1 5186 126 PREMATURITY IN MICE LEADS TO REDUCTION IN NEPHRON NUMBER, HYPERTENSION, AND PROTEINURIA. THE NEPHRON NUMBER AT BIRTH IS A QUANTITATIVE TRAIT THAT CORRELATES INVERSELY WITH THE RISK OF HYPERTENSION AND CHRONIC KIDNEY DISEASE LATER IN LIFE. DURING KIDNEY DEVELOPMENT, THE NEPHRON NUMBER IS CONTROLLED BY MULTIPLE FACTORS INCLUDING GENETIC, EPIGENETIC, AND ENVIRONMENTAL MODIFIERS. PREMATURE BIRTH, WHICH REPRESENTS MORE THAN 12% OF ANNUAL LIVE BIRTHS IN THE UNITED STATES, HAS BEEN LINKED TO LOW NEPHRON NUMBER AND THE DEVELOPMENT OF HYPERTENSION LATER IN LIFE. IN THIS REPORT, WE DESCRIBE THE DEVELOPMENT OF A MOUSE MODEL OF PREMATURITY-INDUCED REDUCTION OF NEPHRON NUMBER. PREMATURE MICE, DELIVERED 1 AND 2 DAYS EARLY, HAVE 17.4 +/- 2.3% (N = 6) AND 23.6 +/- 2% (N = 10) FEWER NEPHRONS, RESPECTIVELY, WHEN COMPARED WITH FULL-TERM ANIMALS (12,252 +/- 571 NEPHRONS/KIDNEY, N = 10). AFTER 5 WEEKS OF AGE, THE MICE DELIVERED 2 DAYS PREMATURE SHOW LOWER REAL-TIME GLOMERULAR FILTRATION RATE (GFR, 283 +/- 13 VS 389 +/- 26 MUL/MIN). THE PREMATURE MICE ALSO DEVELOP HYPERTENSION (MEAN ARTERIAL PRESSURE [MAP], 134 +/- 18 VS 120 +/- 14 MM HG) AND ALBUMINURIA (286 +/- 83 VS 176 +/- 59 MUG ALBUMIN/MG CREATININE). THIS MOUSE MODEL PROVIDES A PROOF OF CONCEPT THAT PREMATURITY LEADS TO REDUCED NEPHRON NUMBER AND HYPERTENSION, AND THIS MODEL WILL BE USEFUL IN STUDYING THE PATHOPHYSIOLOGY OF PREMATURITY-INDUCED NEPHRON NUMBER REDUCTIONS AND HYPERTENSION.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
2  177  31 ACCELERATED EPIGENETIC AGING AND INFLAMMATORY/IMMUNOLOGICAL PROFILE (IPAGE) IN PATIENTS WITH CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS DEFINED BY A REDUCED ESTIMATED GLOMERULAR FILTRATION RATE (EGFR). THIS FAILURE CAN BE RELATED TO A PHENOTYPE OF ACCELERATED AGING. IN THIS WORK, WE CONSIDERED 76 PATIENTS WITH END-STAGE RENAL DISEASE (ESRD) AND 83 HEALTHY CONTROLS. WE CONCOMITANTLY EVALUATED FOR THE FIRST TIME TWO MEASURES THAT CAN BE INFORMATIVE OF THE RATE OF AGING, I.E., WHOLE BLOOD DNA METHYLATION USING THE ILLUMINA INFINIUM EPIC ARRAY AND PLASMA LEVELS OF A SELECTION OF INFLAMMATORY/IMMUNOLOGICAL PROTEINS USING MULTIPLEX IMMUNOASSAYS. FIRST OF ALL, WE DEMONSTRATED ACCELERATED AGING IN TERMS OF THE MOST COMMON EPIGENETIC AGE ESTIMATORS IN CKD PATIENTS. MOREOVER, WE DEVELOPED A NEW CLOCK/PREDICTOR OF AGE BASED ON THE INFLAMMATORY/IMMUNOLOGICAL PROFILE (IPAGE) AND IDENTIFIED THE INFLAMMATORY/IMMUNOLOGICAL BIOMARKERS DIFFERENTIALLY EXPRESSED BETWEEN CASES AND CONTROLS. IPAGE APPEARED TO BE MORE SENSITIVE THAN EPIGENETIC CLOCKS IN QUANTIFYING THE ACCELERATED AGING PHENOTYPE OF ESRD PATIENTS. INTERESTINGLY, WE DID NOT FIND ANY CORRELATION BETWEEN THE AGE ACCELERATION EVALUATED ACCORDING TO THE EPIGENETIC CLOCKS AND IPAGE IN EITHER THE ESRD GROUP OR THE CONTROL GROUP. ON THE WHOLE, OUR DATA SHOW A CONSISTENT ACCELERATED AGING PHENOTYPE IN ESRD PATIENTS, WHICH IS BETTER APPRECIATED BY QUANTIFYING THE UNDERLYING INFLAMMATORY PROCESSES (INFLAMMAGING) BY IPAGE THAN BY USING EPIGENETIC CLOCKS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
3 1271  27 CYTOSINE METHYLATION PREDICTS RENAL FUNCTION DECLINE IN AMERICAN INDIANS. DIABETIC NEPHROPATHY ACCOUNTS FOR MOST OF THE EXCESS MORTALITY IN INDIVIDUALS WITH DIABETES, BUT THE MOLECULAR MECHANISMS BY WHICH NEPHROPATHY DEVELOPS ARE LARGELY UNKNOWN. HERE WE TESTED CYTOSINE METHYLATION LEVELS AT 397,063 GENOMIC CPG SITES FOR ASSOCIATION WITH DECLINE IN THE ESTIMATED GLOMERULAR FILTRATION RATE (EGFR) OVER A SIX YEAR PERIOD IN 181 DIABETIC PIMA INDIANS. METHYLATION LEVELS AT 77 SITES SHOWED SIGNIFICANT ASSOCIATION WITH EGFR DECLINE AFTER CORRECTION FOR MULTIPLE COMPARISONS. A MODEL INCLUDING METHYLATION LEVEL AT TWO PROBES (CG25799291 AND CG22253401) IMPROVED PREDICTION OF EGFR DECLINE IN ADDITION TO BASELINE EGFR AND THE ALBUMIN TO CREATININE RATIO WITH THE PERCENT OF VARIANCE EXPLAINED SIGNIFICANTLY IMPROVING FROM 23.1% TO 42.2%. CG22253401 WAS ALSO SIGNIFICANTLY ASSOCIATED WITH EGFR DECLINE IN A CASE-CONTROL STUDY DERIVED FROM THE CHRONIC RENAL INSUFFICIENCY COHORT. PROBES AT WHICH METHYLATION SIGNIFICANTLY ASSOCIATED WITH EGFR DECLINE WERE LOCALIZED TO GENE REGULATORY REGIONS AND ENRICHED FOR GENES WITH METABOLIC FUNCTIONS AND APOPTOSIS. THREE OF THE 77 PROBES THAT WERE ASSOCIATED WITH EGFR DECLINE IN BLOOD SAMPLES SHOWED DIRECTIONALLY CONSISTENT AND SIGNIFICANT ASSOCIATION WITH FIBROSIS IN MICRODISSECTED HUMAN KIDNEY TISSUE, AFTER CORRECTION FOR MULTIPLE COMPARISONS. THUS, CYTOSINE METHYLATION LEVELS MAY PROVIDE BIOMARKERS OF DISEASE PROGRESSION IN DIABETIC NEPHROPATHY AND EPIGENETIC VARIATIONS CONTRIBUTE TO THE DEVELOPMENT OF DIABETIC KIDNEY DISEASE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
