1 3451 110 HYPERMETHYLATIONS OF RASAL1 AND KLOTHO IS ASSOCIATED WITH RENAL DYSFUNCTION IN A CHINESE POPULATION ENVIRONMENTALLY EXPOSED TO CADMIUM. EXPOSURE TO CADMIUM (CD) CAN AFFECT BOTH DNA METHYLATION AND RENAL FUNCTION, BUT THERE ARE FEW EXAMPLES OF THE ASSOCIATION BETWEEN EPIGENETIC MARKERS AND CD-INDUCED KIDNEY DAMAGE. IT HAS BEEN SUGGESTED THAT HYPERMETHYLATION OF THE GENES RASAL1 AND KLOTHO IS ASSOCIATED WITH RENAL FIBROGENESIS. TO INVESTIGATE WHETHER HYPERMETHYLATION OF RASAL1 AND KLOTHO IN PERIPHERAL BLOOD DNA CAN BE ASSOCIATED WITH CD EXPOSURE AND/OR CD-INDUCED RENAL DYSFUNCTION, THE DEGREES OF METHYLATION OF RASAL1 AND KLOTHO IN PERIPHERAL BLOOD DNA FROM 81 RESIDENTS IN CD-POLLUTED AND NON-POLLUTED AREAS WERE MEASURED USING BISULFATE-PCR-PYROSEQUENCING. CHANGES IN BLOOD CADMIUM (BCD), URINARY CADMIUM (UCD), AND KIDNEY PARAMETERS WERE MEASURED, AND THE GLOMERULAR FILTRATION RATE (EGFR) WAS ESTIMATED. THE LEVELS OF BCD AND UCD CORRELATED POSITIVELY WITH THE LEVELS OF DNA METHYLATION IN RASAL1 AND IN KLOTHO. THE MORE HEAVILY EXPOSED RESIDENTS (BCD, 4.23-13.22MUG/L; UCD, 8.65-32.90MUG/G CREATININE) EXHIBITED OBVIOUS RENAL DYSFUNCTION. NOTABLY, WHEN CD CONCENTRATION IN BLOOD AND URINE WAS ADJUSTED, THE INCREASED METHYLATION LEVEL IN RASAL1 WAS INVERSELY CORRELATED WITH EGFR (P<0.01) BUT THE RELATIONSHIP BETWEEN HYPERMETHYLATION OF KLOTHO AND EGFR WAS NOT STATISTICALLY SIGNIFICANT. THE METHYLATION OF RASAL1 INCREASED ALONG WITH THE INCREASED ABNORMAL PREVALENCE OF EGFR. OUR FINDINGS SUGGEST THAT CD EXPOSURE CAN INDUCE THE HYPERMETHYLATION OF RASAL1 AND KLOTHO. HYPERMETHYLATION OF RASAL1 MAY BE AN INDICATOR OF THE PROGRESS FOR CHRONIC KIDNEY DISEASE.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
2 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
3 2629  34 EPIGENOME-WIDE ASSOCIATION STUDY OF DIABETIC CHRONIC KIDNEY DISEASE PROGRESSION IN THE KOREAN POPULATION: THE KNOW-CKD STUDY. SINCE THE ETIOLOGY OF DIABETIC CHRONIC KIDNEY DISEASE (CKD) IS MULTIFACTORIAL, STUDIES ON DNA METHYLATION FOR KIDNEY FUNCTION DETERIORATION HAVE RARELY BEEN PERFORMED DESPITE THE NEED FOR AN EPIGENETIC APPROACH. THEREFORE, THIS STUDY AIMED TO IDENTIFY EPIGENETIC MARKERS ASSOCIATED WITH CKD PROGRESSION BASED ON THE DECLINE IN THE ESTIMATED GLOMERULAR FILTRATION RATE IN DIABETIC CKD IN KOREA. AN EPIGENOME-WIDE ASSOCIATION STUDY WAS PERFORMED USING WHOLE BLOOD SAMPLES FROM 180 CKD RECRUITED FROM THE KNOW-CKD COHORT. PYROSEQUENCING WAS ALSO PERFORMED ON 133 CKD PARTICIPANTS AS AN EXTERNAL REPLICATION ANALYSIS. FUNCTIONAL ANALYSES, INCLUDING THE ANALYSIS OF DISEASE-GENE NETWORKS, REACTOME PATHWAYS, AND PROTEIN-PROTEIN INTERACTION NETWORKS, WERE CONDUCTED TO IDENTIFY THE BIOLOGICAL MECHANISMS OF CPG SITES. A PHENOME-WIDE ASSOCIATION STUDY WAS PERFORMED TO DETERMINE THE ASSOCIATIONS BETWEEN CPG SITES AND OTHER PHENOTYPES. TWO EPIGENETIC MARKERS, CG10297223 ON AGTR1 AND CG02990553 ON KRT28 INDICATED A POTENTIAL ASSOCIATION WITH DIABETIC CKD PROGRESSION. BASED ON THE FUNCTIONAL ANALYSES, OTHER PHENOTYPES (BLOOD PRESSURE AND CARDIAC ARRHYTHMIA FOR AGTR1) AND BIOLOGICAL PATHWAYS (KERATINIZATION AND CORNIFIED ENVELOPE FOR KRT28) RELATED TO CKD WERE ALSO IDENTIFIED. THIS STUDY SUGGESTS A POTENTIAL ASSOCIATION BETWEEN THE CG10297223 AND CG02990553 AND THE PROGRESSION OF DIABETIC CKD IN KOREANS. NEVERTHELESS, FURTHER VALIDATION IS NEEDED THROUGH ADDITIONAL STUDIES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
