1  5058 145 PHENOTYPIC ALTERATION OF CD8+ T CELLS IN CHRONIC LYMPHOCYTIC LEUKEMIA IS ASSOCIATED WITH EPIGENETIC REPROGRAMMING. IMMUNOSUPPRESSION IS A PREVALENT CLINICAL FEATURE IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) PATIENTS, WITH MANY PATIENTS DEMONSTRATING INCREASED SUSCEPTIBILITY TO INFECTIONS AS WELL AS INCREASED FAILURE OF AN ANTITUMOR IMMUNE RESPONSE. HOWEVER, MUCH IS CURRENTLY NOT UNDERSTOOD REGARDING THE PRECISE MECHANISMS THAT ATTRIBUTE TO THIS IMMUNOSUPPRESSIVE PHENOTYPE IN CLL. TO PROVIDE FURTHER CLARITY TO THIS PARTICULAR PHENOMENON, WE ANALYZED THE T-CELL PROFILE OF CLL PATIENT SAMPLES WITHIN A LARGE COHORT AND OBSERVED THAT PATIENTS WITH AN INVERTED CD4/CD8 RATIO HAD A SHORTER TIME TO FIRST TREATMENT AS WELL AS OVERALL SURVIVAL. THESE OBSERVATIONS COINCIDED WITH HIGHER EXPRESSION OF THE IMMUNE CHECKPOINT RECEPTOR PD-1 IN CLL PATIENT CD8+ T CELLS WHEN COMPARED TO AGE-MATCHED HEALTHY DONORS. INTERESTINGLY, WE DISCOVERED THAT INCREASED PD-1 EXPRESSION IN CD8+ T CELLS CORRESPONDS WITH DECREASED DNA METHYLATION LEVELS IN A DISTAL UPSTREAM LOCUS OF THE PD-1 GENE PDCD1. FURTHER ANALYSIS USING LUCIFERASE REPORTER ASSAYS SUGGESTS THAT THE IDENTIFIED PDCD1 DISTAL UPSTREAM REGION ACTS AS AN ENHANCER FOR PDCD1 TRANSCRIPTION AND THIS REGION BECOMES DEMETHYLATED DURING ACTIVATION OF NAIVE CD8+ T CELLS BY ANTI-CD3/ANTI-CD28 ANTIBODIES AND IL2. FINALLY, WE CONDUCTED A GENOME-WIDE DNA METHYLATION ANALYSIS COMPARING CD8+ T CELLS FROM CLL PATIENTS AGAINST HEALTHY DONORS AND IDENTIFIED ADDITIONAL DIFFERENTIALLY METHYLATED GENES WITH KNOWN IMMUNE REGULATORY FUNCTIONS INCLUDING CCR6 AND KLRG1. TAKEN TOGETHER, OUR FINDINGS REVEAL THE OCCURRENCE OF EPIGENETIC REPROGRAMMING TAKING PLACE WITHIN CLL PATIENT CD8+ T CELLS AND HIGHLIGHT THE POTENTIAL MECHANISM OF HOW IMMUNOSUPPRESSION IS ACCOMPLISHED IN CLL.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
2  1381  34 DI-(2-ETHYLHEXYL) PHTHALATE TRIGGERS DNA METHYLTRANSFERASE 1 EXPRESSION RESULTING IN ELEVATED CPG-METHYLATION AND ENRICHMENT OF MECP2 IN THE P21 PROMOTER IN VITRO. LEACHING OF THE PLASTIC CONSTITUENTS LEADING TO THEIR CHRONIC EXPOSURE TO HUMANS IS A MAJOR CONCERN FOR OUR ENVIRONMENTAL AND OCCUPATIONAL HEALTH. OUR PREVIOUS AND OTHER NUMEROUS STUDIES HAVE DEMONSTRATED THAT ENVIRONMENTAL CHEMICALS LIKE DI (2-ETHYLHEXYL)-PHTHALATE (DEHP) COULD POSE A RISK TOWARDS THE EPIGENETIC MECHANISMS. YET, THE MECHANISMS UNDERLYING ITS