4 5189  30 PRENATAL ARSENIC EXPOSURE INDUCES IMMUNOMETABOLIC ALTERATION AND RENAL INJURY IN RATS. ARSENIC (AS) EXPOSURE IS PROGRESSIVELY ASSOCIATED WITH CHRONIC KIDNEY DISEASE (CKD), A LEADING PUBLIC HEALTH CONCERN PRESENT WORLDWIDE. THE ADVERSE EFFECT OF AS EXPOSURE ON THE KIDNEYS OF PEOPLE LIVING IN AS ENDEMIC AREAS HAVE NOT BEEN EXTENSIVELY STUDIED. FURTHERMORE, THE IMPACT OF ONLY PRENATAL EXPOSURE TO AS ON THE PROGRESSION OF CKD ALSO HAS NOT BEEN FULLY CHARACTERIZED. IN THE PRESENT STUDY, WE EXAMINED THE EFFECT OF PRENATAL EXPOSURE TO LOW DOSES OF AS 0.04 AND 0.4 MG/KG BODY WEIGHT (0.04 AND 0.4 PPM, RESPECTIVELY) ON THE PROGRESSION OF CKD IN MALE OFFSPRING USING A WISTAR RAT MODEL. INTERESTINGLY, ONLY PRENATAL AS EXPOSURE WAS SUFFICIENT TO ELEVATE THE EXPRESSION OF PROFIBROTIC (TGF-BETA1) AND PROINFLAMMATORY (IL-1ALPHA, MIP-2ALPHA, RANTES, AND TNF-ALPHA) CYTOKINES AT 2-DAY, 12- AND 38-WEEK TIME POINTS IN THE EXPOSED PROGENY. FURTHER, ALTERATION IN ADIPOGENIC FACTORS (GHRELIN, LEPTIN, AND GLUCAGON) WAS ALSO OBSERVED IN 12- AND 38-WEEK OLD MALE OFFSPRING PRENATALLY EXPOSED TO AS. AN ALTERED LEVEL OF THESE FACTORS COINCIDES WITH IMPAIRED GLUCOSE METABOLISM AND HOMEOSTASIS ACCOMPANIED BY PROGRESSIVE KIDNEY DAMAGE. WE OBSERVED A SIGNIFICANT INCREASE IN THE DEPOSITION OF EXTRACELLULAR MATRIX COMPONENTS AND GLOMERULAR AND TUBULAR DAMAGE IN THE KIDNEYS OF 38-WEEK-OLD MALE OFFSPRING PRENATALLY EXPOSED TO AS. FURTHERMORE, THE OVEREXPRESSION OF TGF-BETA1 IN KIDNEYS CORRESPONDS WITH HYPERMETHYLATION OF THE TGF-BETA1 GENE-BODY, INDICATING A POSSIBLE INVOLVEMENT OF PRENATAL AS EXPOSURE-DRIVEN EPIGENETIC MODULATIONS OF TGF-BETA1 EXPRESSION. OUR STUDY PROVIDES EVIDENCE THAT PRENATAL AS EXPOSURE TO MALES CAN ADVERSELY AFFECT THE IMMUNOMETABOLISM OF OFFSPRING WHICH CAN PROMOTE KIDNEY DAMAGE LATER IN LIFE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
5 1824  27 EFFECTS OF ENVIRONMENTAL CONDITIONS ON NEPHRON NUMBER: MODELING MATERNAL DISEASE AND EPIGENETIC REGULATION IN RENAL DEVELOPMENT. A GROWING BODY OF EVIDENCE SUGGESTS THAT LOW NEPHRON NUMBERS AT BIRTH CAN INCREASE THE RISK OF CHRONIC KIDNEY DISEASE OR HYPERTENSION LATER IN LIFE. ENVIRONMENTAL STRESSORS, SUCH AS MATERNAL MALNUTRITION, MEDICATION AND SMOKING, CAN INFLUENCE RENAL SIZE AT BIRTH. USING METANEPHRIC ORGAN CULTURES TO MODEL SINGLE-VARIABLE ENVIRONMENTAL CONDITIONS, MODELS OF MATERNAL DISEASE WERE EVALUATED FOR PATTERNS OF DEVELOPMENTAL IMPAIRMENT. WHILE HYPERTHERMIA HAD LIMITED EFFECTS ON RENAL DEVELOPMENT, FETAL IRON DEFICIENCY WAS ASSOCIATED WITH SEVERE IMPAIRMENT OF RENAL GROWTH AND NEPHROGENESIS WITH AN ALL-PROXIMAL PHENOTYPE. CULTURING KIDNEY EXPLANTS UNDER HIGH GLUCOSE CONDITIONS LED TO CELLULAR AND TRANSCRIPTOMIC CHANGES RESEMBLING HUMAN DIABETIC NEPHROPATHY. SHORT-TERM HIGH GLUCOSE CULTURE CONDITIONS WERE SUFFICIENT FOR LONG-TERM ALTERATIONS IN DNA METHYLATION-ASSOCIATED EPIGENETIC MEMORY. FINALLY, THE ROLE OF EPIGENETIC MODIFIERS IN RENAL DEVELOPMENT WAS TESTED USING A SMALL COMPOUND LIBRARY. AMONG THE SELECTED EPIGENETIC INHIBITORS, VARIOUS COMPOUNDS ELICITED AN EFFECT ON RENAL GROWTH, SUCH AS HDAC (ENTINOSTAT, TH39), HISTONE DEMETHYLASE (DEFERASIROX, DEFEROXAMINE) AND HISTONE METHYLTRANSFERASE (CYPROHEPTADINE) INHIBITORS. THUS, METANEPHRIC ORGAN CULTURES PROVIDE A VALUABLE SYSTEM FOR STUDYING METABOLIC CONDITIONS AND A TOOL FOR SCREENING FOR EPIGENETIC MODIFIERS IN RENAL DEVELOPMENT.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
