1 6280 123 THE PLASTICIZER BISPHENOL A PERTURBS THE HEPATIC EPIGENOME: A SYSTEMS LEVEL ANALYSIS OF THE MIRNOME. UBIQUITOUS EXPOSURE TO BISPHENOL A (BPA), AN ENDOCRINE DISRUPTOR (ED), HAS RAISED CONCERNS FOR BOTH HUMAN AND ECOSYSTEM HEALTH. EPIGENETIC FACTORS, INCLUDING MICRORNAS (MIRNAS), ARE KEY REGULATORS OF GENE EXPRESSION DURING CANCER. THE EFFECT OF BPA EXPOSURE ON THE ZEBRAFISH EPIGENOME REMAINS POORLY CHARACTERIZED. ZEBRAFISH REPRESENTS AN EXCELLENT MODEL TO STUDY CANCER AS THE ORGANISM DEVELOPS A DISEASE THAT RESEMBLES HUMAN CANCER. USING ZEBRAFISH AS A SYSTEMS TOXICOLOGY MODEL, WE HYPOTHESIZED THAT CHRONIC BPA-EXPOSURE IMPACTS THE MIRNOME IN ADULT ZEBRAFISH AND ESTABLISHES AN EPIGENOME MORE SUSCEPTIBLE TO CANCER DEVELOPMENT. AFTER A 3 WEEK EXPOSURE TO 100 NM BPA, RNA FROM THE LIVER WAS EXTRACTED TO PERFORM HIGH THROUGHPUT MRNA AND MIRNA SEQUENCING. DIFFERENTIAL EXPRESSION (DE) ANALYSES COMPARING BPA-EXPOSED TO CONTROL SPECIMENS WERE PERFORMED USING ESTABLISHED BIOINFORMATICS PIPELINES. IN THE BPA-EXPOSED LIVER, 6188 MRNAS AND 15 MIRNAS WERE DIFFERENTLY EXPRESSED (Q </= 0.1). BY ANALYZING HUMAN ORTHOLOGS OF THE DE ZEBRAFISH GENES, SIGNATURES ASSOCIATED WITH NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD), OXIDATIVE PHOSPHORYLATION, MITOCHONDRIAL DYSFUNCTION AND CELL CYCLE WERE UNCOVERED. CHRONIC EXPOSURE TO BPA HAS A SIGNIFICANT IMPACT ON THE LIVER MIRNOME AND TRANSCRIPTOME IN ADULT ZEBRAFISH WITH THE POTENTIAL TO CAUSE ADVERSE HEALTH OUTCOMES INCLUDING CANCER.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
2  904  40 CHRONIC EXPOSURE TO CADMIUM INDUCES DIFFERENTIAL METHYLATION IN MICE SPERMATOZOA. CADMIUM EXPOSURE IS UBIQUITOUS AND HAS BEEN LINKED TO DISEASES INCLUDING CANCERS AND REPRODUCTIVE DEFECTS. SINCE CADMIUM IS NONMUTAGENIC, IT IS THOUGHT TO EXERT ITS GENE DYSREGULATORY EFFECTS THROUGH EPIGENETIC REPROGRAMMING. SEVERAL STUDIES HAVE IMPLICATED GERMLINE EXPOSURE TO CADMIUM IN DEVELOPMENTAL REPROGRAMMING. HOWEVER, MOST OF THESE STUDIES HAVE FOCUSED ON MATERNAL EXPOSURE, WHILE THE IMPACT ON SPERM FERTILITY AND DISEASE SUSCEPTIBILITY HAS RECEIVED LESS ATTENTION. IN THIS STUDY, WE USED REDUCED REPRESENTATION BISULFITE SEQUENCING TO COMPREHENSIVELY INVESTIGATE THE IMPACT OF CHRONIC CADMIUM EXPOSURE ON MOUSE SPERMATOZOA DNA METHYLATION. ADULT MALE C57BL/J6 MICE WERE PROVIDED WATER WITH OR WITHOUT CADMIUM CHLORIDE FOR 9 WEEKS. SPERM, TESTES, LIVER, AND KIDNEY TISSUES WERE COLLECTED AT THE END OF THE TREATMENT PERIOD. CADMIUM EXPOSURE WAS CONFIRMED THROUGH GENE EXPRESSION ANALYSIS OF METALLOTHIONEIN-1 AND 2, 2 WELL-KNOWN CADMIUM-INDUCED GENES. ANALYSIS OF SPERM DNA METHYLATION CHANGES REVEALED 1788 DIFFERENTIALLY METHYLATED SITES PRESENT AT REGULATORY REGIONS IN SPERM OF MICE EXPOSED TO CADMIUM COMPARED WITH VEHICLE (CONTROL) MICE. FURTHERMORE, MOST OF THESE DIFFERENTIAL METHYLATION CHANGES POSITIVELY CORRELATED WITH CHANGES IN GENE EXPRESSION AT BOTH THE TRANSCRIPTION INITIATION STAGE AS WELL AS THE SPLICING LEVELS. INTERESTINGLY, THE GENES TARGETED BY CADMIUM EXPOSURE ARE INVOLVED IN SEVERAL CRITICAL DEVELOPMENTAL PROCESSES. OUR RESULTS PRESENT A COMPREHENSIVE ANALYSIS OF THE SPERM METHYLOME IN RESPONSE TO CHRONIC CADMIUM EXPOSURE. THESE DATA, THEREFORE, HIGHLIGHT A FOUNDATIONAL FRAMEWORK TO STUDY GENE EXPRESSION PATTERNS THAT MAY AFFECT FERTILITY IN THE EXPOSED INDIVIDUAL AS WELL AS THEIR OFFSPRING, THROUGH PATERNAL INHERITANCE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                           
