE IMA FROM ATHEROSCLEROSIS.	2023	

7  782  36 CELL-FREE MICRORNA-148A IS ASSOCIATED WITH RENAL ALLOGRAFT DYSFUNCTION: IMPLICATION FOR BIOMARKER DISCOVERY. BACKGROUND: CHRONIC ALLOGRAFT DYSFUNCTION (CAD), THE FOREMOST CAUSE OF RENAL GRAFT LOSS WORLDWIDE, IS A SERIOUS CHALLENGE FOR MOST OF THE RECIPIENTS. AS THE EPIGENETIC ERA IS EMERGING, EPIGENETIC BIOMARKERS ESPECIALLY MICRORNAS (MIRNAS) MAY REFLECT THE CURRENT STAGE OF THE DISEASE AND PATIENT'S THERAPY RESPONSE. THE CURRENT STUDY INVESTIGATED THE POTENTIAL SIGNIFICANCE OF CIRCULATING MIRNA-148A IN PREDICTING THE RENAL GRAFT FUNCTION. DESIGN AND METHODS: CIRCULATING MIRNAS WERE ISOLATED FROM 53 PLASMA SAMPLES OF RECIPIENTS WITH HISTOLOGICALLY VALIDATED INTERSTITIAL FIBROSIS AND TUBULAR ATROPHY (IFTA, N = 26), AND RECIPIENTS WITH STABLE GRAFT FUNCTION (SGF, N = 27), AND ALSO HEALTHY INDIVIDUALS ( N = 15). THE LEVEL OF MIRNA-148A WAS EVALUATED BY THE QUANTITATIVE POLYMERASE CHAIN REACTION (QPCR) AND CORRELATED WITH CLINICAL AND HISTOLOGICAL PARAMETERS. RESULTS: SIGNIFICANTLY, MIRNA-148A DECREASED IN IFTA COMPARED WITH SGF SUBJECTS (P < 0.001). MIRNA-148A LEVELS INDICATED A SIGNIFICANT ASSOCIATION WITH SERUM CREATININE LEVELS ( R = 0.451, P = 0.021) AND GLOMERULAR FILTRATION RATE ( R = -0.520, P = 0.006). MIRNA-148A EXPRESSION LEVELS COULD DISCRIMINATE IFTA CASES FROM SGF INDIVIDUALS WITH AN AREA UNDER THE CURVE OF 0.89 ( P < 0.001), 97% SENSITIVITY, AND 72% SPECIFICITY. A NUMBER OF PREDICTED TARGETS THAT MIGHT BE INVOLVED IN CAD BY MIRNA-148A WERE PREDICTED. CONCLUSION: PLASMA CELL-FREE MIRNA-148A CORRELATED WITH RENAL FUNCTION AND HISTOLOGICAL GRADES; THEREFORE, IT MAY BE FURTHER INVESTIGATED AS A NOVEL NONINVASIVE MOLECULAR MARKER OF THE PROGRESSION TO IFTA IN RENAL TRANSPLANT RECIPIENTS; MOREOVER, THE EMERGING BIOMARKER MAY BECOME A THERAPEUTIC TARGET IN THE FUTURE CLINIC.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
8 1739  42 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	
                                                                                                                                                                                                                        
9 1519  36 DNA METHYLATION AT ATP11A CG11702988 IS A BIOMARKER OF LUNG DISEASE SEVERITY IN CYSTIC FIBROSIS: A LONGITUDINAL STUDY. CYSTIC FIBROSIS (CF) IS A CHRONIC GENETIC DISEASE THAT MAINLY AFFECTS THE RESPIRATORY AND GASTROINTESTINAL SYSTEMS. NO CURATIVE TREATMENTS ARE AVAILABLE, BUT THE FOLLOW-UP IN SPECIALIZED CENTERS HAS GREATLY IMPROVED THE PATIENT LIFE EXPECTANCY. ROBUST BIOMARKERS ARE REQUIRED TO MONITOR THE DISEASE, GUIDE