POSSIBLE EPIGENOTOXICITY ARE POORLY UNDERSTOOD. WE AIMED TO ASSESS THE IMPACT OF DEHP EXPOSURE TO THE HUMAN BREAST CANCER CELLS (MCF-7) AND RESULTANT CHANGES IN DNA METHYLATION REGULATORS ULTIMATELY ALTERING THE EXPRESSION OF THE CELL CYCLE REGULATOR P21 AS A MODEL GENE. THE MCF-7 CELLS WERE EXPOSED TO ENVIRONMENTALLY RELEVANT CONCENTRATIONS (50-500 NM) FOR 24 H. THE RESULTS SHOWED THAT DEHP WAS PROLIFERATIVE TOWARDS THE MCF-7 CELLS WHILE IT INDUCED GLOBAL DNA HYPERMETHYLATION WITH SELECTIVE UPREGULATION OF DNMT1 AND MECP2. IN ADDITION, DEHP SIGNIFICANTLY REDUCED P53 PROTEIN AND ITS ENRICHMENT TO THE DNMT1 PROMOTER BINDING SITE, WHILE ELEVATING SP1 AND E2F1 TRANSCRIPTION FACTOR LEVELS, STIMULATING THEIR BINDING TO THE PROMOTER DNA. COINCIDENTLY, INCREASED DNMT1 LEVEL WAS HIGHLY ASSOCIATED WITH LOSS OF P21 EXPRESSION AND INCREASED CYCLIN D1 LEVELS. IMPORTANTLY, THE P21, BUT NOT CYCLIN D1 PROMOTER CPG-DINUCLEOTIDES WERE HYPERMETHYLATED AFTER EXPOSURE TO 500 NM DEHP FOR 24 H. FURTHERMORE, IT WAS OBSERVED THAT DEHP SIGNIFICANTLY ENRICHED DNMT1 AND MECP2 TO THE P21 PROMOTER TO INDUCE DNA METHYLATION-BASED EPIGENETIC SILENCING OF P21, RESULTING IN INCREASED CELL PROLIFERATION. OUR RESULTS SUGGEST DEHP COULD POTENTIALLY INDUCE THE EPIGENETIC ALTERATIONS THAT MIGHT INCREASE THE RISK OF BREAST CANCER, GIVEN THAT THE UNDERLYING MECHANISMS SHOULD BE FULLY ELUCIDATED.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
3  1723  40 DYSREGULATION OF C-X-C MOTIF LIGAND 10 DURING AGING AND ASSOCIATION WITH COGNITIVE PERFORMANCE. CHRONIC LOW-GRADE INFLAMMATION DURING AGING (INFLAMMAGING) IS ASSOCIATED WITH COGNITIVE DECLINE AND NEURODEGENERATION; HOWEVER, THE MECHANISMS UNDERLYING INFLAMMAGING ARE UNCLEAR. WE STUDIED A POPULATION (N = 361) OF HEALTHY YOUNG AND OLD ADULTS FROM THE MYOAGE COHORT. PERIPHERAL LEVELS OF C-X-C MOTIF CHEMOKINE LIGAND 10 (CXCL10) WAS FOUND TO BE HIGHER IN OLDER ADULTS, COMPARED WITH YOUNG, AND NEGATIVELY ASSOCIATED WITH WORKING MEMORY PERFORMANCE. THIS COINCIDED WITH AN AGE-RELATED REDUCTION IN BLOOD DNA METHYLATION AT SPECIFIC CPGS WITHIN THE CXCL10 GENE PROMOTER. IN VITRO ANALYSIS SUPPORTED THE ROLE OF DNA METHYLATION IN REGULATING CXCL10 TRANSCRIPTION. A POLYMORPHISM (RS56061981) THAT ALTERED METHYLATION AT ONE OF THESE CPG SITES FURTHER ASSOCIATED WITH WORKING MEMORY PERFORMANCE IN 2 INDEPENDENT AGING COHORTS. STUDYING PREFRONTAL CORTEX SAMPLES, WE FOUND HIGHER CXCL10 PROTEIN LEVELS IN THOSE WITH ALZHEIMER'S DISEASE, COMPARED WITH AGED CONTROLS. THESE FINDINGS SUPPORT THE ASSOCIATION OF PERIPHERAL INFLAMMATION, AS DEMONSTRATED BY CXCL10, IN AGING AND COGNITIVE DECLINE. WE REVEAL AGE-RELATED EPIGENETIC AND GENETIC FACTORS WHICH CONTRIBUTE TO THE DYSREGULATION OF CXCL10.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