3  457  35 APPLYING A MULTISCALE SYSTEMS BIOLOGY APPROACH TO STUDY THE EFFECT OF CHRONIC LOW-DOSE EXPOSURE TO URANIUM IN RAT KIDNEYS. PURPOSE: TO EXAMINE THE EFFECTS OF LOW-DOSE EXPOSURE TO URANIUM WITH A SYSTEMS BIOLOGY APPROACH, A MULTISCALE HIGH-THROUGHPUT MULTI-OMICS ANALYSIS WAS APPLIED WITH A PROTOCOL FOR CHRONIC EXPOSURE TO THE RAT KIDNEY. METHODS: MALE AND FEMALE RATS WERE CONTAMINATED FOR NINE MONTHS THROUGH THEIR DRINKING WATER WITH A NONTOXIC SOLUTION OF URANYL NITRATE. A MULTISCALE APPROACH ENABLED CLINICAL MONITORING ASSOCIATED WITH METABOLOMIC AND TRANSCRIPTOMIC (MRNA AND MICRORNA) ANALYSES. RESULTS: A SEX-INTERACTION EFFECT WAS OBSERVED IN THE KIDNEY, URINE, AND PLASMA METABOLOMES OF CONTAMINATED RATS. MOREOVER, URINE AND KIDNEY METABOLIC PROFILES CORRELATED AND CONFIRMED THAT THE PRIMARY DYSREGULATED METABOLISMS ARE THOSE OF NICOTINATE-NICOTINAMIDE AND OF UNSATURATED FATTY ACID BIOSYNTHESIS. UPSTREAM OF THE METABOLIC PATHWAYS, TRANSCRIPTOMIC PROFILES OF THE KIDNEY REVEAL GENE ACTIVITY FOCUSED ON GENE REGULATION MECHANISMS, CELL SIGNALING, CELL STRUCTURE, DEVELOPMENTAL PROCESSES, AND CELL PROLIFERATION. EXAMINATION OF EPIGENETIC POST-TRANSCRIPTIONAL GENE REGULATION PROCESSES SHOWED SIGNIFICANT DYSREGULATION OF 70 MICRO-RNAS. THE MULTI-OMICS APPROACH HIGHLIGHTED THE ACTIVITIES OF THE CELLS' BIOLOGICAL PROCESSES ON MULTIPLE SCALES THROUGH ANALYSIS OF GENE EXPRESSION, CONFIRMED BY CHANGES OBSERVED IN THE METABOLOME. CONCLUSION: OUR RESULTS SHOWED CHANGES IN MULTI-OMIC PROFILES OF RATS EXPOSED TO LOW DOSES OF URANIUM CONTAMINATION, COMPARED WITH CONTROLS. THESE CHANGES INVOLVED GENE EXPRESSION AS WELL AS MODIFICATIONS IN THE TRANSCRIPTOME AND THE METABOLOME. THE METABOLOMIC PROFILE CONFIRMED THAT THE MAIN MOLECULAR TARGETS OF URANIUM IN KIDNEY CELLS ARE THE METABOLISM OF NICOTINATE-NICOTINAMIDE AND THE BIOSYNTHESIS OF UNSATURATED FATTY ACIDS. ADDITIONALLY, GENE EXPRESSION ANALYSIS SHOWED THAT THE METABOLISM OF FATTY ACIDS IS TARGETED BY PROCESSES ASSOCIATED WITH CELL FUNCTION. THESE RESULTS DEMONSTRATE THAT MULTISCALE SYSTEMS BIOLOGY IS USEFUL IN ELUCIDATING THE MOST DISCRIMINATIVE PATHWAYS FROM GENOMIC TO METABOLOMIC LEVELS FOR ASSESSING THE BIOLOGICAL IMPACT OF THIS LOW-LEVEL ENVIRONMENTAL EXPOSURE, I.E. THE EXPOSOME.	2019	

4 3292  43 HIGH FAT DIET AND EXERCISE LEAD TO A DISRUPTED AND PATHOGENIC DNA METHYLOME IN MOUSE LIVER. HIGH-FAT DIET CONSUMPTION AND SEDENTARY LIFESTYLE ELEVATES RISK FOR OBESITY, NON-ALCOHOLIC FATTY LIVER DISEASE, AND CANCER. EXERCISE TRAINING CONVEYS HEALTH BENEFITS IN POPULATIONS WITH OR WITHOUT THESE CHRONIC CONDITIONS. DIET AND EXERCISE REGULATE GENE EXPRESSION BY MEDIATING EPIGENETIC MECHANISMS IN MANY TISSUES; HOWEVER, SUCH EFFECTS ARE POORLY DOCUMENTED IN THE LIVER, A CENTRAL METABOLIC ORGAN. TO DISSECT THE CONSEQUENCES OF DIET AND EXERCISE ON THE LIVER EPIGENOME, WE MEASURED DNA METHYLATION, USING REDUCED REPRESENTATION BISULFITE SEQUENCING, AND TRANSCRIPTION, USING RNA-SEQ, IN MICE MAINTAINED ON A FAST FOOD DIET WITH SEDENTARY LIFESTYLE OR EXERCISE, COMPARED WITH CONTROL DIET WITH AND WITHOUT EXERCISE. OUR ANALYSES REVEAL THAT GENOME-WIDE DIFFERENTIAL DNA METHYLATION AND EXPRESSION OF GENE CLUSTERS ARE INDUCED BY DIET AND/OR EXERCISE. A COMBINATION OF FAST FOOD AND EXERCISE TRIGGERS EXTENSIVE GENE ALTERATIONS, WITH ENRICHMENT OF CARBOHYDRATE/LIPID METABOLIC PATHWAYS AND MUSCLE DEVELOPMENTAL PROCESSES. THROUGH EVALUATION OF PUTATIVE PROTECTIVE EFFECTS OF EXERCISE ON DIET-INDUCED DNA METHYLATION, WE SHOW THAT HYPERMETHYLATION IS EFFECTIVELY PREVENTED, ESPECIALLY AT PROMOTERS AND ENHANCERS, WHEREAS HYPOMETHYLATION IS ONLY PARTIALLY ATTENUATED. WE ASSESSED DIET-INDUCED DNA METHYLATION CHANGES ASSOCIATED WITH LIVER CANCER-RELATED EPIGENETIC MODIFICATIONS AND IDENTIFIED SIGNIFICANT INCREASES AT LIVER-SPECIFIC ENHANCERS IN FAST FOOD GROUPS, SUGGESTING PARTIAL LOSS OF LIVER CELL IDENTITY. HYPERMETHYLATION AT A SUBSET OF GENE PROMOTERS WAS ASSOCIATED WITH INHIBITION OF TISSUE DEVELOPMENT AND PROMOTION OF CARCINOGENIC PROCESSES. OUR STUDY DEMONSTRATES EXTENSIVE REPROGRAMMING OF THE EPIGENOME BY DIET AND EXERCISE, EMPHASIZING THE FUNCTIONAL RELEVANCE OF EPIGENETIC MECHANISMS AS AN INTERFACE BETWEEN LIFESTYLE MODIFICATIONS AND PHENOTYPIC ALTERATIONS.	2017	
                                                                                                                                                                                                                                                                                                