TREATMENTS, STRATIFY PATIENTS, AND PROVIDE OUTCOME MEASURES IN CLINICAL TRIALS. IN THE PRESENT STUDY, WE OUTLINE A STRATEGY TO SELECT PUTATIVE DNA METHYLATION BIOMARKERS OF LUNG DISEASE SEVERITY IN CYSTIC FIBROSIS PATIENTS. IN THE DISCOVERY STEP, WE SELECTED SEVEN POTENTIAL BIOMARKERS USING A GENOME-WIDE DNA METHYLATION DATASET THAT WE GENERATED IN NASAL EPITHELIAL SAMPLES FROM THE METHYLCF COHORT. IN THE REPLICATION STEP, WE ASSESSED THE SAME BIOMARKERS USING SPUTUM CELL SAMPLES FROM THE METHYLBIOMARK COHORT. OF INTEREST, DNA METHYLATION AT THE CG11702988 SITE (ATP11A GENE) POSITIVELY CORRELATED WITH LUNG FUNCTION AND BMI, AND NEGATIVELY CORRELATED WITH LUNG DISEASE SEVERITY, P. AERUGINOSA CHRONIC INFECTION, AND THE NUMBER OF EXACERBATIONS. THESE RESULTS WERE REPLICATED IN PROSPECTIVE SPUTUM SAMPLES COLLECTED AT FOUR TIME POINTS WITHIN AN 18-MONTH PERIOD AND LONGITUDINALLY. TO CONCLUDE, (I) WE IDENTIFIED A DNA METHYLATION BIOMARKER THAT CORRELATES WITH CF SEVERITY, (II) WE PROVIDED A METHOD TO EASILY ASSESS THIS BIOMARKER, AND (III) WE CARRIED OUT THE FIRST LONGITUDINAL ANALYSIS OF DNA METHYLATION IN CF PATIENTS. THIS NEW EPIGENETIC BIOMARKER COULD BE USED TO STRATIFY CF PATIENTS IN CLINICAL TRIALS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
10 5304  41 PROTEOMIC ANALYSIS OF INFLAMMATORY BIOMARKERS ASSOCIATED WITH BREAST CANCER RECURRENCE. INTRODUCTION: BREAST CANCER IS THE MOST FREQUENT CANCER DETECTED FOR WOMEN, AND WHILE OUR ABILITY TO TREAT BREAST CANCER HAS IMPROVED SUBSTANTIALLY OVER THE YEARS, RECURRENCE REMAINS A MAJOR OBSTACLE. STANDARD SCREENING FOR NEW AND RECURRENT BREAST CANCER INVOLVES CLINICAL BREAST IMAGING. HOWEVER, THERE IS NO CLINICALLY APPROVED NONINVASIVE BODY FLUID TEST FOR THE EARLY DETECTION OF RECURRENT BREAST CANCER. MATERIALS AND METHOD: IN THIS STUDY, WE ANALYZED SERUM SAMPLES FROM BOTH RECURRENT AND NONRECURRENT BREAST CANCER PATIENTS BY DIFFERENT PROTEOMICS METHODS TO IDENTIFY BIOMARKERS IN PATIENTS WITH RECURRENCE OF DISEASE. RESULTS: COMPARATIVE DATA ANALYSIS IDENTIFIED SEVERAL HISTONE DEACETYLASE (HDAC) PROTEINS, WHICH WERE FOUND AT SIGNIFICANTLY HIGHER LEVELS IN THE SERUM OF RECURRENT BREAST CANCER PATIENTS: HDAC9 (C-TERM) (P = 0.0035), HDAC5 (C-TERM) (P = 0.013), SMALL UBIQUITIN-LIKE MODIFIER 1 (N-TERM) (P = 0.017), EMBRYONIC STEM CELL-EXPRESSED RAS (INTER) (P = 0.018), AND HDAC7 (C-TERM) (P = 0.020). CHRONIC INFLAMMATION PLAYS A CRITICAL ROLE IN THE DEVELOPMENT OF THE BREAST CANCER RECURRENCE, AND WE IDENTIFIED SEVERAL PROINFLAMMATORY CYTOKINES THAT WERE PRESENT AT ELEVATED LEVELS ONLY IN RECURRENT BREAST CANCER PATIENT SERUM. CONCLUSIONS: OUR DATA INDICATED THAT THE EPIGENETIC REGULATION OF INFLAMMATORY PROCESSES PLAYS A CRITICAL ROLE IN BREAST CANCER RECURRENCE. THE IDENTIFIED PROTEINS COULD LAY THE GROUNDWORK FOR THE DEVELOPMENT OF A SERUM-BASED BREAST CANCER RECURRENCE ASSAY.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