4 3663  23 INDUCTION OF TET3-DEPENDENT EPIGENETIC REMODELING BY LOW-DOSE HYDRALAZINE ATTENUATES PROGRESSION OF CHRONIC KIDNEY DISEASE. PROGRESSION OF CHRONIC KIDNEY DISEASE REMAINS A PRINCIPAL PROBLEM IN CLINICAL NEPHROLOGY AND THERE IS A PRESSING NEED FOR NOVEL THERAPEUTICS AND BIOMARKERS. ABERRANT PROMOTER CPG ISLAND METHYLATION AND SUBSEQUENT TRANSCRIPTIONAL SILENCING OF SPECIFIC GENES HAVE EMERGED AS CONTRIBUTORS TO PROGRESSION OF CHRONIC KIDNEY DISEASE. HERE, WE REPORT THAT TRANSCRIPTIONAL SILENCING OF THE RAS-GTP SUPPRESSOR RASAL1 CONTRIBUTES CAUSALLY TO PROGRESSION OF KIDNEY FIBROSIS AND WE IDENTIFIED THAT CIRCULATING METHYLATED RASAL1 PROMOTER DNA FRAGMENTS IN PERIPHERAL BLOOD CORRESPOND WITH LEVELS OF INTRARENAL LEVELS OF RASAL1 PROMOTER METHYLATION AND DEGREE OF FIBROSIS IN KIDNEY BIOPSIES, ENABLING NON-INVASIVE LONGITUDINAL ANALYSIS OF INTRARENAL CPG ISLAND METHYLATION.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
5 3468  37 HYPOXIA-INDUCED DNA HYPERMETHYLATION IN HUMAN PULMONARY FIBROBLASTS IS ASSOCIATED WITH THY-1 PROMOTER METHYLATION AND THE DEVELOPMENT OF A PRO-FIBROTIC PHENOTYPE. BACKGROUND: PULMONARY FIBROSIS IS A DEBILITATING AND LETHAL DISEASE WITH NO EFFECTIVE TREATMENT OPTIONS. UNDERSTANDING THE PATHOLOGICAL PROCESSES AT PLAY WILL DIRECT THE APPLICATION OF NOVEL THERAPEUTIC AVENUES. HYPOXIA HAS BEEN IMPLICATED IN THE PATHOGENESIS OF PULMONARY FIBROSIS YET THE PRECISE MECHANISM BY WHICH IT CONTRIBUTES TO DISEASE PROGRESSION REMAINS TO BE FULLY ELUCIDATED. IT HAS BEEN SHOWN THAT CHRONIC HYPOXIA CAN ALTER DNA METHYLATION PATTERNS IN TUMOUR-DERIVED CELL LINES. THIS EPIGENETIC ALTERATION CAN INDUCE CHANGES IN CELLULAR PHENOTYPE WITH PROMOTER METHYLATION BEING ASSOCIATED WITH GENE SILENCING. OF PARTICULAR RELEVANCE TO IDIOPATHIC PULMONARY FIBROSIS (IPF) IS THE OBSERVATION THAT THY-1 PROMOTER METHYLATION IS ASSOCIATED WITH A MYOFIBROBLAST PHENOTYPE WHERE LOSS OF THY-1 OCCURS ALONGSIDE INCREASED ALPHA SMOOTH MUSCLE ACTIN (ALPHA-SMA) EXPRESSION. THE INITIAL AIM OF THIS STUDY WAS TO DETERMINE WHETHER HYPOXIA REGULATES DNA METHYLATION IN NORMAL HUMAN LUNG FIBROBLASTS (CCD19LU). AS IT HAS BEEN REPORTED THAT HYPOXIA SUPPRESSES THY-1 EXPRESSION DURING LUNG DEVELOPMENT WE ALSO STUDIED THE EFFECT OF HYPOXIA ON THY-1 PROMOTER METHYLATION AND GENE EXPRESSION. METHODS: CCD19LU WERE GROWN FOR UP TO 8 DAYS IN HYPOXIA AND ASSESSED FOR GLOBAL CHANGES IN DNA METHYLATION USING FLOW CYTOMETRY. REAL-TIME PCR WAS USED TO QUANTIFY EXPRESSION OF THY-1, ALPHA-SMA, COLLAGEN I AND III. GENOMIC DNA WAS BISULPHITE TREATED AND METHYLATION SPECIFIC PCR (MSPCR) WAS USED TO EXAMINE THE METHYLATION STATUS OF THE THY-1 PROMOTER. RESULTS: SIGNIFICANT GLOBAL HYPERMETHYLATION WAS DETECTED IN HYPOXIC FIBROBLASTS RELATIVE TO NORMOXIC CONTROLS AND WAS ACCOMPANIED BY INCREASED EXPRESSION OF MYOFIBROBLAST MARKERS. THY-1 MRNA EXPRESSION WAS SUPPRESSED IN HYPOXIC CELLS, WHICH WAS RESTORED WITH THE DEMETHYLATING AGENT 5-AZA-2'-DEOXYCYTIDINE. MSPCR REVEALED THAT THY-1 BECAME METHYLATED FOLLOWING FIBROBLAST EXPOSURE TO 1% O2. CONCLUSION: THESE DATA SUGGEST THAT GLOBAL AND GENE-SPECIFIC CHANGES IN DNA METHYLATION MAY PLAY AN IMPORTANT ROLE IN FIBROBLAST FUNCTION IN HYPOXIA.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