5 6790  25 [DNA METHYLATION ANALYSIS IN ENVIRONMENTAL AND OCCUPATIONAL CANCER RESEARCH]. THE PRESENT PAPER REVIEWS RECENT LABORATORY METHODS AND EXPERIMENTAL EVIDENCE CONCERNING EPIGENETIC BIOMARKERS INVOLVED IN CARCINOGENESIS MECHANISMS. WE INTRODUCE DNA METHYLATION AND ITS ROLE IN GENE EXPRESSION CONTROL. DNA METHYLATION ANALYSIS MAY ALLOW TO IDENTIFY EARLY CHANGES LEADING TO CANCER AND OTHER CHRONIC DISEASES. WE DESCRIBE HERE STRATEGIES FOR LABORATORY ANALYSES AND THEIR POSSIBLE APPLICATIONS. WE EXAMINE RESULTS FROM RECENT EXPERIMENTAL STUDIES SUGGESTING THAT THE EFFECTS OF CERTAIN OCCUPATIONAL AGENTS ARE MEDIATED BY ALTERATIONS IN DNA METHYLATION. PLANNING AND CONDUCTING INVESTIGATIONS ON EXPOSED HUMAN SUBJECTS WILL ALLOW TO VERIFY WHETHER DNA METHYLATION CHANGES IDENTIFIED IN ANIMAL AND IN-VITRO STUDIES MAY BE USED AS EARLY-EFFECT AND SUSCEPTIBILITY BIOMARKERS. DNA METHYLATION ANALYSIS HAS THE POTENTIAL FOR FUTURE APPLICATIONS IN RISK ASSESSMENT AND PREVENTION PROGRAMS CONDUCTED ON SUBJECTS EXPOSED TO HUMAN CARCINOGENS.	2005	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
6 3738  34 INORGANIC ARSENIC-INDUCED CELLULAR TRANSFORMATION IS COUPLED WITH GENOME WIDE CHANGES IN CHROMATIN STRUCTURE, TRANSCRIPTOME AND SPLICING PATTERNS. BACKGROUND: ARSENIC (AS) EXPOSURE IS A SIGNIFICANT WORLDWIDE ENVIRONMENTAL HEALTH CONCERN. LOW DOSE, CHRONIC ARSENIC EXPOSURE HAS BEEN ASSOCIATED WITH A HIGHER THAN NORMAL RISK OF SKIN, LUNG, AND BLADDER CANCER, AS WELL AS CARDIOVASCULAR DISEASE AND DIABETES. WHILE ARSENIC-INDUCED BIOLOGICAL CHANGES PLAY A ROLE IN DISEASE PATHOLOGY, LITTLE IS KNOWN ABOUT THE DYNAMIC CELLULAR CHANGES RESULTING FROM ARSENIC EXPOSURE AND WITHDRAWAL. RESULTS: IN THESE STUDIES, WE SOUGHT TO UNDERSTAND THE MOLECULAR MECHANISMS BEHIND THE BIOLOGICAL CHANGES INDUCED BY ARSENIC EXPOSURE. A COMPREHENSIVE GLOBAL APPROACH WAS EMPLOYED TO DETERMINE GENOME-WIDE CHANGES TO CHROMATIN STRUCTURE, TRANSCRIPTOME PATTERNS AND SPLICING PATTERNS IN RESPONSE TO CHRONIC LOW DOSE ARSENIC AND ITS SUBSEQUENT WITHDRAWAL. OUR RESULTS SHOW THAT CELLS EXPOSED TO CHRONIC LOW DOSES OF SODIUM ARSENITE HAVE DISTINCT TEMPORAL AND COORDINATED CHROMATIN, GENE EXPRESSION, AND MIRNA CHANGES CONSISTENT WITH DIFFERENTIATION AND ACTIVATION OF MULTIPLE BIOCHEMICAL PATHWAYS. MOST OF THESE TEMPORAL PATTERNS IN GENE EXPRESSION ARE REVERSED WHEN ARSENIC IS WITHDRAWN. HOWEVER, SOME GENE EXPRESSION PATTERNS REMAINED ALTERED, PLAUSIBLY AS A RESULT OF AN ADAPTIVE RESPONSE BY CELLS. ADDITIONALLY, THE CORRELATION OF CHANGES TO GENE EXPRESSION AND CHROMATIN STRUCTURE SOLIDIFY THE ROLE OF CHROMATIN STRUCTURE IN GENE REGULATORY CHANGES DUE TO ARSENITE EXPOSURE. LASTLY, WE SHOW THAT ARSENITE EXPOSURE INFLUENCES GENE REGULATION BOTH AT THE INITIATION OF TRANSCRIPTION AS WELL AS AT THE LEVEL OF SPLICING. CONCLUSIONS: OUR RESULTS SHOW THAT ADAPTATION OF CELLS TO IAS-MEDIATED EMT IS COUPLED TO CHANGES IN CHROMATIN STRUCTURE EFFECTING DIFFERENTIAL TRANSCRIPTIONAL AND SPLICING PATTERNS OF GENES. THESE STUDIES PROVIDE NEW INSIGHTS INTO THE MECHANISM OF IAS-MEDIATED PATHOLOGY, WHICH INCLUDES EPIGENETIC CHROMATIN CHANGES COUPLED WITH CHANGES TO THE TRANSCRIPTOME AND SPLICING PATTERNS OF KEY GENES.	2015	
                                                                                                                                                                     
7 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
8 1269  33 CYTOSINE METHYLATION CHANGES IN ENHANCER REGIONS OF CORE PRO-FIBROTIC GENES CHARACTERIZE KIDNEY FIBROSIS DEVELOPMENT. BACKGROUND: ONE IN ELEVEN PEOPLE IS AFFECTED BY CHRONIC KIDNEY DISEASE, A CONDITION CHARACTERIZED BY KIDNEY FIBROSIS AND PROGRESSIVE LOSS OF KIDNEY FUNCTION. EPIDEMIOLOGICAL STUDIES INDICATE THAT ADVERSE INTRAUTERINE AND POSTNATAL ENVIRONMENTS HAVE A LONG-LASTING ROLE IN CHRONIC KIDNEY DISEASE DEVELOPMENT. EPIGENETIC INFORMATION REPRESENTS A PLAUSIBLE CARRIER FOR MEDIATING THIS PROGRAMMING EFFECT. HERE WE DEMONSTRATE THAT GENOME-WIDE CYTOSINE METHYLATION PATTERNS OF HEALTHY AND CHRONIC KIDNEY DISEASE TUBULE SAMPLES OBTAINED FROM PATIENTS SHOW SIGNIFICANT DIFFERENCES. RESULTS: WE IDENTIFY DIFFERENTIALLY METHYLATED REGIONS AND VALIDATE THESE IN A LARGE REPLICATION DATASET. THE DIFFERENTIALLY METHYLATED REGIONS ARE RARELY OBSERVED ON PROMOTERS, BUT MOSTLY OVERLAP WITH PUTATIVE ENHANCER REGIONS, AND THEY ARE ENRICHED IN CONSENSUS BINDING SEQUENCES FOR IMPORTANT RENAL TRANSCRIPTION FACTORS. THIS INDICATES THEIR IMPORTANCE IN GENE EXPRESSION REGULATION. A CORE SET OF GENES THAT ARE KNOWN TO BE RELATED TO KIDNEY FIBROSIS, INCLUDING GENES ENCODING COLLAGENS, SHOW CYTOSINE METHYLATION CHANGES CORRELATING WITH DOWNSTREAM TRANSCRIPT LEVELS. CONCLUSIONS: OUR REPORT RAISES THE POSSIBILITY THAT EPIGENETIC DYSREGULATION PLAYS A ROLE IN CHRONIC KIDNEY DISEASE DEVELOPMENT VIA INFLUENCING CORE PRO-FIBROTIC PATHWAYS AND CAN AID THE DEVELOPMENT OF NOVEL BIOMARKERS AND FUTURE THERAPEUTICS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
9 2920  31 GENE-SET ANALYSIS IS SEVERELY BIASED WHEN APPLIED TO GENOME-WIDE METHYLATION DATA. MOTIVATION: DNA METHYLATION IS AN EPIGENETIC MARK THAT CAN STABLY REPRESS GENE EXPRESSION. BECAUSE OF ITS BIOLOGICAL AND CLINICAL SIGNIFICANCE, SEVERAL METHODS HAVE BEEN DEVELOPED TO COMPARE GENOME-WIDE PATTERNS OF METHYLATION BETWEEN GROUPS OF SAMPLES. THE APPLICATION OF GENE SET ANALYSIS TO IDENTIFY RELEVANT GROUPS OF GENES THAT ARE ENRICHED FOR DIFFERENTIALLY METHYLATED GENES IS OFTEN A MAJOR COMPONENT OF THE ANALYSIS OF THESE DATA. THIS CAN BE USED, FOR EXAMPLE, TO IDENTIFY PROCESSES OR PATHWAYS THAT ARE PERTURBED IN DISEASE DEVELOPMENT. WE SHOW THAT GENE-SET ANALYSIS, AS IT IS TYPICALLY APPLIED TO GENOME-WIDE METHYLATION ASSAYS, IS SEVERELY BIASED AS A RESULT OF DIFFERENCES IN THE NUMBERS OF CPG SITES ASSOCIATED WITH DIFFERENT CLASSES OF GENES AND GENE PROMOTERS. RESULTS: WE DEMONSTRATE THIS BIAS USING PUBLISHED DATA FROM A STUDY OF DIFFERENTIAL CPG ISLAND METHYLATION IN LUNG CANCER AND A DATASET WE GENERATED TO STUDY METHYLATION CHANGES IN PATIENTS WITH LONG-STANDING ULCERATIVE COLITIS. WE SHOW THAT SEVERAL OF THE GENE SETS THAT SEEM ENRICHED WOULD ALSO BE IDENTIFIED WITH RANDOMIZED DATA. WE SUGGEST TWO EXISTING APPROACHES THAT CAN BE ADAPTED TO CORRECT THE BIAS. ACCOUNTING FOR THE BIAS IN THE LUNG CANCER AND ULCERATIVE COLITIS DATASETS PROVIDES NOVEL BIOLOGICAL INSIGHTS INTO THE ROLE OF METHYLATION IN CANCER DEVELOPMENT AND CHRONIC INFLAMMATION, RESPECTIVELY. OUR RESULTS HAVE SIGNIFICANT IMPLICATIONS FOR MANY PREVIOUS GENOME-WIDE METHYLATION STUDIES THAT HAVE DRAWN CONCLUSIONS ON THE BASIS OF SUCH STRONGLY BIASED ANALYSIS. CONTACT: CATHAL.SEOIGHE@NUIGALWAY.IE SUPPLEMENTARY INFORMATION: SUPPLEMENTARY DATA ARE AVAILABLE AT BIOINFORMATICS ONLINE.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
10  287  27 AGING AND CHRONIC SUN EXPOSURE CAUSE DISTINCT EPIGENETIC CHANGES IN HUMAN SKIN. EPIGENETIC CHANGES ARE WIDELY CONSIDERED TO PLAY AN IMPORTANT ROLE IN AGING, BUT EXPERIMENTAL EVIDENCE TO SUPPORT THIS HYPOTHESIS HAS BEEN SCARCE. WE HAVE USED ARRAY-BASED ANALYSIS TO DETERMINE GENOME-SCALE DNA METHYLATION PATTERNS FROM HUMAN SKIN SAMPLES AND TO INVESTIGATE THE EFFECTS OF AGING, CHRONIC SUN EXPOSURE, AND TISSUE VARIATION. OUR RESULTS REVEAL A HIGH DEGREE OF TISSUE SPECIFICITY IN THE METHYLATION PATTERNS AND ALSO SHOWED VERY LITTLE INTERINDIVIDUAL VARIATION WITHIN TISSUES. DATA STRATIFICATION BY AGE REVEALED THAT DNA FROM OLDER INDIVIDUALS WAS CHARACTERIZED BY A SPECIFIC HYPERMETHYLATION PATTERN AFFECTING LESS THAN 1% OF THE MARKERS ANALYZED. INTERESTINGLY, STRATIFICATION BY SUN EXPOSURE PRODUCED A FUNDAMENTALLY DIFFERENT PATTERN WITH A SIGNIFICANT TREND TOWARDS HYPOMETHYLATION. OUR RESULTS THUS IDENTIFY DEFINED AGE-RELATED DNA METHYLATION CHANGES AND SUGGEST THAT THESE ALTERATIONS MIGHT CONTRIBUTE TO THE PHENOTYPIC CHANGES ASSOCIATED WITH SKIN AGING.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