6  658  31 BLOOD DNA METHYLATION PREDICTS DIABETIC KIDNEY DISEASE PROGRESSION IN HIGH FAT DIET-FED MICE. DIABETIC KIDNEY DISEASE (DKD) PROGRESSES AT DIFFERENT RATES AMONG PATIENTS WITH TYPE 2 DIABETES MELLITUS (T2D). EARLY IDENTIFICATION OF PATIENTS WITH A HIGHER RISK OF DKD PROGRESSION IS ESSENTIAL TO IMPROVE PROGNOSIS. EPIGENETIC MODIFICATIONS, PARTICULARLY DNA METHYLATION, HAVE BEEN INDEPENDENTLY IMPLICATED IN T2D AND CHRONIC KIDNEY DISEASE. THE CURRENT STUDY AIMED TO DETERMINE CHANGES IN BLOOD DNA METHYLATION THAT REFLECTS AND PREDICTS DKD PROGRESSION. C57BL/6 MICE WERE FED A HIGH-FAT DIET (HFD) FROM WEANING AND SUBCLASSIFIED INTO TWO GROUPS, HFD-1 AND HFD-2, ACCORDING TO URINARY KIDNEY INJURY MARKER KIM-1/CREATININE RATIOS (LOW VS. HIGH) AND HISTOLOGICAL ABNORMALITIES (MILD-MODERATE VS. ADVANCED). DNA METHYLATION PROFILES WERE DETERMINED BY REDUCED REPRESENTATIVE BISULFIDE SEQUENCING (RRBS). OUR RESULTS CONFIRMED EARLY AND ESTABLISHED DKD AT WEEK 9 AND WEEK 32, RESPECTIVELY. AT WEEK 32, ADVANCED KIDNEY INJURY WAS ASSOCIATED WITH DYSREGULATION OF METHYLATION AND DEMETHYLATION ENZYMES IN THE KIDNEY. BLOOD RRBS REVEALED 579 AND 203 DIFFERENTIALLY METHYLATED SITES (DMS) BETWEEN HFD-1 AND HFD-2 ANIMALS AT WEEK 32 AND WEEK 9, RESPECTIVELY, AMONG WHICH 11 WERE COMMON. THE DMS IN BLOOD AND KIDNEY AT WEEK 32 WERE BOTH RELATED TO ORGAN DEVELOPMENT, NEUROGENESIS, CELL JUNCTION, AND WNT SIGNALLING, WHILE THE DMS IN BLOOD AT WEEK 9 SUGGESTED A SPECIFIC ENRICHMENT OF KIDNEY DEVELOPMENT PROCESSES. IN CONCLUSION, OUR DATA STRONGLY SUPPORT THE IMPLICATION OF EARLY BLOOD DNA METHYLATION MODIFICATIONS AND DKD PROGRESSION IN T2D THAT COULD BE USED TO IMPROVE THE DISEASE'S PROGNOSTICATION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
7 2420  23 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
8 1537  23 DNA METHYLATION IN ADOLESCENTS WITH ANXIETY DISORDER: A LONGITUDINAL STUDY. ANXIETY DISORDERS (AD) TYPICALLY MANIFEST IN CHILDREN AND ADOLESCENTS AND MIGHT PERSIST INTO ADULTHOOD. HOWEVER, THERE ARE STILL FEW DATA CONCERNING EPIGENETIC MECHANISMS ASSOCIATED WITH ONSET, PERSISTENCE OR REMISSION OF AD OVER TIME. WE INVESTIGATED A COHORT OF ADOLESCENTS AND YOUNG ADULTS AT BASELINE (AGE; 13.19 +/- 2.38) AND AFTER 5 YEARS AND CLASSIFIED THEM ACCORDING TO THE AD DIAGNOSIS AND THEIR LONGITUDINAL TRAJECTORIES INTO 4 GROUPS: (1) TYPICALLY DEVELOPING COMPARISONS (TDC; CONTROL GROUP, N = 14); (2) INCIDENT (AD IN THE SECOND EVALUATION ONLY, N = 11); (3) PERSISTENT (AD IN BOTH EVALUATIONS, N = 14) AND (4) REMITTENT (AD IN THE FIRST EVALUATION ONLY, N = 8). DNA METHYLATION WAS EVALUATED WITH THE INFINIUM HUMANMETHYLATION450 BEADCHIP FROM SALIVA SAMPLES COLLECTED AT BOTH EVALUATIONS. GENE SET ENRICHMENT ANALYSIS WAS APPLIED TO CONSIDER BIOLOGICAL PATHWAYS. WE FOUND DECREASED DNA METHYLATION IN TDC GROUP WHILE THE CHRONIC CASES OF AD PRESENTED HYPERMETHYLATION IN CENTRAL NERVOUS SYSTEM DEVELOPMENT PATHWAYS. MOREOVER, WE SHOWED THAT THIS PERSISTENT GROUP ALSO PRESENTED HYPERMETHYLATION WHILE THE OTHER THREE GROUPS WERE ASSOCIATED WITH HYPOMETHYLATION IN NERVOUS SYSTEM DEVELOPMENT PATHWAY. INCIDENCE AND REMISSION GROUPS WERE ASSOCIATED WITH INCREASED AND DECREASED METHYLATION IN NEURON DEVELOPMENT PATHWAYS, RESPECTIVELY. LARGER STUDIES ARE LIKELY TO DETECT SPECIFIC GENES RELEVANT TO AD.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
9 2776  29 EXTRAUTERINE GROWTH RESTRICTION ON PULMONARY VASCULAR ENDOTHELIAL DYSFUNCTION IN ADULT MALE RATS: THE ROLE OF EPIGENETIC MECHANISMS. OBJECTIVE: EARLY POSTNATAL LIFE IS CONSIDERED AS A CRITICAL TIME WINDOW FOR THE DETERMINATION OF LONG-TERM METABOLIC STATES AND ORGAN FUNCTIONS. EXTRAUTERINE GROWTH RESTRICTION (EUGR) CAUSES THE DEVELOPMENT OF ADULT-ONSET CHRONIC DISEASES, INCLUDING PULMONARY HYPERTENSION. HOWEVER, THE EFFECTS OF NUTRITIONAL DISADVANTAGES DURING THE EARLY POSTNATAL PERIOD ON PULMONARY VASCULAR CONSEQUENCES IN LATER LIFE ARE NOT FULLY UNDERSTOOD. OUR STUDY WAS DESIGNED TO TEST WHETHER EPIGENETICS DYSREGULATION MEDIATES THE CELLULAR MEMORY OF THIS EARLY POSTNATAL EVENT. METHODS AND RESULTS: TO TEST THIS HYPOTHESIS, WE ISOLATED PULMONARY VASCULAR ENDOTHELIAL CELLS BY MAGNETIC-ACTIVATED CELL SORTING FROM EUGR AND CONTROL RATS. A POSTNATAL INSULT, NUTRITIONAL RESTRICTION-INDUCED EUGR CAUSED DEVELOPMENT OF AN INCREASED PULMONARY ARTERY PRESSURE AT 9 WEEKS OF AGE IN MALE SPRAGUE-DAWLEY RATS. METHYL-DNA IMMUNE PRECIPITATION CHIP, GENOME-SCALE MAPPING STUDIES TO SEARCH FOR DIFFERENTIALLY METHYLATED LOCI BETWEEN