4  2392  36 EPIGENETIC REPRESSION OF INTERLEUKIN 2 EXPRESSION IN SENESCENT CD4+ T CELLS DURING CHRONIC HIV TYPE 1 INFECTION. THE MOLECULAR MECHANISMS FOR IL2 GENE-SPECIFIC DYSREGULATION DURING CHRONIC HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 (HIV-1) INFECTION ARE UNKNOWN. HERE, WE INVESTIGATED THE ROLE OF DNA METHYLATION IN SUPPRESSING INTERLEUKIN 2 (IL-2) EXPRESSION IN MEMORY CD4(+) T CELLS DURING CHRONIC HIV-1 INFECTION. WE OBSERVED THAT CPG SITES IN THE IL2 PROMOTER OF CD4(+) T CELLS WERE FULLY METHYLATED IN NAIVE CD4(+) T CELLS AND SIGNIFICANTLY DEMETHYLATED IN THE MEMORY POPULATIONS. INTERESTINGLY, WE FOUND THAT THE MEMORY CELLS THAT HAD A TERMINALLY DIFFERENTIATED PHENOTYPE AND EXPRESSED CD57 HAD INCREASED IL2 PROMOTER METHYLATION RELATIVE TO LESS DIFFERENTIATED MEMORY CELLS IN HEALTHY INDIVIDUALS. IMPORTANTLY, EARLY EFFECTOR MEMORY SUBSETS FROM HIV-1-INFECTED SUBJECTS EXPRESSED HIGH LEVELS OF CD57 AND WERE HIGHLY METHYLATED AT THE IL2 LOCUS. FURTHERMORE, THE INCREASED CD57 EXPRESSION ON MEMORY CD4(+) T CELLS WAS INVERSELY CORRELATED WITH IL-2 PRODUCTION. THESE DATA SUGGEST THAT DNA METHYLATION AT THE IL2 LOCUS IN CD4(+) T CELLS IS COUPLED TO IMMUNOSENESCENCE AND PLAYS A CRITICAL ROLE IN THE BROAD DYSFUNCTION THAT OCCURS IN POLYCLONAL T CELLS DURING HIV-1 INFECTION.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
5  6764  39 ZINC DEFICIENCY ENHANCED INFLAMMATORY RESPONSE BY INCREASING IMMUNE CELL ACTIVATION AND INDUCING IL6 PROMOTER DEMETHYLATION. SCOPE: ZINC DEFICIENCY RESULTS IN IMMUNE DYSFUNCTION AND PROMOTES SYSTEMIC INFLAMMATION. THE OBJECTIVE OF THIS STUDY WAS TO EXAMINE THE EFFECTS OF ZINC DEFICIENCY ON CELLULAR IMMUNE ACTIVATION AND EPIGENETIC MECHANISMS THAT PROMOTE INFLAMMATION. THIS WORK IS POTENTIALLY RELEVANT TO THE AGING POPULATION GIVEN THAT AGE-RELATED IMMUNE DEFECTS, INCLUDING CHRONIC INFLAMMATION, COINCIDE WITH DECLINING ZINC STATUS. METHODS AND RESULTS: AN IN VITRO CELL CULTURE SYSTEM AND THE AGED MOUSE MODEL WERE USED TO CHARACTERIZE IMMUNE ACTIVATION AND DNA METHYLATION PROFILES THAT MAY CONTRIBUTE TO THE