11  652  33 BISPHENOL A AS EPIGENETIC MODULATOR: SETTING THE STAGE FOR CARCINOGENESIS? BACKGROUND: BISPHENOL A (BPA) IS ONE OF THE MOST WIDELY PRODUCED CHEMICALS WORLDWIDE AND IS OFTEN USED IN THE PRODUCTION OF FOOD AND BEVERAGE CONTAINERS. AS A RESULT OF BPA CONTACT WITH FOOD, DRINK AND TOILETRIES, ITS INGESTION AND ABSORPTION BY HUMANS HAS BEEN GROWING. THE INDUSTRIALIZATION AND MODERN LIFESTYLES BROUGHT A CONSTANT EXPOSURE TO SEVERAL HEALTH-DISTURBING COMPOUNDS AND USHERED A NEW ERA OF CHRONIC DISEASES. THE ENDOCRINE DISRUPTOR POTENTIAL OF BPA IS WELL KNOWN, BUT THE RESEARCH AROUND ITS EPIGENOTOXIC EFFECTS RAISED FURTHER CONCERNS WHETHER CHRONIC EXPOSURE TO BPA CAN CONTRIBUTE TO CHRONIC HUMAN ILLNESS, INCLUDING CANCER IN HORMONE-SENSITIVE ORGANS. MATERIALS AND METHODS: FOCUSING ON COMPUTERIZED DATABASES, WE REVIEWED ORIGINAL AND REVIEW ARTICLES WHICH ELUCIDATE AND LINK SOME OF THE INFORMATION ALREADY AVAILABLE ABOUT BPA AND RELATED EPIGENETIC ALTERATIONS. RESULTS: A NUMBER OF STUDIES INDICATE THAT SHORT-TERM ADMINISTRATION OF LOW OR HIGH-DOSES OF BPA MAY BE ASSOCIATED WITH AN INCREASED RISK OF EPIGENETIC MODIFICATIONS, INCREASING THE RISK FOR CARCINOGENESIS. HOWEVER, IT IS CLEAR THAT MORE STUDIES CONSIDERING REAL DAILY EXPOSURES ARE ESSENTIAL TO DEFINE A REAL TOLERABLE DAILY INTAKE AND TO TIGHTEN UP MANUFACTORY REGULATIONS. CONCLUSION: IN THIS REVIEW, WE HIGHLIGHT SOME EVIDENCES SUGGESTING A RELATIONSHIP BETWEEN BPA EXPOSURE, GENOTOXIC ACTIVITY AND EPIGENETIC MODIFICATIONS, WHICH MAY PRIME FOR CARCINOGENESIS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
12 1583  28 DNA METHYLATION PROFILES OF BLOOD CELLS ARE DISTINCT BETWEEN EARLY-ONSET OBESE AND CONTROL INDIVIDUALS. OBESITY IS A HIGHLY PREVALENT, CHRONIC DISORDER THAT HAS BEEN INCREASING IN INCIDENCE IN YOUNG PATIENTS. BOTH EPIGENETIC AND GENETIC ABERRATIONS MAY PLAY A ROLE IN THE PATHOGENESIS OF OBESITY. THEREFORE, IN-DEPTH EPIGENOMIC AND GENOMIC ANALYSES WILL ADVANCE OUR UNDERSTANDING OF THE DETAILED MOLECULAR MECHANISMS UNDERLYING OBESITY AND AID IN THE SELECTION OF POTENTIAL BIOMARKERS FOR OBESITY IN YOUTH. HERE, WE PERFORMED MICROARRAY-BASED DNA METHYLATION AND GENE EXPRESSION PROFILING OF PERIPHERAL WHITE BLOOD CELLS OBTAINED FROM SIX YOUNG, OBESE INDIVIDUALS AND SIX HEALTHY CONTROLS. WE OBSERVED THAT THE HIERARCHICAL CLUSTERING OF DNA METHYLATION, BUT NOT GENE EXPRESSION, CLEARLY SEGREGATES THE OBESE INDIVIDUALS FROM THE CONTROLS, SUGGESTING THAT THE METABOLIC DISTURBANCE THAT OCCURS AS A RESULT OF OBESITY AT A YOUNG AGE MAY AFFECT THE DNA METHYLATION OF PERIPHERAL BLOOD CELLS WITHOUT ACCOMPANYING TRANSCRIPTIONAL CHANGES. TO EXAMINE THE GENOME-WIDE DIFFERENCES IN THE DNA METHYLATION PROFILES OF YOUNG OBESE AND CONTROL INDIVIDUALS, WE IDENTIFIED DIFFERENTIALLY METHYLATED CPG SITES AND INVESTIGATED THEIR GENOMIC AND EPIGENOMIC CONTEXTS. THE ABERRANT DNA METHYLATION PATTERNS IN OBESE INDIVIDUALS CAN BE SUMMARIZED AS RELATIVE GAINS AND LOSSES OF DNA METHYLATION IN GENE PROMOTERS AND GENE BODIES, RESPECTIVELY. WE ALSO OBSERVED THAT THE CPG ISLANDS OF OBESE INDIVIDUALS ARE MORE SUSCEPTIBLE TO DNA METHYLATION COMPARED TO CONTROLS. OUR PILOT STUDY SUGGESTS THAT THE GENOME-WIDE ABERRANT DNA METHYLATION PATTERNS OF OBESE INDIVIDUALS MAY ADVANCE NOT ONLY OUR UNDERSTANDING OF THE EPIGENOMIC PATHOGENESIS BUT ALSO EARLY SCREENING OF OBESITY IN YOUTH.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
13 1599  33 DNA METHYLATION SIGNATURE OF CHILDHOOD CHRONIC PHYSICAL AGGRESSION IN T CELLS OF BOTH MEN AND WOMEN. BACKGROUND: HIGH FREQUENCY OF PHYSICAL AGGRESSION IS THE CENTRAL FEATURE OF SEVERE CONDUCT DISORDER AND IS ASSOCIATED WITH A WIDE RANGE OF SOCIAL, MENTAL AND PHYSICAL HEALTH PROBLEMS. WE HAVE PREVIOUSLY TESTED THE HYPOTHESIS THAT DIFFERENTIAL DNA METHYLATION SIGNATURES IN PERIPHERAL T CELLS ARE ASSOCIATED WITH A CHRONIC AGGRESSION TRAJECTORY IN MALES. DESPITE THE FACT THAT SEX DIFFERENCES APPEAR TO PLAY A PIVOTAL ROLE IN DETERMINING THE DEVELOPMENT, MAGNITUDE AND FREQUENCY OF AGGRESSION, MOST OF PREVIOUS STUDIES FOCUSED ON MALES, SO LITTLE IS KNOWN ABOUT FEMALE CHRONIC PHYSICAL AGGRESSION. WE THEREFORE TESTED HERE WHETHER OR NOT THERE IS A SIGNATURE OF PHYSICAL AGGRESSION IN FEMALE DNA METHYLATION AND, IF THERE IS, HOW IT RELATES TO THE SIGNATURE OBSERVED IN