CONTROL AND EUGR RATS, REVEALED SIGNIFICANT DIFFERENCE IN CYTOSINE METHYLATION BETWEEN EUGR AND CONTROL RATS. EUGR CHANGES THE CYTOSINE METHYLATION AT APPROXIMATELY 500 LOCI IN MALE RATS AT 9 WEEKS OF AGE, PRECEDING THE DEVELOPMENT OF PULMONARY HYPERTENSION AND THESE REPRESENT THE CANDIDATE LOCI FOR MEDIATING THE PATHOGENESIS OF PULMONARY VASCULAR DISEASE THAT OCCURS LATER IN LIFE. GENE ONTOLOGY ANALYSIS ON DIFFERENTIALLY METHYLATED GENES SHOWED THAT HYPERMETHYLATED GENES IN EUGR ARE VASCULAR DEVELOPMENT-ASSOCIATED GENES AND HYPOMETHYLATED GENES IN EUGR ARE LATE-DIFFERENTIATION-ASSOCIATED AND SIGNAL TRANSDUCTION GENES. WE VALIDATED CANDIDATE DYSREGULATED LOCI WITH THE QUANTITATIVE ASSAYS OF CYTOSINE METHYLATION AND GENE EXPRESSIONS. CONCLUSION: THESE RESULTS DEMONSTRATE THAT EPIGENETICS DYSREGULATION IS A STRONG MECHANISM FOR PROPAGATING THE CELLULAR MEMORY OF EARLY POSTNATAL EVENTS, CAUSING CHANGES IN THE EXPRESSION OF GENES AND LONG-TERM SUSCEPTIBILITY TO PULMONARY HYPERTENSION, AND FURTHER PROVIDING A NEW INSIGHT INTO THE PREVENTION AND TREATMENT OF EUGR-RELATED PULMONARY HYPERTENSION.	2014	
                                                                                                                                                                                                                                                                                                                                           
10 4238  29 METHYLATION PATTERN OF URINARY DNA AS A MARKER OF KIDNEY FUNCTION DECLINE IN DIABETES. INTRODUCTION: RENAL TUBULAR INJURY CONTRIBUTES TO THE DECLINE IN KIDNEY FUNCTION IN PATIENTS WITH DIABETES. CELL TYPE-SPECIFIC DNA METHYLATION PATTERNS HAVE BEEN USED TO CALCULATE PROPORTIONS OF PARTICULAR CELL TYPES. IN THIS STUDY, WE DEVELOPED A METHOD TO DETECT RENAL TUBULAR INJURY IN PATIENTS WITH DIABETES BY DETECTING EXFOLIATED TUBULAR CELLS SHED INTO THE URINE BASED ON TUBULAR CELL-SPECIFIC DNA METHYLATION PATTERNS. RESEARCH DESIGN AND METHODS: WE IDENTIFIED DNA METHYLATION PATTERNS SPECIFIC FOR HUMAN RENAL PROXIMAL TUBULAR CELLS THROUGH COMPARTMENT-SPECIFIC METHYLOME ANALYSIS. WE NEXT DETERMINED THE METHYLATION LEVELS OF PROXIMAL TUBULE-SPECIFIC LOCI IN URINE SEDIMENT OF PATIENTS WITH DIABETES AND ANALYZED CORRELATION WITH CLINICAL VARIABLES. RESULTS: WE IDENTIFIED GENOMIC LOCI IN SMTNL2 AND G6PC TO BE SELECTIVELY UNMETHYLATED IN HUMAN PROXIMAL TUBULAR CELLS. THE METHYLATION LEVELS OF SMTNL2 AND G6PC IN URINE SEDIMENT, DEEMED TO REFLECT THE PROPORTION OF EXFOLIATED PROXIMAL TUBULAR CELLS DUE TO INJURY, CORRELATED WELL WITH EACH OTHER. METHYLATION LEVELS OF SMTNL2 IN URINE SEDIMENT SIGNIFICANTLY CORRELATED WITH THE ANNUAL DECLINE IN ESTIMATED GLOMERULAR FILTRATION RATE. MOREOVER, ADDITION OF URINARY SMTNL2 METHYLATION TO A MODEL CONTAINING KNOWN RISK FACTORS SIGNIFICANTLY IMPROVED DISCRIMINATION OF PATIENTS WITH DIABETES WITH FASTER ESTIMATED GLOMERULAR FILTRATION RATE DECLINE. CONCLUSIONS: THIS STUDY DEMONSTRATES THAT PATIENTS WITH DIABETES WITH CONTINUAL LOSS IN KIDNEY FUNCTION MAY BE STRATIFIED BY A SPECIFIC DNA METHYLATION SIGNATURE THROUGH EPIGENETIC URINALYSIS AND PROVIDES FURTHER EVIDENCE AT THE LEVEL OF EXFOLIATED CELLS IN THE URINE THAT INJURY OF PROXIMAL TUBULAR CELLS MAY CONTRIBUTE TO PATHOGENESIS OF DIABETIC KIDNEY DISEASE.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
11 3914  25 LIFETIME STRESS ACCELERATES EPIGENETIC AGING IN AN URBAN, AFRICAN AMERICAN COHORT: RELEVANCE OF GLUCOCORTICOID SIGNALING. BACKGROUND: CHRONIC PSYCHOLOGICAL STRESS IS ASSOCIATED WITH ACCELERATED AGING AND INCREASED RISK FOR AGING-RELATED DISEASES, BUT THE UNDERLYING MOLECULAR MECHANISMS ARE UNCLEAR. RESULTS: WE EXAMINED THE EFFECT OF LIFETIME STRESSORS ON A DNA METHYLATION-BASED AGE PREDICTOR, EPIGENETIC CLOCK. AFTER CONTROLLING FOR BLOOD CELL-TYPE COMPOSITION AND LIFESTYLE PARAMETERS, CUMULATIVE LIFETIME STRESS, BUT NOT CHILDHOOD MALTREATMENT OR CURRENT STRESS ALONE, PREDICTED ACCELERATED EPIGENETIC AGING IN AN URBAN, AFRICAN AMERICAN COHORT (N = 392). THIS EFFECT WAS PRIMARILY DRIVEN BY PERSONAL LIFE STRESSORS, WAS MORE PRONOUNCED WITH ADVANCING AGE, AND WAS BLUNTED IN INDIVIDUALS WITH HIGHER CHILDHOOD ABUSE EXPOSURE. HYPOTHESIZING THAT THESE EPIGENETIC