6  658  30 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 1271  35 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
8  177  33 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
9 6080  43 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	
                                                                                                                                                                                                                                                                                                                                                                                                                           
10 3125  21 GHSR DNA HYPERMETHYLATION IS A COMMON EPIGENETIC ALTERATION OF HIGH DIAGNOSTIC VALUE IN A BROAD SPECTRUM OF CANCERS. IDENTIFICATION OF A SINGLE MOLECULAR TRAIT THAT IS DETERMINANT OF COMMON MALIGNANCIES MAY SERVE AS A POWERFUL DIAGNOSTIC SUPPLEMENT TO CANCER TYPE-SPECIFIC MARKERS. HERE, WE REPORT A DNA METHYLATION MARK THAT IS CHARACTERISTIC OF SEVEN STUDIED MALIGNANCIES, NAMELY CANCERS OF LUNG, BREAST, PROSTATE, PANCREAS, COLORECTUM, GLIOBLASTOMA AND B CELL CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) (N = 137). THIS MARK WAS DEFINED BY SUBSTANTIAL HYPERMETHYLATION AT THE PROMOTER AND FIRST EXON OF GROWTH HORMONE SECRETAGOUGE RECEPTOR (GHSR) THROUGH BISULFITE PYROSEQUENCING. THE DEGREE OF ABERRANT METHYLATION WAS CAPABLE OF ACCURATE DISCRIMINATION BETWEEN CANCER AND CONTROL SAMPLES. THE HIGHEST SENSITIVITY AND SPECIFICITY OF CANCER DETECTION WAS ACHIEVED FOR CANCERS OF PANCREAS, LUNG, BREAST AND CLL YIELDING THE AREA UNDER THE CURVE (AUC) VALUES OF 1.0000, 0.9952, 0.9800 AND 0.9400, RESPECTIVELY. NARROWING TO A SINGLE CPG SITE WITHIN THE GENE'S PROMOTER OR FOUR CONSECUTIVE CPG UNITS OF THE HIGHEST METHYLATION LEVELS WITHIN THE FIRST EXON IMPROVED THE DETECTION POWER. GHSR HYPERMETHYLATION WAS DETECTED ALREADY AT THE EARLY STAGE TUMORS. THE ACCURATE PERFORMANCE OF THIS MARKER WAS FURTHER REPLICATED IN AN INDEPENDENT SET OF PANCREATIC CANCER AND CONTROL SAMPLES (N = 78). THESE FINDINGS SUPPORT THE CANDIDATURE OF GHSR METHYLATION AS A HIGHLY ACCURATE PAN-CANCER MARKER.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
11  546  31 ATTENUATED EXPRESSION OF SLCO2A1 CAUSED BY DNA METHYLATION IN PEDIATRIC INFLAMMATORY BOWEL DISEASE. BACKGROUND: SLCO2A1 ENCODES A PROSTAGLANDIN (PG) TRANSPORTER, AND AUTOSOMAL RECESSIVE PATHOGENIC VARIANTS OF THIS GENE CAUSE CHRONIC ENTEROPATHY ASSOCIATED WITH SLCO2A1. IT IS UNCLEAR WHETHER A HETEROZYGOUS PATHOGENIC VARIANT OF SLCO2A1 HAS A ROLE IN THE PATHOGENESIS OF OTHER TYPES OF INFLAMMATORY BOWEL DISEASE (IBD). IN THIS STUDY, WE INVESTIGATED THE POSSIBLE INVOLVEMENT OF A LOCAL EPIGENETIC ALTERATION IN SLCO2A1 IN PATIENTS WITH A HETEROZYGOUS PATHOGENIC VARIANT. METHODS: WE CONDUCTED WHOLE-EXOME SEQUENCING OF SAMPLES FROM 2 SISTERS WITH SUSPECTED