MALES. METHODOLOGY/PRINCIPAL FINDINGS: METHYLATION PROFILES WERE CREATED USING THE METHOD OF METHYLATED DNA IMMUNOPRECIPITATION (MEDIP) FOLLOWED BY MICROARRAY HYBRIDIZATION AND STATISTICAL AND BIOINFORMATIC ANALYSES ON T CELL DNA OBTAINED FROM ADULT WOMEN WHO WERE FOUND TO BE ON A CHRONIC PHYSICAL AGGRESSION TRAJECTORY (CPA) BETWEEN 6 AND 12 YEARS OF AGE COMPARED TO WOMEN WHO FOLLOWED A NORMAL PHYSICAL AGGRESSION TRAJECTORY. WE CONFIRMED THE EXISTENCE OF A WELL-DEFINED, GENOME-WIDE SIGNATURE OF DNA METHYLATION ASSOCIATED WITH CHRONIC PHYSICAL AGGRESSION IN THE PERIPHERAL T CELLS OF ADULT FEMALES THAT INCLUDES MANY OF THE GENES SIMILARLY ASSOCIATED WITH PHYSICAL AGGRESSION IN THE SAME CELL TYPES OF ADULT MALES. CONCLUSIONS: THIS STUDY IN A SMALL NUMBER OF WOMEN PRESENTS PRELIMINARY EVIDENCE FOR A GENOME-WIDE VARIATION IN PROMOTER DNA METHYLATION THAT ASSOCIATES WITH CPA IN WOMEN THAT WARRANT LARGER STUDIES FOR FURTHER VERIFICATION. A SIGNIFICANT PROPORTION OF THESE ASSOCIATIONS WERE PREVIOUSLY OBSERVED IN MEN WITH CPA SUPPORTING THE HYPOTHESIS THAT THE EPIGENETIC SIGNATURE OF EARLY LIFE AGGRESSION IN FEMALES IS COMPOSED OF A COMPONENT SPECIFIC TO FEMALES AND ANOTHER COMMON TO BOTH MALES AND FEMALES.	2014	
                                                                                                                                                                           
14 2483  25 EPIGENETIC VARIATION AND HUMAN DISEASE. CYTOSINE GUANINE DINUCLEOTIDE (CPG) ISLAND METHYLATION IS A KNOWN MECHANISM OF EPIGENETIC INHERITANCE IN POSTMEIOTIC CELLS. THROUGH ASSOCIATED CHROMATIN CHANGES AND SILENCING, SUCH EPIGENETIC STATES CAN INFLUENCE CELLULAR PHYSIOLOGY AND AFFECT DISEASE RISK AND SEVERITY. OUR STUDIES OF CPG ISLAND METHYLATION IN NORMAL COLORECTAL MUCOSA REVEALED PROGRESSIVE AGE-RELATED INCREASES AT MULTIPLE GENE LOCI, SUGGESTING GENOME-WIDE MOLECULAR ALTERATIONS WITH POTENTIAL TO SILENCE GENE EXPRESSION. HOWEVER, THERE WAS CONSIDERABLE VARIATION IN THE DEGREE OF METHYLATION AMONG INDIVIDUALS OF COMPARABLE AGES. SUCH VARIATION COULD BE RELATED TO GENETIC FACTORS, LIFESTYLE, OR ENVIRONMENTAL EXPOSURES. STUDIES IN ULCERATIVE COLITIS AND HEPATOCELLULAR CIRRHOSIS AND NEOPLASIA REVEALED THAT CHRONIC INFLAMMATORY STATES ARE ACCOMPANIED BY MARKED INCREASES IN CPG ISLAND METHYLATION IN NORMAL-APPEARING TISSUES, CONFIRMING THE HYPOTHESIS THAT PROINFLAMMATORY EXPOSURES COULD ACCOUNT FOR PART OF THE EPIGENETIC VARIATION IN HUMAN POPULATIONS. PRELIMINARY DATA ALSO SUGGEST POTENTIAL INFLUENCES OF LIFESTYLE AND EXPOSURE FACTORS ON CPG ISLAND METHYLATION. IT IS SUGGESTED THAT EPIGENETIC VARIATION RELATED TO AGING, LIFESTYLE, EXPOSURES AND POSSIBLY GENETIC FACTORS, IS ONE OF THE MODULATORS OF ACQUIRED, AGE-RELATED HUMAN DISEASES, INCLUDING NEOPLASIA.	2002	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
15 4093  29 MATERNAL SEPARATION FOLLOWED BY CHRONIC MILD STRESS IN ADULTHOOD IS ASSOCIATED WITH CONCERTED EPIGENETIC REGULATION OF AP-1 COMPLEX GENES. DEPRESSION IS ONE OF THE MOST PREVALENT MENTAL DISEASES WORLDWIDE. PATIENTS WITH PSYCHIATRIC DISEASES OFTEN HAVE A HISTORY OF CHILDHOOD NEGLECT, INDICATING THAT EARLY-LIFE EXPERIENCES PREDISPOSE TO PSYCHIATRIC DISEASES IN ADULTHOOD. TWO STRONG MODELS WERE USED IN THE PRESENT STUDY: THE MATERNAL SEPARATION/EARLY DEPRIVATION MODEL (MS) AND THE CHRONIC MILD STRESS MODEL (CMS). IN BOTH MODELS, WE FOUND CHANGES IN THE EXPRESSION OF A NUMBER OF GENES SUCH AS CREB AND NPY. STRIKINGLY, THERE WAS A CLEAR REGULATION OF EXPRESSION OF FOUR GENES INVOLVED IN THE AP-1 COMPLEX: C-FOS, C-JUN, FOSB, AND JUN-B. INTERESTINGLY, DIFFERENT EXPRESSION LEVELS WERE OBSERVED DEPENDING ON THE MODEL, WHEREAS THE COMBINATION OF THE MODELS RESULTED IN A NORMAL LEVEL OF GENE EXPRESSION. THE EFFECTS OF MS AND CMS ON GENE EXPRESSION WERE ASSOCIATED WITH DISTINCT HISTONE METHYLATION/ACETYLATION PATTERNS OF ALL FOUR GENES. THE EPIGENETIC CHANGES, LIKE GENE EXPRESSION, WERE ALSO DEPENDENT ON THE SPECIFIC STRESSOR OR THEIR COMBINATION. THE OBTAINED RESULTS SUGGEST THAT SINGLE LIFE EVENTS LEAVE A MARK ON GENE EXPRESSION AND THE EPIGENETIC SIGNATURE OF GENE PROMOTERS, BUT A COMBINATION OF DIFFERENT STRESSORS AT DIFFERENT LIFE STAGES CAN FURTHER CHANGE GENE EXPRESSION THROUGH EPIGENETIC FACTORS, POSSIBLY CAUSING THE LONG-LASTING ADVERSE EFFECTS OF STRESS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