EFFECTS COULD BE MEDIATED BY GLUCOCORTICOID SIGNALING, WE FOUND THAT A HIGH NUMBER (N = 85) OF EPIGENETIC CLOCK CPG SITES WERE LOCATED WITHIN GLUCOCORTICOID RESPONSE ELEMENTS. WE FURTHER EXAMINED THE FUNCTIONAL EFFECTS OF GLUCOCORTICOIDS ON EPIGENETIC CLOCK CPGS IN AN INDEPENDENT SAMPLE WITH GENOME-WIDE DNA METHYLATION (N = 124) AND GENE EXPRESSION DATA (N = 297) BEFORE AND AFTER EXPOSURE TO THE GLUCOCORTICOID RECEPTOR AGONIST DEXAMETHASONE. DEXAMETHASONE INDUCED DYNAMIC CHANGES IN METHYLATION IN 31.2 % (110/353) OF THESE CPGS AND TRANSCRIPTION IN 81.7 % (139/170) OF GENES NEIGHBORING EPIGENETIC CLOCK CPGS. DISEASE ENRICHMENT ANALYSIS OF THESE DEXAMETHASONE-REGULATED GENES SHOWED ENRICHED ASSOCIATION FOR AGING-RELATED DISEASES, INCLUDING CORONARY ARTERY DISEASE, ARTERIOSCLEROSIS, AND LEUKEMIAS. CONCLUSIONS: CUMULATIVE LIFETIME STRESS MAY ACCELERATE EPIGENETIC AGING, AN EFFECT THAT COULD BE DRIVEN BY GLUCOCORTICOID-INDUCED EPIGENETIC CHANGES. THESE FINDINGS CONTRIBUTE TO OUR UNDERSTANDING OF MECHANISMS LINKING CHRONIC STRESS WITH ACCELERATED AGING AND HEIGHTENED DISEASE RISK.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
12  274  21 AGE-RELATED CHANGES IN DNA METHYLATION AFFECT RENAL HISTOLOGY AND POST-TRANSPLANT FIBROSIS. DURING AGEING, KIDNEY FUNCTION DECREASES DUE TO RENAL TUBULAR ATROPHY, INTERSTITIAL FIBROSIS, GLOMERULOSCLEROSIS AND ARTERIOSCLEROSIS. RECENTLY, CHANGES IN DNA METHYLATION WERE SHOWN TO CONTRIBUTE TO VARIOUS AGEING PROCESSES. HOWEVER, IT IS UNKNOWN WHETHER SUCH CHANGES ALSO CONTRIBUTE TO AGE-RELATED KIDNEY DYSFUNCTION. TO ASSESS THIS, WE PROFILED GENOME-WIDE CHANGES IN DNA METHYLATION (OVER 800 000 CPG SITES) IN 95 RENAL BIOPSIES OBTAINED PRIOR TO KIDNEY TRANSPLANTATION FROM DONORS AGED 16 TO 73 YEARS. DONOR AGE SIGNIFICANTLY ASSOCIATED WITH THE METHYLATION OF 92 778 CPGS (FALSE DISCOVERY RATE UNDER 0.05), CORRESPONDING TO 10 285 DIFFERENTIALLY METHYLATED REGIONS. THESE REGIONS WERE MOST FREQUENTLY LOCATED IN GENES INVOLVED IN THE WNT/BETA-CATENIN SIGNALING PATHWAY. USING AN INDEPENDENT COHORT OF 67 BIOPSIES, WE AUTONOMOUSLY VALIDATED THESE FINDINGS. INTERESTINGLY, THE METHYLATION STATUS OF THESE 92 778 AGE-RELATED CPGS WAS ASSOCIATED WITH GLOMERULOSCLEROSIS (34.4% OF CPGS AT A FALSE DISCOVERY RATE UNDER 0.05) AND INTERSTITIAL FIBROSIS (0.9%) AND GRAFT FUNCTION AT ONE YEAR AFTER TRANSPLANTATION, BUT NOT WITH TUBULAR ATROPHY AND ARTERIOSCLEROSIS. NO ASSOCIATION WAS OBSERVED WITH ANY OF THESE PATHOLOGIES AT THE TIME OF TRANSPLANTATION (0% AT A FALSE DISCOVERY RATE UNDER 0.05). THUS, AGE-ASSOCIATED CHANGES IN DNA METHYLATION AT THE TIME OF TRANSPLANTATION PREDICT FUTURE INJURY OF TRANSPLANTED KIDNEYS. SPECIFICALLY, OUR EPIGENOME-WIDE ASSOCIATION STUDY DEMONSTRATES THAT EPIGENETIC RENAL AGEING IS IMPLICATED IN PROGRESSIVE FIBROSIS IN BOTH THE GLOMERULUS AND THE INTERSTITIUM.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
13 1579  24 DNA METHYLATION PROFILE OF LIVER OF MICE CONCEIVED BY IN VITRO FERTILIZATION. OFFSPRING GENERATED BY IN VITRO FERTILIZATION (IVF) ARE BELIEVED TO BE HEALTHY BUT DISPLAY A POSSIBLE PREDISPOSITION TO CHRONIC DISEASES, LIKE HYPERTENSION AND GLUCOSE INTOLERANCE. SINCE EPIGENETIC CHANGES ARE BELIEVED TO UNDERLIE SUCH PHENOTYPE, THIS STUDY AIMED AT DESCRIBING GLOBAL DNA METHYLATION CHANGES IN THE LIVER OF ADULT MICE GENERATED BY NATURAL MATING (FB GROUP) OR BY IVF. EMBRYOS WERE GENERATED BY IVF OR NATURAL MATING. AT 30 WEEKS OF AGE, MICE WERE SACRIFICED. THE LIVER WAS REMOVED, AND GLOBAL DNA METHYLATION WAS ASSESSED USING WHOLE-GENOME BISULFITE SEQUENCING (WGBS). GENOMIC REGIONS FOR ENRICHMENT ANALYSIS TOOL (GREAT) AND G:PROFILERBETA WERE USED TO IDENTIFY DIFFERENTIALLY METHYLATED REGIONS (DMRS) AND FOR FUNCTIONAL ENRICHMENT ANALYSIS. OVERREPRESENTED GENE ONTOLOGY TERMS WERE SUMMARIZED WITH REVIGO, WHILE CANONICAL PATHWAYS (CPS) WERE IDENTIFIED WITH INGENUITY(R) PATHWAY ANALYSIS. OVERALL, 2692 DMRS (4.91%) WERE DIFFERENT BETWEEN THE GROUPS. THE MAJORITY OF DMRS (84.92%) WERE HYPOMETHYLATED IN THE IVF GROUP. SURPRISINGLY, ONLY 0.16% OF CPG ISLANDS WERE DIFFERENTIALLY METHYLATED AND ONLY A FEW DMRS WERE LOCATED ON KNOWN GENE PROMOTERS (N = 283) OR ENHANCERS (N = 190). NOTABLY, THE LONG-INTERSPERSED ELEMENT (LINE), SHORT-INTERSPERSED ELEMENT (SINE), AND LONG TERMINAL REPEAT (LTR1) TRANSPOSABLE ELEMENTS SHOWED REDUCED METHYLATION (P < 0.05) IN IVF LIVERS. CELLULAR METABOLIC PROCESS, HEPATIC FIBROSIS, AND INSULIN RECEPTOR SIGNALING WERE SOME OF THE PRINCIPAL BIOLOGICAL PROCESSES AND CPS MODIFIED BY IVF. IN SUMMARY, IVF MODIFIES THE DNA METHYLATION SIGNATURE IN THE ADULT LIVER, RESULTING IN HYPOMETHYLATION OF GENES INVOLVED IN METABOLISM AND GENE TRANSCRIPTION REGULATION. THESE FINDINGS MAY SHED LIGHT ON THE MECHANISMS UNDERLYING THE DEVELOPMENTAL ORIGIN OF HEALTH AND DISEASE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