ENHANCED PROINFLAMMATORY RESPONSE MEDIATED BY ZINC DEFICIENCY. ZINC DEFICIENCY UPREGULATED CELL ACTIVATION MARKERS ICAM1, MHC CLASS II, AND CD86 IN THP1 CELLS, WHICH COINCIDED WITH INCREASED IL1BETA AND IL6 RESPONSES FOLLOWING LPS STIMULATION. A DECREASED ZINC STATUS IN AGED MICE WAS SIMILARLY ASSOCIATED WITH INCREASED ICAM1 AND IL6 GENE EXPRESSION. REDUCED IL6 PROMOTER METHYLATION WAS OBSERVED IN ZINC-DEFICIENT THP1 CELLS, AS WELL AS IN AGED MICE AND HUMAN LYMPHOBLASTOID CELL LINES DERIVED FROM AGED INDIVIDUALS. CONCLUSION: ZINC DEFICIENCY INDUCED INFLAMMATORY RESPONSE IN PART BY ELICITING ABERRANT IMMUNE CELL ACTIVATION AND ALTERED PROMOTER METHYLATION. OUR RESULTS SUGGESTED POTENTIAL INTERACTIONS BETWEEN ZINC STATUS, EPIGENETICS, AND IMMUNE FUNCTION, AND HOW THEIR DYSREGULATION COULD CONTRIBUTE TO CHRONIC INFLAMMATION.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
6  5057  20 PHENOBARBITAL MECHANISTIC DATA AND RISK ASSESSMENT: ENZYME INDUCTION, ENHANCED CELL PROLIFERATION, AND TUMOR PROMOTION. CHRONIC EXPOSURE TO HIGH DOSES OF PHENOBARBITAL (PB) CAUSES HEPATOCELLULAR ADENOMAS IN BOTH MICE AND RATS AND HEPATOCELLULAR CARCINOMAS IN SOME STRAINS OF MICE. LONG-TERM PB THERAPY HAS NOT BEEN FOUND TO CAUSE HUMAN TUMORS. PB IS NOT DNA REACTIVE, AND MOST GENOTOXICITY TESTS HAVE YIELDED NEGATIVE RESULTS. PB HAS BEEN EXTENSIVELY STUDIED AS AN EPIGENETIC, RODENT LIVER TUMOR PROMOTER. AT EXPOSURES CAUSING RODENT LIVER TUMORS, PB HAS MEASURABLE EFFECTS ON HEPATOCYTES: PB INHIBITS CELL-TO-CELL COMMUNICATION; PB INDUCES ENZYMES, INCLUDING P450 CYTOCHROMES; PB STIMULATES PROLIFERATION AND INHIBITS APOPTOSIS OF HEPATOCYTES IN NEOPLASTIC FOCI. THRESHOLD EXPOSURES FOR SOME OF THESE ENDPOINTS COINCIDE WITH THE THRESHOLD EXPOSURE FOR TUMORIGENESIS.	1996	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
7  1960  35 EPIGENETIC AGING IN CHILDREN FROM A SMALL-SCALE FARMING SOCIETY IN THE CONGO BASIN: ASSOCIATIONS WITH CHILD GROWTH AND FAMILY CONFLICT. DEVELOPMENTAL ENVIRONMENTS INFLUENCE INDIVIDUALS' LONG-TERM HEALTH TRAJECTORIES, AND THERE IS INCREASING EMPHASIS ON UNDERSTANDING THE BIOLOGICAL PATHWAYS THROUGH WHICH THIS OCCURS. EPIGENETIC AGING EVALUATES DNA METHYLATION AT A SUITE OF DISTINCT CPG SITES IN THE GENOME, AND EPIGENETIC AGE ACCELERATION (EAA) IS LINKED TO HEIGHTENED CHRONIC MORBIDITY AND MORTALITY RISKS IN ADULTS. CONSEQUENTLY, EAA PROVIDES INSIGHTS ON TRAJECTORIES OF BIOLOGICAL AGING, WHICH