16 1817  33 EFFECTS OF CHRONIC METAL EXPOSURE ON WILD FISH POPULATIONS REVEALED BY HIGH-THROUGHPUT CDNA SEQUENCING. GIVEN THE INHERENT VARIABILITY OF AQUATIC SYSTEMS, PREDICTING THE IN SITU EFFECTS OF CONTAMINANTS ON SUCH ECOSYSTEMS STILL REPRESENTS A MAJOR CHALLENGE FOR ECOTOXICOLOGY. IN THIS CONTEXT, TRANSCRIPTOMIC TOOLS CAN HELP IDENTIFY AND INVESTIGATE THE MECHANISMS OF TOXICITY BEYOND THE TRADITIONAL MORPHOMETRIC, PHYSIOLOGICAL AND POPULATION-LEVEL ENDPOINTS. IN THIS STUDY, WE USED THE 454 SEQUENCING TECHNOLOGY TO EXAMINE THE IN SITU EFFECTS OF CHRONIC METAL (CD, CU) EXPOSURE ON THE YELLOW PERCH (PERCA FLAVESCENS) TRANSCRIPTOME. TOTAL HEPATIC MRNA FROM FISH SAMPLED ALONG A POLYMETALLIC GRADIENT WAS EXTRACTED, REVERSE TRANSCRIBED, LABELED WITH UNIQUE BARCODE SEQUENCES AND SEQUENCED. THIS APPROACH ALLOWED US TO IDENTIFY CORRELATIONS BETWEEN THE TRANSCRIPTION LEVEL OF SINGLE GENES AND THE HEPATIC CONCENTRATIONS OF INDIVIDUAL METALS; 71% OF THE CORRELATIONS ESTABLISHED WERE NEGATIVE. CHRONIC METAL EXPOSURE WAS THUS ASSOCIATED WITH A DECREASE IN THE TRANSCRIPTION LEVELS OF NUMEROUS GENES INVOLVED IN PROTEIN BIOSYNTHESIS, IN THE IMMUNE SYSTEM, AND IN LIPID AND ENERGY METABOLISM. OUR RESULTS SUGGEST THAT THIS MARKED DECREASE COULD RESULT FROM AN IMPAIRMENT OF BILE ACID METABOLISM BY CD AND ENERGY RESTRICTION BUT ALSO FROM THE RECRUITMENT OF SEVERAL GENES INVOLVED IN EPIGENETIC MODIFICATIONS OF HISTONES AND DNA THAT LEAD TO GENE SILENCING.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
17 4292  44 MICRORNA PROFILES OF MATERNAL AND NEONATAL ENDOTHELIAL PROGENITOR CELLS IN PREECLAMPSIA. PREECLAMPSIA IS ASSOCIATED WITH AN INCREASED CARDIOVASCULAR MORBIDITY OF MOTHER AND OFFSPRING, THUS CONTRIBUTING TO A SUBSTANTIAL BURDEN IN WOMEN AND CHILDREN'S HEALTH. IT HAS BEEN PROVEN THAT ENDOTHELIAL PROGENITOR CELL (EPC) NUMBERS AND FUNCTIONAL CHARACTERISTICS ARE IMPAIRED IN CARDIOVASCULAR DISEASE AND PREECLAMPSIA, ALTHOUGH CAUSATIVE FACTORS FOR THE LATTER HAVE REMAINED ELUSIVE. MICRORNA (MIRNA) MODIFICATIONS ARE A POTENTIAL MECHANISM THROUGH WHICH EXPOSURE TO AN ALTERED ENVIRONMENT TRANSLATES INTO THE DEVELOPMENT OF CHRONIC DISEASE. IN THIS STUDY, WE EXAMINED WHETHER DEVELOPMENT OF PREECLAMPSIA CORRESPONDS TO ALTERATIONS OF MIRNAS IN MATERNAL- AND CORD-BLOOD-DERIVED EPC. TO TEST THIS END, WE ANALYZED MATERNAL AND NEONATAL MIRNAS VIA RNA SEQUENCING FROM ENDOTHELIAL CELLS OF PREECLAMPTIC AND HEALTHY CONTROLS IN DIFFERENT CELL CULTURE PASSAGES. WE WERE ABLE TO DEMONSTRATE DIFFERENTIALLY REPRESENTED MIRNAS IN ALL GROUPS. HSA-MIR-1270 SHOWED SIGNIFICANTLY DIFFERENT LEVELS IN CORD BLOOD EPC FROM PREECLAMPSIA VERSUS CONTROL AND WAS NEGATIVELY CORRELATED WITH MRNA LEVELS OF ITS PREDICTED TARGETS ANGPTL7 AND TFRC. TRANSFECTION WITH AN HSA-MIR-1270 INHIBITOR DECREASED THE TUBE FORMATION CAPACITY AND CHEMOTACTIC MOTILITY BUT DID NOT CHANGE PROLIFERATION IN VITRO. TARGET PREDICTIONS AND GENE SET ENRICHMENT ANALYSES IDENTIFIED ALTERNATIVE SPLICING AS A SIGNIFICANTLY ENRICHED PATHWAY FOR HSA-MIR-1270. THE TOP MIRNAS IN THREE OTHER GROUPS WERE PREDICTED TO TARGET TRANSCRIPTIONAL AND DEVELOPMENTAL PATHWAYS. HERE, WE SHOWED FOR THE FIRST TIME SIGNIFICANTLY DIFFERENT LEVELS OF MIRNAS AND DIFFERENTLY REPRESENTED MRNA LEVELS OF PREDICTED TARGET GENES IN EPC DERIVED FROM PREECLAMPSIA. UNDERSTANDING THE EFFECTS OF PREECLAMPSIA ON THE EPIGENETIC MECHANISMS OF EPC WILL BE CRUCIAL AND MAY PROVIDE INITIAL INSIGHTS FOR FURTHER EVALUATION OF THE BENEFITS OF THERAPIES TARGETING THIS CELL POPULATION.	2021	
                                                                                                                                                                                                                                                                   