14 1295  24 DECREASED GLOBAL DNA METHYLATION IN THE WHITE BLOOD CELLS OF HIGH FAT DIET FED VERVET MONKEYS (CHLOROCEBUS AETHIOPS). EPIGENETIC MECHANISMS ARE ASSOCIATED WITH THE DEVELOPMENT OF MANY CHRONIC DISEASES AND DUE TO THEIR REVERSIBLE NATURE OFFER A UNIQUE WINDOW OF OPPORTUNITY TO REVERSE THE DISEASE PHENOTYPE. THIS STUDY INVESTIGATED WHETHER GLOBAL DNA METHYLATION CORRELATES WITH DYSGLYCEMIA IN THE VERVET MONKEY (CHLOROCEBUS AETHIOPS). DIET-INDUCED CHANGES IN DNA METHYLATION WERE OBSERVED WHERE GLOBAL DNA METHYLATION WAS TWOFOLD LOWER IN MONKEYS FED A HIGH FAT DIET (N = 10) COMPARED TO MONKEYS FED A STANDARD DIET (N = 15). AN INVERSE CORRELATION WAS OBSERVED BETWEEN DNA METHYLATION, BLOOD GLUCOSE CONCENTRATIONS, BODYWEIGHT, AND AGE, ALTHOUGH THE ASSOCIATION WAS NOT STATISTICALLY SIGNIFICANT. CONSUMPTION OF A HIGH FAT DIET IS ASSOCIATED WITH THE DEVELOPMENT OF METABOLIC DISEASE; THUS, THESE RESULTS SUGGEST THE USE OF GLOBAL DNA METHYLATION AS A BIOMARKER TO ASSESS THE RISK FOR METABOLIC DISEASE. MOREOVER, THIS STUDY PROVIDES FURTHER SUPPORT FOR THE USE OF THE VERVET MONKEY AS A MODEL SYSTEM TO STUDY METABOLIC DISEASES SUCH AS TYPE 2 DIABETES. INTEGRATION OF ALTERED DNA METHYLATION PROFILES INTO PREDICTIVE MODELS COULD FACILITATE RISK STRATIFICATION AND ENABLE INTERVENTION STRATEGIES TO INHIBIT DISEASE PROGRESSION. SUCH INTERVENTIONS COULD INCLUDE LIFESTYLE MODIFICATIONS, FOR EXAMPLE, THE INCREASED CONSUMPTION OF FUNCTIONAL FOODS WITH THE CAPACITY TO MODULATE DNA METHYLATION, THUS POTENTIALLY REVERSING THE DISEASE PHENOTYPE AND PREVENTING DISEASE.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
15 1567  28 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
16 6080  29 THE EFFECT OF DNA METHYLATION IN THE DEVELOPMENT AND PROGRESSION OF CHRONIC KIDNEY DISEASE IN THE GENERAL POPULATION: AN EPIGENOME-WIDE ASSOCIATION STUDY USING THE KOREAN GENOME AND EPIDEMIOLOGY STUDY DATABASE. BACKGROUND: ALTHOUGH KNOWLEDGE OF THE GENETIC FACTORS INFLUENCING KIDNEY DISEASE IS INCREASING, EPIGENETIC PROFILES, WHICH ARE ASSOCIATED WITH CHRONIC KIDNEY DISEASE (CKD), HAVE NOT BEEN FULLY ELUCIDATED. WE SOUGHT TO IDENTIFY THE DNA METHYLATION STATUS OF CPG SITES ASSOCIATED WITH REDUCED KIDNEY FUNCTION AND EXAMINE WHETHER THE IDENTIFIED CPG SITES ARE ASSOCIATED WITH CKD DEVELOPMENT. METHOD: WE ANALYZED DNA METHYLATION PATTERNS OF 440 PARTICIPANTS IN THE KOREAN GENOME AND EPIDEMIOLOGY STUDY (KOGES) WITH ESTIMATED GLOMERULAR FILTRATION RATES (EGFRS) >/= 60 ML/MIN/1.73 M(2) AT BASELINE. CKD DEVELOPMENT WAS DEFINED AS A DECREASE IN THE EGFR OF <60 AT ANY TIME DURING AN 8-YEAR FOLLOW-UP PERIOD ("CKD PREDICTION" ANALYSIS). IN ADDITION, AMONG THE 440 PARTICIPANTS, 49 PARTICIPANTS WHO UNDERWENT A SECOND METHYLATION PROFILING WERE ASSESSED FOR AN ASSOCIATION BETWEEN A DECLINE IN KIDNEY FUNCTION AND CHANGES IN THE DEGREE OF METHYLATION OF CPG SITES DURING THE 8 YEARS ("KIDNEY FUNCTION SLOPE" ANALYSIS). RESULTS: IN THE CKD PREDICTION ANALYSIS, METHYLATION PROFILES OF A TOTAL OF 403,129 CPG SITES WERE EVALUATED AT BASELINE IN 440 PARTICIPANTS, AND INCREASED AND DECREASED METHYLATION OF 268 AND 189 CPG SITES, RESPECTIVELY, WERE SIGNIFICANTLY CORRELATED WITH THE DEVELOPMENT OF CKD IN MULTIVARIABLE LOGISTIC REGRESSION. DURING KIDNEY FUNCTION SLOPE ANALYSIS USING FOLLOW-UP METHYLATION PROFILES OF 49 PARTICIPANTS, THE PERCENT METHYLATION CHANGES IN 913 CPG SITES SHOWED A LINEAR RELATIONSHIP WITH THE PERCENT CHANGE IN EGFR DURING 8 YEARS. DURING FUNCTIONAL ENRICHMENT ANALYSES FOR SIGNIFICANT CPG SITES FOUND IN THE CKD PREDICTION AND KIDNEY FUNCTION SLOPE ANALYSES, WE FOUND THAT THOSE CPG SITES REPRESENTED MAPK, PI3K/AKT, AND RAP1 PATHWAYS. IN ADDITION, THREE CPG SITES FROM THREE GENES, NPHS2, CHCHD4, AND AHR, WERE FOUND TO BE SIGNIFICANT IN THE CKD PREDICTION ANALYSIS AND RELATED TO A DECLINE IN KIDNEY FUNCTION. CONCLUSION: IT IS SUGGESTED THAT DNA METHYLATION ON SPECIFIC GENES IS ASSOCIATED WITH THE DEVELOPMENT OF CKD AND THE DETERIORATION OF KIDNEY FUNCTION.	