EARLY LIFE EXPERIENCES MAY HELP SHAPE. HOWEVER, FEW STUDIES HAVE MEASURED CORRELATES OF CHILDREN'S EPIGENETIC AGING, ESPECIALLY OUTSIDE OF THE U.S. AND EUROPE. IN PARTICULAR, LITTLE IS KNOWN ABOUT HOW CHILDREN'S GROWTH AND DEVELOPMENT RELATE TO EAA IN ECOLOGIES IN WHICH ENERGETIC AND PATHOGENIC STRESSORS ARE COMMONPLACE. WE STUDIED EAA FROM DRIED BLOOD SPOTS AMONG BONDONGO CHILDREN (N = 54) RESIDING IN A SMALL-SCALE, FISHER-FARMER SOCIETY IN A REMOTE REGION OF THE REPUBLIC OF THE CONGO. HERE, INFECTIOUS DISEASE BURDENS AND THEIR RESULTANT ENERGY DEMANDS ARE HIGH. CHILDREN WHO WERE HEAVIER FOR HEIGHT OR TALLER FOR AGE, RESPECTIVELY, EXHIBITED GREATER EAA, INCLUDING INTRINSIC EAA, WHICH IS CONSIDERED TO MEASURE EAA INTERNAL TO CELLS. FURTHERMORE, WE FOUND THAT CHILDREN IN FAMILIES WITH MORE CONFLICT BETWEEN PARENTS HAD GREATER INTRINSIC EAA. THESE RESULTS SUGGEST THAT IN CONTEXTS IN WHICH LIMITED ENERGY MUST BE ALLOCATED TO COMPETING DEMANDS, MORE INVESTMENT IN GROWTH MAY COINCIDE WITH GREATER EAA, WHICH PARALLELS FINDINGS IN EUROPEAN CHILDREN WHO DO NOT FACE SIMILAR ENERGETIC CONSTRAINTS. OUR FINDINGS ALSO INDICATE THAT ASSOCIATIONS BETWEEN ADVERSE FAMILY ENVIRONMENTS AND GREATER INTRINSIC EAA WERE NONETHELESS OBSERVABLE BUT ONLY AFTER ADJUSTMENT FOR COVARIATES RELEVANT TO THE ENERGETICALLY AND IMMUNOLOGICALLY DEMANDING NATURE OF THE LOCAL ECOLOGY.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
8  3857  39 ISCHEMIA- REPERFUSION INJURY AND ITS INFLUENCE ON THE EPIGENETIC MODIFICATION OF THE DONOR KIDNEY GENOME. BACKGROUND: IN CLINICAL TRANSPLANTATION, ISCHEMIA-REPERFUSION INJURY (I/RI) CAUSES DAMAGE TO DNA. WE HYPOTHESIZE THAT ONE FORM OF DAMAGE IS THE DEMETHYLATION OF METHYLATED CYTOSINES IN THE DONOR GENOME CAUSED BY THE OXIDATIVE ENVIRONMENT CREATED FIRST BY ISCHEMIA, AND SUBSEQUENTLY BY REPERFUSION ON TRANSPLANTATION. THIS STUDY CONTRIBUTES TO THE UNDERSTANDING OF HOW THE SHORT-LIVED AND TRANSIENT ISCHEMIC INSULT MAY INFLUENCE CHRONIC PATHOLOGICAL CHANGES THAT OCCUR IN CLINICAL TRANSPLANTATION IN THE LONG TERM. METHODS: A MODEL OF I/RI AND CHRONIC REJECTION; FISHER TO FISHER KIDNEY TRANSPLANT RENDERED COLD-ISCHEMIC FOR 4 HR BEFORE TRANSPLANTATION, TO INDUCE ANTIGEN-INDEPENDENT CHRONIC NEPHROPATHY OVER A 6-MONTH PERIOD, WAS USED. TISSUE WAS ASSESSED BY HISTOPATHOLOGY AND METHYLATION BY PYROSEQUENCING ANALYSIS. RESULTS: AN EPIGENETIC MAP OF THE RAT RENAL C3 PROMOTER WAS PRODUCED, WHICH