MONOGENIC IBD. IN ADDITION, WE PERFORMED BISULFITE SEQUENCING USING DNA EXTRACTED FROM THEIR SMALL AND LARGE INTESTINE SAMPLES TO EXPLORE EPIGENETIC ALTERATIONS. RESULTS: A HETEROZYGOUS SPLICING SITE VARIANT, SLCO2A1:C.940 + 1G > A, WAS DETECTED IN BOTH PATIENTS. TO EXPLORE THE POSSIBLE INVOLVEMENT OF EPIGENETIC ALTERATIONS, WE ANALYZED PROTEIN AND MESSENGER RNA EXPRESSION OF SLCO2A1, AND OBSERVED ATTENUATED SLCO2A1 EXPRESSION IN THE INFLAMED LESIONS OF THESE PATIENTS COMPARED WITH THAT IN THE CONTROL INDIVIDUALS. FURTHERMORE, BISULFITE SEQUENCING INDICATED DENSE METHYLATION IN THE PROMOTER REGION OF SLCO2A1 ONLY IN THE INFLAMED LESIONS OF BOTH PATIENTS. THE URINARY PG METABOLITE LEVELS IN THESE PATIENTS WERE COMPARABLE TO THOSE IN PATIENTS WITH CHRONIC ENTEROPATHY ASSOCIATED WITH SLCO2A1 AND HIGHER THAN THOSE IN THE CONTROL INDIVIDUALS. WE FOUND CONSIDERABLY HIGHER LEVELS OF THE METABOLITES IN PATIENT 1, WHO SHOWED MORE SEVERE SYMPTOMS THAN PATIENT 2. CONCLUSIONS: LOCAL DNA METHYLATION ATTENUATED SLCO2A1 EXPRESSION, WHICH MAY EVOKE LOCAL INFLAMMATION OF THE MUCOSA BY THE UNINCORPORATED PG. THESE FINDINGS MAY IMPROVE OUR UNDERSTANDING OF THE EPIGENETIC MECHANISMS UNDERLYING IBD DEVELOPMENT.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
12 3206  34 HDAC9 IS AN EPIGENETIC REPRESSOR OF KIDNEY ANGIOTENSINOGEN ESTABLISHING A SEX DIFFERENCE. BACKGROUND: SEXUAL DIFFERENCE HAS BEEN SHOWN IN THE PATHOGENESIS OF CHRONIC KIDNEY DISEASE INDUCED BY HYPERTENSION. FEMALES ARE PROTECTED FROM HYPERTENSION AND RELATED END-ORGAN DAMAGE. AUGMENTATION OF RENAL PROXIMAL TUBULAR ANGIOTENSINOGEN (AGT) EXPRESSION CAN PROMOTE INTRARENAL ANGIOTENSIN FORMATION AND THE DEVELOPMENT OF ASSOCIATED HYPERTENSION AND KIDNEY INJURY. FEMALE RODENTS EXHIBIT LOWER INTRARENAL AGT LEVELS THAN MALES UNDER NORMAL CONDITIONS, SUGGESTING THAT THE SUPPRESSED INTRARENAL AGT PRODUCTION BY PROGRAMMED MECHANISMS IN FEMALES MAY PROVIDE PROTECTION FROM THESE DISEASES. THIS STUDY WAS PERFORMED TO EXAMINE WHETHER EPIGENETIC MECHANISMS SERVE AS REPRESSORS OF AGT. METHODS: MALE AND FEMALE SPRAGUE DAWLEY RATS WERE USED TO INVESTIGATE SEX DIFFERENCES OF SYSTEMIC, HEPATIC, AND INTRARENAL AGT LEVELS. ALL HISTONE DEACETYLASE (HDAC) MRNA LEVELS IN THE KIDNEYS WERE DETERMINED USING A PCR ARRAY. HDAC9 PROTEIN EXPRESSION IN THE KIDNEYS AND CULTURED RENAL PROXIMAL TUBULAR CELLS (PTC) WAS ANALYZED BY WESTERN BLOT ANALYSIS AND IMMUNOHISTOCHEMISTRY. THE EFFECTS OF HDAC9 ON AGT EXPRESSION WERE EVALUATED BY USING AN INHIBITOR AND SIRNA. CHIP ASSAY WAS PERFORMED TO INVESTIGATE THE INTERACTION BETWEEN THE AGT PROMOTER AND HDAC9. RESULTS: PLASMA AND LIVER AGT LEVELS DID NOT SHOW DIFFERENCES BETWEEN MALE AND FEMALE SPRAGUE-DAWLEY RATS. IN CONTRAST, FEMALES EXHIBITED LOWER AGT LEVELS THAN MALES IN THE RENAL CORTEX AND URINE. IN THE ABSENCE OF SUPPLEMENTED SEX HORMONES, PRIMARY CULTURED RENAL CORTICAL CELLS ISOLATED FROM FEMALE RATS SUSTAINED LOWER AGT LEVELS THAN THOSE FROM MALES, SUGGESTING THAT THE KIDNEYS HAVE A UNIQUE MECHANISM OF AGT REGULATION CONTROLLED BY EPIGENETIC FACTORS RATHER THAN SEX HORMONES. HDAC9 MRNA AND PROTEIN LEVELS WERE HIGHER IN THE RENAL CORTEX OF FEMALE RATS VERSUS MALE RATS (7.09 +/- 