2023	
                                                                                                                                                                                                                                                                                     
17 1841  19 EFFECTS OF SHORT CHAIN FATTY ACID PRODUCING BACTERIA ON EPIGENETIC REGULATION OF FFAR3 IN TYPE 2 DIABETES AND OBESITY. THE HUMAN GUT MICROBIOTA AND MICROBIAL INFLUENCES ON LIPID AND GLUCOSE METABOLISM, SATIETY, AND CHRONIC LOW-GRADE INFLAMMATION ARE KNOWN TO BE INVOLVED IN METABOLIC SYNDROME. FERMENTATION END PRODUCTS, ESPECIALLY SHORT CHAIN FATTY ACIDS, ARE BELIEVED TO ENGAGE THE EPIGENETIC REGULATION OF INFLAMMATORY REACTIONS VIA FFARS (FREE FATTY ACID RECEPTOR) AND OTHER SHORT CHAIN FATTY ACID RECEPTORS. WE STUDIED A POTENTIAL INTERACTION OF THE MICROBIOTA WITH EPIGENETIC REGULATION IN OBESE AND TYPE 2 DIABETES PATIENTS COMPARED TO A LEAN CONTROL GROUP OVER A FOUR MONTH INTERVENTION PERIOD. INTERVENTION COMPRISED A GLP-1 AGONIST (GLUCAGON-LIKE PEPTIDE 1) FOR TYPE 2 DIABETICS AND NUTRITIONAL COUNSELING FOR BOTH INTERVENTION GROUPS. MICROBIOTA WAS ANALYZED FOR ABUNDANCE, BUTYRYL-COA:ACETATE COA-TRANSFERASE GENE AND FOR DIVERSITY BY POLYMERASE CHAIN REACTION AND 454 HIGH-THROUGHPUT SEQUENCING. EPIGENETIC METHYLATION OF THE PROMOTER REGION OF FFAR3 AND LINE1 (LONG INTERSPERSED NUCLEAR ELEMENT 1) WAS ANALYZED USING BISULFITE CONVERSION AND PYROSEQUENCING. THE DIVERSITY OF THE MICROBIOTA AS WELL AS THE ABUNDANCE OF FAECALIBACTERIUM PRAUSNITZII WERE SIGNIFICANTLY LOWER IN OBESE AND TYPE 2 DIABETIC PATIENTS COMPARED TO LEAN INDIVIDUALS. RESULTS FROM CLOSTRIDIUM CLUSTER IV AND CLOSTRIDIUM CLUSTER XIVA SHOWED A DECREASING TREND IN TYPE 2 DIABETICS IN COMPARISON TO THE BUTYRYL-COA:ACETATE COA-TRANSFERASE GENE AND ACCORDING TO MELT CURVE ANALYSIS. DURING INTERVENTION NO SIGNIFICANT CHANGES WERE OBSERVED IN EITHER INTERVENTION GROUP. THE ANALYSIS OF FIVE CPGS IN THE PROMOTER REGION OF FFAR3 SHOWED A SIGNIFICANT LOWER METHYLATION IN OBESE AND TYPE 2 DIABETICS WITH AN INCREASE IN OBESE PATIENTS OVER THE INTERVENTION PERIOD. THESE RESULTS DISCLOSED A SIGNIFICANT CORRELATION BETWEEN A HIGHER BODY MASS INDEX AND LOWER METHYLATION OF FFAR3. LINE-1, A MARKER OF GLOBAL METHYLATION, INDICATED NO SIGNIFICANT DIFFERENCES BETWEEN THE THREE GROUPS OR THE TIME POINTS, ALTHOUGH METHYLATION OF TYPE 2 DIABETICS TENDED TO INCREASE OVER TIME. OUR RESULTS PROVIDE EVIDENCE THAT A DIFFERENT COMPOSITION OF GUT MICROBIOTA IN OBESITY AND TYPE 2 DIABETES AFFECT THE EPIGENETIC REGULATION OF GENES. INTERACTIONS BETWEEN THE MICROBIOTA AND EPIGENETIC REGULATION MAY INVOLVE NOT ONLY SHORT CHAIN FATTY ACIDS BINDING TO FFARS. THEREFORE DIETARY INTERVENTIONS INFLUENCING MICROBIAL COMPOSITION MAY BE CONSIDERED AS AN OPTION IN THE ENGAGEMENT AGAINST METABOLIC SYNDROME.	2014	

18 1503  25 DNA METHYLATION AND GENE EXPRESSION DIFFERENCES IN CHILDREN CONCEIVED IN VITRO OR IN VIVO. EPIDEMIOLOGICAL DATA INDICATE THAT CHILDREN CONCEIVED IN VITRO HAVE A GREATER RELATIVE RISK OF LOW BIRTH-WEIGHT, MAJOR AND MINOR BIRTH DEFECTS, AND RARE DISORDERS INVOLVING IMPRINTED GENES, SUGGESTING THAT EPIGENETIC CHANGES MAY BE ASSOCIATED WITH ASSISTED REPRODUCTION. WE EXAMINED DNA METHYLATION AT MORE THAN 700 GENES (1536 CPG SITES) IN PLACENTA AND CORD BLOOD AND MEASURED GENE EXPRESSION LEVELS OF A SUBSET OF GENES THAT DIFFERED IN METHYLATION LEVELS BETWEEN CHILDREN CONCEIVED IN VITRO VERSUS IN VIVO. OUR RESULTS SUGGEST THAT IN VITRO CONCEPTION IS ASSOCIATED WITH LOWER MEAN METHYLATION AT CPG SITES IN PLACENTA AND HIGHER MEAN METHYLATION AT CPG SITES IN CORD BLOOD. WE ALSO FIND THAT IN VITRO CONCEPTION-ASSOCIATED DNA METHYLATION DIFFERENCES ARE ASSOCIATED WITH GENE EXPRESSION DIFFERENCES AT BOTH IMPRINTED AND NON-IMPRINTED GENES. THE RANGE OF INTER-INDIVIDUAL VARIATION