IDENTIFIED METHYLATED CYTOSINE PHOSPHO GUANINE (CPG) SITES COINCIDENT TO CYTOKINE RESPONSE ELEMENTS AND NUCLEAR FACTOR KAPPA-LIGHT-CHAIN-ENHANCER OF ACTIVATED B CELLS (NF-KAPPAB) BINDING SITES. PYROSEQUENCING ANALYSIS SHOWED THAT THE TISSUE THAT HAD UNDERGONE 4 HR ISCHEMIA AND REPERFUSION DEVELOPED ABERRANT DEMETHYLATION OF CYTOSINES IN PUTATIVE REGULATORY SITES WITHIN THE C3 PROMOTER. CONCLUSION: THESE FINDINGS MAY DESCRIBE A NEWLY RECOGNIZED PHENOMENA IN THE FIELD OF TRANSPLANTATION. ABERRANT DEMETHYLATION HAS LONG BEEN LINKED TO THE DEVELOPMENT OF TUMORS, AND OUR DATA SUGGEST A SIMILAR MECHANISM OF GENE DYSREGULATION THAT MAY BE INITIATED BY I/RI WITH ACUTE AND CHRONIC EFFECTS. THESE DATA MAY CONTRIBUTE TO A FURTHER UNDERSTANDING OF HOW THE SHORT LIVED AND TRANSIENT ISCHEMIC INSULT INFLUENCES CHRONIC PATHOLOGICAL CHANGES THAT OCCUR EVEN IN THE ABSENCE OF MAJOR HISTOCOMPATIBILITY COMPLEX DISPARITY IN TRANSPLANTATION.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
9  3042  38 GENOME-WIDE ALTERATION OF HISTONE METHYLATION PROFILES ASSOCIATED WITH COGNITIVE CHANGES IN RESPONSE TO DEVELOPMENTAL ARSENIC EXPOSURE IN MICE. INORGANIC ARSENIC IS A XENOBIOTIC ENTERING THE BODY PRIMARILY THROUGH CONTAMINATED DRINKING WATER AND FOOD. THERE ARE DEFINED MECHANISMS THAT DESCRIBE ARSENIC'S ASSOCIATION WITH INCREASED CANCER INCIDENCE, HOWEVER MECHANISMS EXPLAINING ARSENIC EXPOSURE AND NEURODEVELOPMENTAL OR AGING DISORDERS ARE POORLY DEFINED. IN RECENT YEARS, ARSENIC EFFECTS ON EPIGENOME HAVE BECOME A PARTICULAR FOCUS. WE HYPOTHESIZE THAT HUMAN RELEVANT ARSENIC EXPOSURE DURING PARTICULAR DEVELOPMENTAL WINDOWS, OR LONG-TERM EXPOSURE LATER IN LIFE INDUCE PATHOPHYSIOLOGICAL NEURAL CHANGES THROUGH EPIGENOMIC ALTERATIONS, IN PARTICULAR HISTONE METHYLATION PROFILE, MANIFESTING AS COGNITIVE DECLINE. C57BL/6 WILD-TYPE MICE WERE CONTINUALLY EXPOSED TO SODIUM ARSENITE (100 MICROG/L) IN DRINKING WATER PRIOR TO MATING THROUGH WEANING OF THE EXPERIMENTAL PROGENY. A SECOND COHORT OF AGED APP/PS MICE WERE CHRONICALLY EXPOSED TO THE SAME LEVEL OF ARSENIC. COGNITIVE TESTING, HISTOLOGICAL EXAMINATION OF BRAINS AND GENOME-WIDE METHYLATION LEVELS OF H3K4ME3 AND H3K27ME3 EXAMINED AFTER CHIP-SEQ WERE USED TO DETERMINE THE EFFECTS OF ARSENIC EXPOSURE. DEVELOPMENTAL ARSENIC EXPOSURE CAUSED SIGNIFICANTLY DIMINISHED COGNITION IN WILD-TYPE MICE. THE ANALYSIS OF CHIP-SEQ DATA AND EXPERIMENTS WITH MOUSE EMBRYONIC STEM CELLS DEMONSTRATED