11 1587  31 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
12 2653  44 EPIGENOTYPING IN PERIPHERAL BLOOD CELL DNA AND BREAST CANCER RISK: A PROOF OF PRINCIPLE STUDY. BACKGROUND: EPIGENETIC CHANGES ARE EMERGING AS ONE OF THE MOST IMPORTANT EVENTS IN CARCINOGENESIS. TWO ALTERATIONS IN THE PATTERN OF DNA METHYLATION IN BREAST CANCER (BC) HAVE BEEN PREVIOUSLY REPORTED; ACTIVE ESTROGEN RECEPTOR-ALPHA (ER-ALPHA) IS ASSOCIATED WITH DECREASED METHYLATION OF ER-ALPHA TARGET (ERT) GENES, AND POLYCOMB GROUP TARGET (PCGT) GENES ARE MORE LIKELY THAN OTHER GENES TO HAVE PROMOTER DNA HYPERMETHYLATION IN CANCER. HOWEVER, WHETHER DNA METHYLATION IN NORMAL UNRELATED CELLS IS ASSOCIATED WITH BC RISK AND WHETHER THESE IMPRINTS CAN BE RELATED TO FACTORS WHICH CAN BE MODIFIED BY THE ENVIRONMENT, IS UNCLEAR. METHODOLOGY/PRINCIPAL FINDINGS: USING QUANTITATIVE METHYLATION ANALYSIS IN A CASE-CONTROL STUDY (N = 1,083) WE FOUND THAT DNA METHYLATION OF PERIPHERAL BLOOD CELL DNA PROVIDES GOOD PREDICTION OF BC RISK. WE ALSO REPORT THAT INVASIVE DUCTAL AND INVASIVE LOBULAR BC IS CHARACTERIZED BY TWO DIFFERENT SETS OF GENES, THE LATTER PARTICULAR BY GENES INVOLVED IN THE DIFFERENTIATION OF THE MESENCHYME (PITX2, TITF1, GDNF AND MYOD1). FINALLY WE DEMONSTRATE THAT ONLY ERT GENES PREDICT ER POSITIVE BC; LACK OF PERIPHERAL BLOOD CELL DNA METHYLATION OF ZNF217 PREDICTED BC INDEPENDENT OF AGE AND FAMILY HISTORY (ODDS RATIO 1.49; 95% CONFIDENCE INTERVAL 1.12-1.97; P = 0.006) AND WAS ASSOCIATED WITH ER-ALPHA BIOACTIVITY IN THE CORRESPONDING SERUM. CONCLUSION/SIGNIFICANCE: THIS FIRST LARGE-SCALE EPIGENOTYPING STUDY DEMONSTRATES THAT DNA METHYLATION MAY SERVE AS A LINK BETWEEN THE ENVIRONMENT AND THE GENOME. FACTORS THAT CAN BE MODULATED BY THE ENVIRONMENT (LIKE ESTROGENS) LEAVE AN IMPRINT IN THE DNA OF CELLS THAT ARE UNRELATED TO THE TARGET ORGAN AND INDICATE THE PREDISPOSITION TO DEVELOP A CANCER. FURTHER RESEARCH WILL NEED TO DEMONSTRATE WHETHER DNA METHYLATION PROFILES WILL BE ABLE TO SERVE AS A NEW TOOL TO PREDICT THE RISK OF DEVELOPING CHRONIC DISEASES WITH SUFFICIENT ACCURACY TO GUIDE PREVENTIVE MEASURES.	2008	
                                                                                                                                                                                                                                                                                                            