IN GENE EXPRESSION OF THE IN VITRO AND IN VIVO GROUPS OVERLAPS SUBSTANTIALLY BUT SOME INDIVIDUALS FROM THE IN VITRO GROUP DIFFER FROM THE IN VIVO GROUP MEAN BY MORE THAN TWO STANDARD DEVIATIONS. SEVERAL OF THE GENES WHOSE EXPRESSION DIFFERS BETWEEN THE TWO GROUPS HAVE BEEN IMPLICATED IN CHRONIC METABOLIC DISORDERS, SUCH AS OBESITY AND TYPE II DIABETES. THESE FINDINGS SUGGEST THAT THERE MAY BE EPIGENETIC DIFFERENCES IN THE GAMETES OR EARLY EMBRYOS DERIVED FROM COUPLES UNDERGOING TREATMENT FOR INFERTILITY. ALTERNATIVELY, ASSISTED REPRODUCTION TECHNOLOGY MAY HAVE AN EFFECT ON GLOBAL PATTERNS OF DNA METHYLATION AND GENE EXPRESSION. IN EITHER CASE, THESE DIFFERENCES OR CHANGES MAY AFFECT LONG-TERM PATTERNS OF GENE EXPRESSION.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
19 2997  22 GENETIC VARIANTS IN DNMT1 AND THE RISK OF CARDIAC AUTONOMIC NEUROPATHY IN WOMEN WITH TYPE 1 DIABETES. AIMS/INTRODUCTION: EPIGENETICS PARTICIPATE IN THE PATHOGENESIS OF METABOLIC MEMORY, A SITUATION IN WHICH HYPERGLYCEMIA EXERTS PROLONGED DELETERIOUS EFFECTS EVEN AFTER ITS NORMALIZATION. WE TESTED THE HYPOTHESIS THAT GENETIC VARIANTS IN AN EPIGENETIC GENE COULD PREDISPOSE TO DIABETES COMPLICATIONS. MATERIAL AND METHODS: WE ASSESSED THE FREQUENCY OF FIVE SINGLE-NUCLEOTIDE POLYMORPHISMS IN THE GENE ENCODING DEOXYRIBONUCLEIC ACID METHYTRANSFERASE 1 (DNMT1; RS8112895, RS7254567, RS11085721, RS17291414 AND RS10854076), AND THEIR ASSOCIATIONS WITH DIABETIC KIDNEY DISEASE, RETINOPATHY, DISTAL POLYNEUROPATHY AND AUTONOMIC CARDIOVASCULAR NEUROPATHY IN 359 INDIVIDUALS WITH LONG-TERM TYPE 1 DIABETES. RESULTS: NONE OF THE SINGLE-NUCLEOTIDE POLYMORPHISMS STUDIED WAS SIGNIFICANTLY ASSOCIATED WITH THE PRESENCE OF CHRONIC COMPLICATIONS IN THE OVERALL POPULATION. HOWEVER, AFTER SEX STRATIFICATION, THE MINOR ALLELE C OF RS11085721 CONFERRED RISK FOR CARDIOVASCULAR NEUROPATHY IN WOMEN AFTER ADJUSTMENT FOR CONFOUNDING VARIABLES (ODDS RATIO 2.32; 95% CONFIDENCE INTERVAL 1.26-4.33; P = 0.006). CONCLUSIONS: THE FACT THAT HETEROZYGOUS MUTATIONS IN DNMT1 ARE ASSOCIATED WITH HEREDITARY SENSORY AUTONOMIC NEUROPATHY PROVIDES PLAUSIBILITY TO THE PRESENT FINDING. IF CONFIRMED IN INDEPENDENT SAMPLES, IT SUGGESTS THAT GENETIC VARIANTS IN EPIGENETIC GENES MIGHT PREDISPOSE TO MORE OR FEWER EPIGENETIC CHANGES IN THE FACE OF SIMILAR METABOLIC DERANGEMENTS TRIGGERED BY HYPERGLYCEMIA, CONSTITUTING THE "GENETICS OF EPIGENETICS" FOR MICROVASCULAR DIABETES COMPLICATIONS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
20 3652  27 INDIVIDUAL DNA METHYLATION PATTERN SHIFTS IN NANOPARTICLES-EXPOSED WORKERS ANALYZED IN FOUR CONSECUTIVE YEARS. A DNA METHYLATION PATTERN REPRESENTS AN ORIGINAL PLAN OF THE FUNCTION SETTINGS OF INDIVIDUAL CELLS AND TISSUES. THE BASIC STRATEGIES OF ITS DEVELOPMENT AND CHANGES DURING THE HUMAN LIFETIME ARE KNOWN, BUT THE DETAILS RELATED TO ITS MODIFICATION OVER THE YEARS ON AN INDIVIDUAL BASIS HAVE NOT YET BEEN STUDIED. MOREOVER, CURRENT EVIDENCE SHOWS THAT ENVIRONMENTAL EXPOSURE COULD GENERATE CHANGES IN DNA METHYLATION SETTINGS AND, SUBSEQUENTLY, THE FUNCTION OF GENES. IN THIS STUDY, WE ANALYZED THE EFFECT OF CHRONIC EXPOSURE TO NANOPARTICLES (NP) IN OCCUPATIONALLY EXPOSED WORKERS REPEATEDLY SAMPLED IN FOUR CONSECUTIVE YEARS (2016-2019). A DETAILED METHYLATION PATTERN ANALYSIS OF 14 PERSONS (10 EXPOSED AND 4 CONTROLS) WAS PERFORMED ON AN INDIVIDUAL BASIS. A MICROARRAY-BASED APPROACH USING CHIPS, ALLOWING THE ASSESSMENT OF MORE THAN 850 K CPG LOCI, WAS USED. INDIVIDUAL DNA METHYLATION PATTERNS WERE COMPARED BY PRINCIPAL COMPONENT ANALYSIS (PCA). THE RESULTS SHOW THE SHIFT IN DNA METHYLATION PATTERNS IN INDIVIDUAL YEARS IN ALL THE EXPOSED AND CONTROL SUBJECTS. THE OVERALL RANGE OF DIFFERENCES VARIED BETWEEN THE YEARS IN INDIVIDUAL PERSONS. THE DIFFERENCES BETWEEN THE FIRST AND LAST YEAR OF EXAMINATION (A THREE-YEAR TIME PERIOD) SEEM TO BE CONSISTENTLY GREATER IN THE NP-EXPOSED SUBJECTS IN COMPARISON WITH THE CONTROLS. THE SELECTED 14 MOST DIFFERENTLY METHYLATED CG LOCI WERE RELATIVELY STABLE IN THE CHRONICALLY EXPOSED SUBJECTS. IN SUMMARY, THE SPECIFIC TYPE OF LONG-TERM EXPOSURE CAN CONTRIBUTE TO THE FIXING OF RELEVANT EPIGENETIC CHANGES RELATED TO A SPECIFIC ENVIRONMENT AS, E.G., NP INHALATION.	2021