0.88, RATIO TO MALE) WHILE OTHER HDACS DID NOT EXHIBIT A SEX DIFFERENCE. HDAC9 EXPRESSION WAS LOCALIZED IN PTC WHICH ARE THE PRIMARY SOURCE OF INTRARENAL AGT. IMPORTANTLY, HDAC9 KNOCKDOWN AUGMENTED AGT MRNA (1.92 +/- 0.35-FOLD) AND PROTEIN (2.25 +/- 0.50-FOLD) LEVELS, SIMILAR TO AN HDAC9 INHIBITOR. FURTHERMORE, AN INTERACTION BETWEEN HDAC9 AND A DISTAL 5' FLANKING REGION OF AGT VIA A HISTONE COMPLEX CONTAINING H3 AND H4 WAS DEMONSTRATED. CONCLUSIONS: THESE RESULTS INDICATE THAT HDAC9 IS A NOVEL SUPPRESSING FACTOR INVOLVED IN AGT REGULATION IN PTC, LEADING TO LOW LEVELS OF INTRARENAL AGT IN FEMALES. THESE FINDINGS WILL HELP TO DELINEATE MECHANISMS UNDERLYING SEX DIFFERENCES IN THE DEVELOPMENT OF HYPERTENSION AND RENIN-ANGIOTENSIN SYSTEM (RAS) ASSOCIATED KIDNEY INJURY.	2017	

13 3858  27 ISCHEMIA-INDUCED DNA HYPERMETHYLATION DURING KIDNEY TRANSPLANT PREDICTS CHRONIC ALLOGRAFT INJURY. BACKGROUND ISCHEMIA DURING KIDNEY TRANSPLANT CAUSES CHRONIC ALLOGRAFT INJURY AND ADVERSELY AFFECTS OUTCOME, BUT THE UNDERLYING MECHANISMS ARE INCOMPLETELY UNDERSTOOD. IN TUMORS, OXYGEN SHORTAGE REDUCES THE DNA DEMETHYLATING ACTIVITY OF THE TEN-11 TRANSLOCATION (TET) ENZYMES, YIELDING HYPERMETHYLATED GENOMES THAT PROMOTE TUMOR PROGRESSION. WE INVESTIGATED WHETHER ISCHEMIA SIMILARLY INDUCES DNA HYPERMETHYLATION IN KIDNEY TRANSPLANTS AND CONTRIBUTES TO CHRONIC INJURY.METHODS WE PROFILED GENOME-WIDE DNA METHYLATION IN THREE COHORTS OF BRAIN-DEAD DONOR KIDNEY ALLOGRAFT BIOPSY SPECIMENS: A LONGITUDINAL COHORT WITH PAIRED BIOPSY SPECIMENS OBTAINED AT ALLOGRAFT PROCUREMENT (PREISCHEMIA; N=13), AFTER IMPLANTATION AND REPERFUSION (POSTISCHEMIA; N=13), AND AT 3 OR 12 MONTHS AFTER TRANSPLANT (N=5 EACH); A CROSS-SECTIONAL COHORT WITH PREIMPLANTATION BIOPSY SPECIMENS (N=82); AND A CROSS-SECTIONAL COHORT WITH POSTREPERFUSION BIOPSY SPECIMENS (N=46).RESULTS ANALYSIS OF THE PAIRED PREISCHEMIA AND POSTISCHEMIA SPECIMENS REVEALED THAT METHYLATION INCREASED DRASTICALLY IN ALL ALLOGRAFTS ON ISCHEMIA. HYPERMETHYLATION WAS CAUSED BY LOSS OF 5-HYDROXYMETHYLCYTOSINE, THE PRODUCT OF TET ACTIVITY, AND IT WAS STABLE 1 YEAR AFTER TRANSPLANT. IN THE PREIMPLANTATION COHORT, CPG HYPERMETHYLATION DIRECTLY CORRELATED WITH ISCHEMIA TIME AND FOR SOME CPGS, INCREASED 2.6% PER ADDITIONAL HOUR OF ISCHEMIA. HYPERMETHYLATION PREFERENTIALLY AFFECTED AND REDUCED THE EXPRESSION OF GENES INVOLVED IN SUPPRESSING KIDNEY INJURY AND FIBROSIS. MOREOVER, CPG HYPERMETHYLATION IN PREIMPLANTATION SPECIMENS PREDICTED CHRONIC INJURY, PARTICULARLY FIBROSIS AND GLOMERULOSCLEROSIS, 1 YEAR AFTER TRANSPLANT. THIS FINDING WAS VALIDATED IN THE INDEPENDENT POSTREPERFUSION COHORT, IN WHICH HYPERMETHYLATION ALSO PREDICTED REDUCED ALLOGRAFT FUNCTION 1 YEAR AFTER TRANSPLANT, OUTPERFORMING ESTABLISHED CLINICAL VARIABLES.CONCLUSIONS WE HIGHLIGHT A NOVEL EPIGENETIC BASIS FOR ISCHEMIA-INDUCED CHRONIC ALLOGRAFT INJURY WITH BIOMARKER POTENTIAL.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
14 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