THAT EPIGENETIC CHANGES INDUCED BY ARSENIC EXPOSURE TRANSLATED INTO GENE EXPRESSION ALTERATIONS ASSOCIATED WITH NEURONAL DEVELOPMENT AND NEUROLOGICAL DISEASE. INCREASED HIPPOCAMPAL AMYLOID PLAQUES LEVELS OF APP/PS MICE AND COGNITIVE DECLINE PROVIDED EVIDENCE THAT ARSENIC EXPOSURE AGGRAVATED AN EXISTING ALZHEIMER'S DISEASE-LIKE PHENOTYPE. WE SHOW DEVELOPMENTAL ARSENIC EXPOSURE SIGNIFICANTLY IMPACTS HISTONE MODIFICATIONS IN BRAIN WHICH REMAIN PRESENT INTO ADULTHOOD AND PROVIDE A POTENTIAL MECHANISM BY WHICH DEVELOPMENTAL ARSENIC EXPOSURE INFLUENCES COGNITIVE FUNCTIONS. WE ALSO SHOW THAT HUMAN RELEVANT, CHRONIC ARSENIC EXPOSURE HAS DELETERIOUS EFFECTS ON ADULT APP/PS MICE AND EXACERBATES EXISTING ALZHEIMER'S DISEASE-LIKE SYMPTOMS. THE RESULTS DEMONSTRATE HOW DEVELOPMENTAL ARSENIC EXPOSURE IMPACTS THE BRAIN EPIGENOME, LEADING TO ALTERED GENE EXPRESSION LATER IN LIFE.	2022	
                                                                                                                                               
10  1007  41 CHRONIC VIRUS INFECTION ENFORCES DEMETHYLATION OF THE LOCUS THAT ENCODES PD-1 IN ANTIGEN-SPECIFIC CD8(+) T CELLS. FUNCTIONALLY EXHAUSTED T CELLS HAVE HIGH EXPRESSION OF THE PD-1 INHIBITORY RECEPTOR, AND THERAPIES THAT BLOCK PD-1 SIGNALING SHOW PROMISE FOR RESOLVING CHRONIC VIRAL INFECTIONS AND CANCER. BY USING HUMAN AND MURINE SYSTEMS OF ACUTE AND CHRONIC VIRAL INFECTIONS, WE ANALYZED EPIGENETIC REGULATION OF PD-1 EXPRESSION DURING CD8(+) T CELL DIFFERENTIATION. DURING ACUTE INFECTION, NAIVE TO EFFECTOR CD8(+) T CELL DIFFERENTIATION WAS ACCOMPANIED BY A TRANSIENT LOSS OF DNA METHYLATION OF THE PDCD1 LOCUS THAT WAS DIRECTLY COUPLED TO THE DURATION AND STRENGTH OF T CELL RECEPTOR SIGNALING. FURTHER DIFFERENTIATION INTO FUNCTIONAL MEMORY CELLS COINCIDED WITH PDCD1 REMETHYLATION, PROVIDING AN ADAPTED PROGRAM FOR REGULATION OF PD-1 EXPRESSION. IN CONTRAST, THE PDCD1 REGULATORY REGION WAS COMPLETELY DEMETHYLATED IN EXHAUSTED CD8(+) T CELLS AND REMAINED UNMETHYLATED EVEN WHEN VIRUS TITERS DECREASED. THIS LACK OF DNA REMETHYLATION LEAVES THE PDCD1 LOCUS POISED FOR RAPID EXPRESSION, POTENTIALLY PROVIDING A SIGNAL FOR PREMATURE TERMINATION OF ANTIVIRAL FUNCTIONS.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