18 3836  35 IONIZING RADIATION POTENTIATES HIGH-FAT DIET-INDUCED INSULIN RESISTANCE AND REPROGRAMS SKELETAL MUSCLE AND ADIPOSE PROGENITOR CELLS. EXPOSURE TO IONIZING RADIATION INCREASES THE RISK OF CHRONIC METABOLIC DISORDERS SUCH AS INSULIN RESISTANCE AND TYPE 2 DIABETES LATER IN LIFE. WE HYPOTHESIZED THAT IRRADIATION REPROGRAMS THE EPIGENOME OF METABOLIC PROGENITOR CELLS, WHICH COULD ACCOUNT FOR IMPAIRED METABOLISM AFTER CANCER TREATMENT. C57BL/6 MICE WERE TREATED WITH A SINGLE DOSE OF IRRADIATION AND SUBJECTED TO HIGH-FAT DIET (HFD). RNA SEQUENCING AND REDUCED REPRESENTATION BISULFITE SEQUENCING WERE USED TO CREATE TRANSCRIPTOMIC AND EPIGENOMIC PROFILES OF PREADIPOCYTES AND SKELETAL MUSCLE SATELLITE CELLS COLLECTED FROM IRRADIATED MICE. MICE SUBJECTED TO TOTAL BODY IRRADIATION SHOWED ALTERATIONS IN GLUCOSE METABOLISM AND, WHEN CHALLENGED WITH HFD, MARKED HYPERINSULINEMIA. INSULIN SIGNALING WAS CHRONICALLY DISRUPTED IN SKELETAL MUSCLE AND ADIPOSE PROGENITOR CELLS COLLECTED FROM IRRADIATED MICE AND DIFFERENTIATED IN CULTURE. EPIGENOMIC PROFILING OF SKELETAL MUSCLE AND ADIPOSE PROGENITOR CELLS FROM IRRADIATED ANIMALS REVEALED SUBSTANTIAL DNA METHYLATION CHANGES, NOTABLY FOR GENES REGULATING THE CELL CYCLE, GLUCOSE/LIPID METABOLISM, AND EXPRESSION OF EPIGENETIC MODIFIERS. OUR RESULTS SHOW THAT TOTAL BODY IRRADIATION ALTERS INTRACELLULAR SIGNALING AND EPIGENETIC PATHWAYS REGULATING CELL PROLIFERATION AND DIFFERENTIATION OF SKELETAL MUSCLE AND ADIPOSE PROGENITOR CELLS AND PROVIDE A POSSIBLE MECHANISM BY WHICH IRRADIATION USED IN CANCER TREATMENT INCREASES THE RISK FOR METABOLIC DISEASE LATER IN LIFE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
19 1511  34 DNA METHYLATION AND POTENTIAL MULTIGENERATIONAL EPIGENETIC EFFECTS LINKED TO URANIUM CHRONIC LOW-DOSE EXPOSURE IN GONADS OF MALES AND FEMALES RATS. INTRODUCTION: AN INCREASED HEALTH PROBLEM IN INDUSTRIALISED COUNTRIES IS THE CONTEMPORARY CONCERN OF PUBLIC AND SCIENTIFIC COMMUNITY AS WELL. THIS HAS BEEN ATTRIBUTED IN PART TO ACCUMULATED ENVIRONMENTAL POLLUTANTS ESPECIALLY RADIOACTIVE SUBSTANCES AND THE USE OF NUCLEAR POWER PLANTS WORLDWIDE. HOWEVER, THE OUTCOME OF CHRONIC EXPOSURE TO LOW DOSES OF A RADIONUCLIDE SUCH AS URANIUM REMAINS UNKNOWN. RECENTLY, A PARADIGM SHIFT IN THE PERCEPTION OF RISK OF RADIOTOXICOLOGY HAS EMERGED THROUGH INVESTIGATING THE POSSIBILITY OF TRANSMISSION OF BIOLOGICAL EFFECTS OVER GENERATIONS, IN PARTICULAR BY EPIGENETIC PATHWAYS. THESE PROCESSES ARE KNOWN FOR THEIR CRUCIAL ROLES ASSOCIATED WITH THE DEVELOPMENT OF SEVERAL DISEASES. OBJECTIVE: THE CURRENT WORK INVESTIGATES THE EPIGENETIC EFFECT OF CHRONIC EXPOSURE TO LOW DOSES OF URANIUM AND ITS INHERITANCE ACROSS GENERATIONS. MATERIALS AND METHODS TO TEST THIS PROPOSITION, A RODENT MULTIGENERATIONAL MODEL, MALES AND FEMALES, WERE EXPOSED TO A NON-TOXIC CONCENTRATION OF URANIUM (40MGL(-1) DRINKING WATER) FOR NINE MONTHS. THE URANIUM EFFECTS ON WERE EVALUATED OVER THREE GENERATIONS (F0, F1 AND F2) BY ANALYSING THE DNA METHYLATION PROFILE AND DNMT GENES EXPRESSION IN OVARIES AND TESTES TISSUES. RESULTS: HERE WE REPORT A SIGNIFICANT HYPERMETHYLATION OF TESTES DNA (P <0.005) WHEREAS OVARIES SHOWED HYPOMETHYLATED DNA (P <0.005). INTERESTINGLY, THIS DNA METHYLATION PROFILE WAS SIGNIFICANTLY MAINTAINED ACROSS GENERATIONS F0, F1 AND F2. FURTHERMORE, QPCR RESULTS OF BOTH TISSUES IMPLY A SIGNIFICANT CHANGE IN THE EXPRESSION OF DNA METHYLTRANSFERASE GENES (DNMT 1 AND DNMT3A/B) AS WELL. CONCLUSION: ALTOGETHER, OUR WORK DEMONSTRATES FOR THE FIRST TIME A SEX-DEPENDANCE AND INHERITANCE OF EPIGENETIC MARKS, DNA METHYLATION, AS A BIOLOGICAL RESPONSE TO THE EXPOSURE TO LOW DOSES OF URANIUM. HOWEVER, IT IS NOT CLEAR WHICH TYPE OF REPRODUCTIVE CELL TYPE IS MORE RESPONSIVE IN THIS CONTEXT.	2018	
                                                                                                                                                                                     
20 3652  33 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