15 1576  33 DNA METHYLATION PROFILE ASSOCIATED WITH RAPID DECLINE IN KIDNEY FUNCTION: FINDINGS FROM THE CRIC STUDY. BACKGROUND: EPIGENETIC MECHANISMS MAY BE IMPORTANT IN THE PROGRESSION OF CHRONIC KIDNEY DISEASE (CKD). METHODS: WE STUDIED THE GENOME-WIDE DNA METHYLATION PATTERN ASSOCIATED WITH RAPID LOSS OF KIDNEY FUNCTION USING THE INFINIUM HUMANMETHYLATION 450 K BEADCHIP IN 40 CHRONIC RENAL INSUFFICIENCY (CRIC) STUDY PARTICIPANTS (N = 3939) WITH THE HIGHEST AND LOWEST RATES OF DECLINE IN ESTIMATED GLOMERULAR FILTRATION RATE. RESULTS: THE MEAN EGFR SLOPE WAS 2.2 (1.4) AND -5.1 (1.2) ML/MIN/1.73 M(2) IN THE STABLE KIDNEY FUNCTION GROUP AND THE RAPID PROGRESSION GROUP, RESPECTIVELY. CPG ISLANDS IN NPHP4, IQSEC1 AND TCF3 WERE HYPERMETHYLATED TO A LARGER EXTENT IN SUBJECTS WITH STABLE KIDNEY FUNCTION (P-VALUES OF 7.8E-05 TO 9.5E-05). THESE GENES ARE INVOLVED IN PATHWAYS KNOWN TO PROMOTE THE EPITHELIAL TO MESENCHYMAL TRANSITION AND RENAL FIBROSIS. OTHER CKD-RELATED GENES THAT WERE DIFFERENTIALLY METHYLATED ARE NOS3, NFKBIL2, CLU, NFKBIB, TGFB3 AND TGFBI, WHICH ARE INVOLVED IN OXIDATIVE STRESS AND INFLAMMATORY PATHWAYS (P-VALUES OF 4.5E-03 TO 0.046). PATHWAY ANALYSIS USING INGENUITY PATHWAY ANALYSIS SHOWED THAT GENE NETWORKS RELATED TO CELL SIGNALING, CARBOHYDRATE METABOLISM AND HUMAN BEHAVIOR ARE EPIGENETICALLY REGULATED IN CKD. CONCLUSIONS: EPIGENETIC MODIFICATIONS MAY BE IMPORTANT IN DETERMINING THE RATE OF LOSS OF KIDNEY FUNCTION IN PATIENTS WITH ESTABLISHED CKD.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
16 4736  27 NOVEL EPIGENETIC BIOMARKERS MEDIATING BISPHENOL A EXPOSURE AND METABOLIC PHENOTYPES IN FEMALE MICE. THERE IS COMPELLING EVIDENCE THAT EPIGENETIC MODIFICATIONS LINK DEVELOPMENTAL ENVIRONMENTAL INSULTS TO ADULT DISEASE SUSCEPTIBILITY. ANIMAL STUDIES HAVE ASSOCIATED PERINATAL BISPHENOL A (BPA) EXPOSURE TO ALTERED DNA METHYLATION, BUT THESE STUDIES ARE OFTEN LIMITED TO CANDIDATE GENE AND GLOBAL NON-LOCI-SPECIFIC APPROACHES. BY USING AN EPIGENOME-WIDE DISCOVERY PLATFORM, WE ELUCIDATED EPIGENETIC ALTERATIONS IN LIVER TISSUE FROM ADULT MICE OFFSPRING (10 MONTHS) FOLLOWING PERINATAL BPA EXPOSURE AT HUMAN PHYSIOLOGICALLY RELEVANT DOSES (50-NG, 50-MUG, AND 50-MG BPA/KG DIET). BIOLOGICAL PATHWAY ANALYSIS IDENTIFIED AN ENRICHMENT OF SIGNIFICANT DIFFERENTIALLY METHYLATED REGIONS IN METABOLIC PATHWAYS AMONG FEMALES. FURTHERMORE, THROUGH THE USE OF TOP ENRICHED BIOLOGICAL PATHWAYS, 4 CANDIDATE GENES WERE CHOSEN TO ASSESS DNA METHYLATION AS A MEDIATING FACTOR LINKING THE ASSOCIATION OF PERINATAL BPA EXPOSURE TO METABOLIC PHENOTYPES PREVIOUSLY OBSERVED IN FEMALE OFFSPRING. DNA METHYLATION STATUS AT JANUS KINASE-2 (JAK-2), RETINOID X RECEPTOR (RXR), REGULATORY FACTOR X-ASSOCIATED PROTEIN (RFXAP), AND TRANSMEMBRANE PROTEIN 238 (TMEM238) WAS USED WITHIN A MEDIATIONAL REGRESSION ANALYSIS. DNA METHYLATION IN ALL FOUR OF THE CANDIDATE GENES WAS IDENTIFIED AS A MEDIATOR IN THE MECHANISTIC PATHWAY OF DEVELOPMENTAL BPA EXPOSURE AND FEMALE-SPECIFIC ENERGY EXPENDITURE, BODY WEIGHT, AND BODY FAT PHENOTYPES. DATA GENERATED FROM THIS STUDY ARE CRUCIAL FOR DECIPHERING THE MECHANISTIC ROLE OF EPIGENETICS IN THE PATHOGENESIS OF CHRONIC DISEASE AND THE DEVELOPMENT OF EPIGENETIC-BASED PREVENTION AND THERAPEUTIC STRATEGIES FOR COMPLEX HUMAN DISEASE.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