13 1345  46 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
14 6684  33 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
15 1607  37 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
16 1718  29 DYSREGULATED LONG NON-CODING RNAS IN THE TEMPORAL LOBE EPILEPSY MOUSE MODEL. PURPOSE: TO PERFORM COMPREHENSIVE PROFILING OF LONG NON-CODING RNAS (LNCRNAS) IN TEMPORAL LOBE EPILEPSY. METHODS: WE PERFORMED EXTENSIVE PROFILING OF LNCRNAS AND MRNAS IN THE MOUSE PILOCARPINE MODEL IN SPECIFIC BRAIN REGIONS, THE HIPPOCAMPUS AND CORTEX, AND COMPARED THE RESULTS TO THOSE OF THE CONTROL MOUSE. DIFFERENTIALLY EXPRESSED LNCRNAS AND MRNAS WERE IDENTIFIED WITH A MICROARRAY ANALYSIS (ARRAYSTAR MOUSE LNCRNA EXPRESSION MICROARRAY V3.0). THEN, GENE ONTOLOGY (GO) AND PATHWAY ANALYSIS WERE PERFORMED TO INVESTIGATE THE POTENTIAL ROLES OF THE DIFFERENTIALLY EXPRESSED MRNAS IN THE PILOCARPINE MODEL. PROTEIN-PROTEIN INTERACTIONS TRANSCRIBED BY DYSREGULATED MRNAS WITH/WITHOUT CO-DYSREGULATED LNCRNAS WERE ANALYZED USING STRING V10 (HTTP://STRING-DB.ORG/). RESULTS: A TOTAL OF 22 AND 83 LNCRNAS WERE UP- AND DOWN-REGULATED (>/=2.0-FOLD, ALL P < .05), RESPECTIVELY, IN THE HIPPOCAMPUS OF THE EPILEPSY MODEL, WHILE 46 AND 659 LNCRNAS WERE UP- AND DOWN-REGULATED, RESPECTIVELY, IN THE CORTEX OF THE EPILEPSY MODEL. GO AND PATHWAY ANALYSIS REVEALED THAT THE DYSREGULATED MRNAS WERE CLOSELY ASSOCIATED WITH A PROCESS ALREADY KNOWN TO BE INVOLVED IN EPILEPTOGENESIS: ACUTE INFLAMMATION, CALCIUM ION REGULATION, EXTRACELLULAR MATRIX REMODELING, AND NEURONAL DIFFERENTIATION. AMONG THE LNCRNAS, WE IDENTIFIED 10 LNCRNAS COMMONLY DYSREGULATED WITH CORRESPONDING MRNAS IN THE CORTEX. THE STRING ANALYSIS SHOWED THAT THE DYSREGULATED MRNAS WERE INTERCONNECTED AROUND TWO CENTERS: THE MTOR PATHWAY-RELATED GENES AND REST PATHWAY-RELATED GENES. CONCLUSION: LNCRNAS WERE DYSREGULATED IN THE PILOCARPINE MOUSE MODEL ACCORDING TO THE BRAIN REGIONS OF THE HIPPOCAMPUS AND CORTEX. THE DYSREGULATED LNCRNAS WITH CO-DYSREGULATED MRNAS MIGHT BE POSSIBLE THERAPEUTIC TARGETS FOR THE EPIGENETIC REGULATION OF CHRONIC EPILEPSY.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                
17 1909  38 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	
                                                                                                                                                                                                                                                                                                                                                                                                               