17 3084  28 GENOME-WIDE SCREEN OF DNA METHYLATION IDENTIFIES NOVEL MARKERS IN CHILDHOOD OBESITY. EPIGENETIC MODIFICATIONS HAVE BEEN HIGHLIGHTED IN CHRONIC NON-COMMUNICABLE DISEASES. THE AIM OF THIS STUDY WAS TO INVESTIGATE GENOME-WIDE DNA METHYLATION FOR THE IDENTIFICATION OF METHYLATION MARKERS IN OBESITY. WITH OBESE CHINESE PRESCHOOL CHILDREN, WE PERFORMED COMPREHENSIVE DNA METHYLATION PROFILING OF GENE PROMOTERS AND CPG ISLANDS TO DETERMINE THE DIFFERENTIALLY METHYLATED GENES USING METHYLATED DNA IMMUNOPRECIPITATION FOLLOWED BY HYBRIDIZATION TO THE NIMBLEGEN HUMAN DNA METHYLATION 385K PROMOTER PLUS CPG ISLAND MICROARRAY. WE FOUND THAT COMPARED TO LEAN CHILDREN, 251 PROMOTERS AND 575 CGIS WERE DEMETHYLATED, AND 141 PROMOTERS AND 277 CGIS WERE HYPERMETHYLATED IN OBESE CHILDREN, AND THEIR DISTRIBUTION ON CHROMOSOMES WAS IMBALANCED, SHOWING MORE PROMOTERS AND CGIS WITH DEMETHYLATION ON CHROMOSOMES 3, 16, 17 AND 19 AND MORE DIFFERENTIALLY METHYLATED PROMOTERS AND CGIS ON CHROMOSOME X COMPARED WITH CHROMOSOME Y. FURTHER ANALYSIS INDICATED THAT ABERRANT METHYLATIONS OCCURRED MOSTLY IN HCP PROMOTERS AND PROMOTER CGIS. AMONG THE TOP 80 PROMOTERS AND CGIS THAT HAD DIFFERENTIATED METHYLATION BETWEEN OBESE AND LEAN CHILDREN, NEARLY HALF HAVE BEEN PREVIOUSLY STUDIED, AND ALMOST ALL OF THEM ARE INVOLVED IN THE PATHOGENESIS OF CANCERS THAT ARE ASSOCIATED WITH MANY ORGANS. FURTHERMORE, FOUR GENES (FZD7, PRLHR, EXOSC4, AND EIF6) WITH DIFFERENTIAL PROMOTER METHYLATION WERE VALIDATED, AND THEIR ASSOCIATIONS WITH OBESITY MUST BE CLARIFIED. IN CONCLUSION, THIS STUDY REPRESENTS THE FIRST EFFORT TO DETERMINE METHYLATION MARKERS IN OBESE CHINESE CHILDREN, WHICH HAS POTENTIAL RELEVANCE FOR IDENTIFYING MARKERS THAT ARE USEFUL IN ELUCIDATING THE MECHANISMS OF OBESITY PATHOGENESIS AND ITS COMPLICATIONS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
18 3764  32 INTEGRATIVE ANALYSIS OF DNA METHYLATION AND GENE EXPRESSION DATA IDENTIFIES EPAS1 AS A KEY REGULATOR OF COPD. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A COMPLEX DISEASE. GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS ARE KNOWN TO CONTRIBUTE TO COPD RISK AND DISEASE PROGRESSION. THEREFORE WE DEVELOPED A SYSTEMATIC APPROACH TO IDENTIFY KEY REGULATORS OF COPD THAT INTEGRATES GENOME-WIDE DNA METHYLATION, GENE EXPRESSION, AND PHENOTYPE DATA IN LUNG TISSUE FROM COPD AND CONTROL SAMPLES. OUR INTEGRATIVE ANALYSIS IDENTIFIED 126 KEY REGULATORS OF COPD. WE IDENTIFIED EPAS1 AS THE ONLY KEY REGULATOR WHOSE DOWNSTREAM GENES SIGNIFICANTLY OVERLAPPED WITH MULTIPLE GENES SETS ASSOCIATED WITH COPD DISEASE SEVERITY. EPAS1 IS DISTINCT IN COMPARISON WITH OTHER KEY REGULATORS IN TERMS OF METHYLATION PROFILE AND DOWNSTREAM TARGET GENES. GENES PREDICTED TO BE REGULATED BY EPAS1 WERE ENRICHED FOR BIOLOGICAL PROCESSES INCLUDING SIGNALING, CELL COMMUNICATIONS, AND SYSTEM DEVELOPMENT. WE CONFIRMED THAT EPAS1 PROTEIN LEVELS ARE LOWER IN HUMAN COPD LUNG TISSUE COMPARED TO NON-DISEASE CONTROLS AND THAT EPAS1 GENE EXPRESSION IS REDUCED IN MICE CHRONICALLY EXPOSED TO CIGARETTE SMOKE. AS EPAS1 DOWNSTREAM GENES WERE SIGNIFICANTLY ENRICHED FOR HYPOXIA RESPONSIVE GENES IN ENDOTHELIAL CELLS, WE TESTED EPAS1 FUNCTION IN HUMAN ENDOTHELIAL CELLS. EPAS1 KNOCKDOWN BY SIRNA IN ENDOTHELIAL CELLS IMPACTED GENES THAT SIGNIFICANTLY OVERLAPPED WITH EPAS1 DOWNSTREAM GENES IN LUNG TISSUE INCLUDING HYPOXIA RESPONSIVE GENES, AND GENES ASSOCIATED WITH EMPHYSEMA SEVERITY. OUR FIRST INTEGRATIVE ANALYSIS OF GENOME-WIDE DNA METHYLATION AND GENE EXPRESSION PROFILES ILLUSTRATES THAT NOT ONLY DOES DNA METHYLATION PLAY A 'CAUSAL' ROLE IN THE MOLECULAR PATHOPHYSIOLOGY OF COPD, BUT IT CAN BE LEVERAGED TO DIRECTLY IDENTIFY NOVEL KEY MEDIATORS OF THIS PATHOPHYSIOLOGY.