18 1567  35 DNA METHYLATION OF THE KLF14 GENE REGION IN WHOLE BLOOD CELLS PROVIDES PREDICTION FOR THE CHRONIC INFLAMMATION IN THE ADIPOSE TISSUE. KRUPPEL-LIKE FACTOR 14 (KLF14) GENE, WHICH APPEARS TO BE A MASTER REGULATOR OF GENE EXPRESSION IN THE ADIPOSE TISSUE AND HAVE PREVIOUSLY BEEN ASSOCIATED WITH BMI AND TYPE 2 DIABETES (T2D) BY LARGE GENOME-WIDE ASSOCIATION STUDIES. IN ORDER TO FIND PREDICTIVE BIOMARKERS FOR THE DEVELOPMENT OF T2D, IT IS NECESSARY TO TAKE EPIGENOMIC CHANGES AFFECTED BY ENVIRONMENTAL FACTORS INTO ACCOUNT. THIS STUDY FOCUSES ON AGEING AND OBESITY, WHICH ARE T2D RISK FACTORS, AND EXAMINES EPIGENETIC CHANGES AND INFLAMMATORY CHANGES. WE INVESTIGATED DNA METHYLATION CHANGES IN THE KLF14 PROMOTER REGION IN DIFFERENT ORGANS OF MICE FOR COMPARING AGING AND WEIGHT. WE FOUND THAT METHYLATION LEVELS OF THESE SITES WERE INCREASED WITH AGING AND WEIGHT IN THE SPLEEN, THE ADIPOSE TISSUE, THE KIDNEY, THE LUNG, THE COLON AND THE WHOLE BLOOD CELLS. IN ADDITION, IN THE SPLEEN, THE ADIPOSE TISSUE AND THE WHOLE BLOOD, THESE EPIGENETIC CHANGES WERE ALSO SIGNIFICANTLY ASSOCIATED WITH INFLAMMATORY LEVELS. MOREOVER, NOT ONLY KLF14, BUT ALSO EXPRESSION LEVELS OF SOME DOWNSTREAM GENES WERE DECREASED WITH METHYLATION IN THE SPLEEN, THE ADIPOSE TISSUE AND THE WHOLE BLOOD CELLS. TAKEN TOGETHER, OUR RESULTS SUGGEST THAT METHYLATION CHANGES OF KLF14 IN THOSE TISSUES MAY BE ASSOCIATED WITH CHANGES IN GENE EXPRESSION AND INFLAMMATION ON THE ADIPOSE TISSUE OF OBESITY AND T2D. IN ADDITION, THE METHYLATION CHANGES IN THE WHOLE BLOOD CELLS MAY SERVE AS A PREDICTIVE EPIGENETIC BIOMARKER FOR THE DEVELOPMENT OF T2D.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
19 2420  44 EPIGENETIC SIGNATURE OF IMPAIRED FASTING GLUCOSE IN THE OLD ORDER AMISH. INTRODUCTION: TYPE 2 DIABETES (T2D) IS A COMMON CHRONIC DISEASE WITH SUBSTANTIAL DISEASE BURDEN AND ECONOMIC IMPACT. LIFESTYLE CHANGES CAN SIGNIFICANTLY ALTER THE COURSE OF THE DISEASE, IF DETECTED AT AN EARLY STAGE. DNA METHYLATION SIGNATURE MAY SERVE AS A BIOMARKER FOR EARLY DETECTION OF INCREASED T2D RISK. DESIGN: DNA METHYLATION PROFILING WAS PERFORMED USING THE ILLUMINA INFINIUM HUMAN METHYLATION 450K BEAD CHIP ARRAY IN 24 NORMOGLYCEMIC OLD ORDER AMISH (OOA) INDIVIDUALS WHO LATER DEVELOPED IMPAIRED FASTING GLUCOSE (IFG) (CASES), AND 24 OOA INDIVIDUALS WHO REMAINED NORMOGLYCEMIC AFTER AN AVERAGE FOLLOW UP OF 10 YEARS (CONTROLS). CASES AND CONTROLS WERE MATCHED ON AGE, SEX, BMI, BASELINE FASTING GLUCOSE, AND GLUCOSE LEVEL AFTER 2 H FROM 75 G ORAL GLUCOSE TOLERANCE TEST (OGTT). RESULTS: ASSOCIATION ANALYSIS FOUND NO SIGNIFICANT DIFFERENCE IN EITHER GLOBAL METHYLATION OR INDIVIDUAL PROBE METHYLATION BETWEEN CASES AND CONTROLS, HOWEVER, THE TOP 34 SUGGESTIVE SIGNIFICANT SITES WERE LOCATED IN GENES WITH INTERESTING BIOLOGICAL LINKS TO T2D AND GLYCEMIC TRAITS. THESE GENES INCLUDE BTC THAT PLAYS A ROLE IN PANCREATIC CELL PROLIFERATION AND INSULIN SECRETION, ITGA1 A KNOWN BONE MINERAL DENSITY GENE THAT WAS RECENTLY FOUND TO BE ASSOCIATED ALSO WITH T2D AND GLYCEMIC TRAITS, AND MAY EXPLAIN THE LINK BETWEEN T2D AND BMD, AND RPTOR AND TSC2 BOTH OF WHICH ARE PART OF INSULIN SIGNALING PATHWAY. CONCLUSIONS: THESE RESULTS MAY SHED LIGHT ON THE INITIATION AND DEVELOPMENT OF HYPERGLYCEMIA AND T2D AND HELP TO IDENTIFY HIGH RISK INDIVIDUALS FOR EARLY INTERVENTION; HOWEVER, FURTHER STUDIES ARE REQUIRED FOR VALIDATION.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
20 2908  33 GENE EXPRESSION PROFILE OF NORMAL BREAST TISSUE AND BODY MASS INDEX. BACKGROUND: IN HUMAN BREAST, ADIPOSE TISSUE REPRESENTS UP TO 80% OF THE TOTAL VOLUME AND PLAYS A CRITICAL ROLE IN MAMMARY GLAND REMODELING. GIVEN THE EMERGING ROLE OF OBESITY IN BREAST CANCER GROWTH AND DEVELOPMENT, WE EXPLORED THE RELATIONSHIP BETWEEN BODY MASS INDEX (BMI), AS A PROXY OF WOMAN'S OBESITY STATUS, AND THE EXPRESSION IN NORMAL BREAST TISSUE FROM HEALTHY WOMEN OF A SELECTED PANEL OF GENES, KNOWN TO BE INVOLVED IN MAMMARY GLAND HOMEOSTASIS. METHODS: TWO INDEPENDENT PUBLICLY AVAILABLE DATASETS, COMPOSED OF 180 SPECIMENS OF NORMAL BREAST TISSUE FROM REDUCTION MAMMOPLASTY WERE INTERROGATED. DIFFERENTIAL GENE EXPRESSION AMONG BMI CLASSES WAS EVALUATED BY ANOVA, AND PARTIAL CORRELATION COEFFICIENT WAS USED TO ASSAY THE CORRELATION BETWEEN GENES CONTROLLING FOR BMI. RESULTS: DESPITE THE DIFFERENCES IN MICROARRAY PLATFORMS AND ANALYTICAL PROCEDURES, THE TWO DATASETS SHARED A CORE OF 9 GENES DIFFERENTIALLY EXPRESSED IN BMI CLASSES AND SIGNIFICANTLY CORRELATED WITH BMI. FOUR (44%) OF THESE GENES BELONG TO THE FUNCTIONAL CLASS OF CYTOKINES AND CYTOKINE RECEPTORS (IL1R1, IL2RA, IL12A, AND IL12RB2). THE OTHERS BELONG TO THE FUNCTIONAL CLASS OF THE EPIGENETIC REGULATION (MEDAG AND SETD7), SIGNAL TRANSDUCTION (STAT1), CELL ADHESION (ITGAV), AND ENZYMATIC ACTIVITY (STS). CONCLUSIONS: ALTHOUGH EXPLORATORY, PRESENT FINDINGS ARE IN AGREEMENT WITH THE ROLE OF INFLAMMATION MODULATORS IN THE HOMEOSTASIS OF NORMAL BREAST TISSUE AND THE BELIEVE THAT AN INCREASE IN BODY ADIPOSE TISSUE MAY HAVE A POTENTIALLY DANGEROUS LOCAL EFFECT, THROUGH THE INCREASED EXPRESSION OF INFLAMMATION-RELATED GENES AND THE ESTABLISHMENT OF A LOW-GRADE CHRONIC INFLAMMATION.	2021