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
19 1121  22 COMPARISON OF EPIGENETIC PROFILES OF HUMAN ORAL EPITHELIAL CELLS FROM HIV-POSITIVE (ON HAART) AND HIV-NEGATIVE SUBJECTS. HIV-INFECTED SUBJECTS ON HIGHLY ACTIVE ANTIRETROVIRAL THERAPY (HAART) ARE SUSCEPTIBLE TO COMORBID MICROBIAL INFECTIONS IN THE ORAL CAVITY. WE OBSERVED THAT PRIMARY ORAL EPITHELIAL CELLS (POECS) ISOLATED FROM HIV+ SUBJECTS ON HAART GROW MORE SLOWLY AND ARE LESS INNATE IMMUNE RESPONSIVE TO MICROBIAL CHALLENGE WHEN COMPARED WITH POECS FROM NORMAL SUBJECTS. THESE ABERRANT CELLS ALSO DEMONSTRATE EPIGENETIC DIFFERENCES THAT INCLUDE REDUCTION IN HISTONE DEACETYLASE 1 (HDAC-1) LEVELS AND REDUCED TOTAL DNA METHYLTRANSFERASE (DNMT) ACTIVITY SPECIFIC TO ENZYMES DNMT1 AND DNMT3A. THE DNMT ACTIVITY CORRELATES WELL WITH GLOBAL DNA METHYLATION, INDICATING THAT ABERRANT DNMT ACTIVITY IN HIV+ (ON HAART) POECS LEADS TO AN ABERRANTLY METHYLATED EPITHELIAL CELL PHENOTYPE. OVERALL, OUR RESULTS LEAD US TO HYPOTHESIZE THAT, IN PATIENTS WITH CHRONIC HIV INFECTION ON HAART, EPIGENETIC CHANGES IN KEY GENES RESULT IN INCREASED VULNERABILITY TO MICROBIAL INFECTION IN THE ORAL CAVITY.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
20  217  29 ACUTE EXERCISE INCREASES THE EXPRESSION OF KIR2DS4 BY PROMOTER DEMETHYLATION IN NK CELLS. POSITIVE EFFECTS OF EXERCISE ON CANCER PREVENTION AND PROGRESSION HAVE BEEN PROPOSED TO BE MEDIATED BY STIMULATING NATURAL KILLER (NK) CELLS. BECAUSE NK CELL RECEPTORS ARE REGULATED BY EPIGENETIC MODIFICATIONS, WE INVESTIGATED WHETHER ACUTE AEROBIC EXERCISE AND TRAINING CHANGE PROMOTER DNA METHYLATION AND GENE EXPRESSION OF THE ACTIVATING KIR2DS4 AND THE INHIBITING KIR3DL1 GENE. SIXTEEN HEALTHY WOMEN (50-60 YEARS) PERFORMED A GRADED EXERCISE TEST (GXT) AND WERE RANDOMIZED INTO EITHER A PASSIVE CONTROL GROUP OR AN INTERVENTION GROUP PERFORMING A FOUR-WEEK ENDURANCE EXERCISE INTERVENTION. BLOOD SAMPLES (PRE-, POST-GXT AND POST-TRAINING) WERE USED FOR ISOLATION OF DNA/RNA OF NK CELLS TO ASSESS DNA PROMOTER METHYLATION BY TARGETED DEEP-AMPLICON SEQUENCING AND GENE EXPRESSION BY QRT-PCR. POTENTIAL CHANGES IN NK CELL SUBSETS WERE DETERMINED BY FLOW CYTOMETRY. ACUTE AND CHRONIC EXERCISE DID NOT PROVOKE SIGNIFICANT ALTERATIONS OF NK CELL PROPORTIONS. PROMOTER METHYLATION DECREASED AND GENE EXPRESSION INCREASED FOR KIR2DS4 AFTER ACUTE EXERCISE. A HIGH GENE EXPRESSION CORRELATED WITH A LOW METHYLATION OF CPGS THAT WERE ALTERED BY ACUTE EXERCISE. CHRONIC EXERCISE RESULTED IN A MINOR DECREASE OF DNA METHYLATION AND DID NOT ALTER GENE EXPRESSION. ACUTE EXERCISE PROVOKES EPIGENETIC MODIFICATIONS, AFFECTING THE BALANCE BETWEEN THE ACTIVATING KIR2DS4 AND THE INHIBITING KIR3DL1, WITH POTENTIAL BENEFITS ON NK CELL FUNCTION.	2019