11  1488  23 DNA DAMAGE RECOGNITION IN THE RAT ZYGOTE FOLLOWING CHRONIC PATERNAL CYCLOPHOSPHAMIDE EXPOSURE. THE DETRIMENTAL EFFECTS OF PRECONCEPTIONAL PATERNAL EXPOSURE TO THE ALKYLATING ANTICANCER AGENT, CYCLOPHOSPHAMIDE, INCLUDE ABERRANT EPIGENETIC PROGRAMMING, DYSREGULATED ZYGOTIC GENE ACTIVATION, AND ABNORMALITIES IN THE OFFSPRING THAT ARE TRANSMITTED TO THE NEXT GENERATION. THE ADVERSE DEVELOPMENTAL CONSEQUENCES OF GENOMIC INSTABILITIES TRANSMITTED VIA THE SPERMATOZOON EMPHASIZE THE NEED TO ELUCIDATE THE MECHANISMS BY WHICH THE EARLY EMBRYO RECOGNIZES DNA DAMAGE IN THE PATERNAL GENOME. LITTLE INFORMATION EXISTS ON DNA DAMAGE DETECTION IN THE ZYGOTE. WE ASSESSED THE IMPACT OF PATERNAL CYCLOPHOSPHAMIDE EXPOSURE ON PHOSPHORYLATED H2AX (GAMMAH2AX) AND POLY(ADP-RIBOSE) POLYMERASE-1(PARP-1), BIOMARKERS OF DNA DAMAGE, TO DETERMINE THE CAPACITY IN THE RAT ZYGOTE TO RECOGNIZE GENOMIC DAMAGE AND INITIATE A RESPONSE TO DNA LESIONS. AN AMPLIFIED BIPHASIC GAMMAH2AX RESPONSE WAS TRIGGERED IN THE PATERNAL PRONUCLEUS IN ZYGOTES SIRED BY DRUG-TREATED MALES; THE MATERNAL GENOME WAS NOT AFFECTED. PARP-1 IMMUNOREACTIVITY WAS SUBSTANTIALLY ELEVATED IN BOTH PARENTAL GENOMES, COINCIDENT WITH THE SECOND PHASE OF GAMMAH2AX INDUCTION IN EMBRYOS SIRED BY CYCLOPHOSPHAMIDE-EXPOSED SPERMATOZOA. THUS, PATERNAL EXPOSURE TO A DNA DAMAGING AGENT RAPIDLY ACTIVATES SIGNALS IMPLEMENTAL FOR DNA DAMAGE RECOGNITION IN THE ZYGOTE. INEFFICIENT REPAIR OF DNA LESIONS MAY LEAD TO PERSISTENT ALTERATIONS OF THE HISTONE CODE AND CHROMATIN INTEGRITY, RESULTING IN ABERRANT EMBRYOGENESIS. WE PROPOSE THAT THE RESPONSE OF THE EARLY EMBRYO TO DISTURBANCES IN SPERMATOZOAL GENOMIC INTEGRITY PLAYS A VITAL ROLE IN DETERMINING ITS OUTCOME.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
12  2741  23 EXPOSURE TO IONIZING RADIATION DISRUPTS NORMAL EPIGENETIC AGING IN JAPANESE MEDAKA. ALTERATIONS TO THE EPIGENOME ARE A HALLMARK OF BIOLOGICAL AGING AND AGE-DEPENDENT PATTERNING OF THE DNA METHYLOME ("EPIGENETIC AGING") CAN BE MODELED TO PRODUCE EPIGENETIC AGE PREDICTORS. RATES OF EPIGENETIC AGING VARY AMONGST INDIVIDUALS AND CORRELATE TO THE ONSET OF AGE-RELATED DISEASE AND ALL-CAUSE MORTALITY. YET, THE ORIGINS OF EPIGENETIC-TO-CHRONOLOGICAL AGE DISCORDANCE ARE NOT EMPIRICALLY RESOLVED. HERE, WE INVESTIGATE THE RELATIONSHIP BETWEEN AGING, DNA METHYLATION, AND ENVIRONMENTAL EXPOSURES IN JAPANESE MEDAKA (ORYZIAS LATIPES). WE FIND AGE-ASSOCIATED DNA METHYLATION PATTERNING ENRICHED IN GENOMIC REGIONS OF LOW CPG DENSITY AND THAT, SIMILAR TO MAMMALS, MOST AGE-RELATED CHANGES OCCUR DURING EARLY LIFE. WE CONSTRUCT AN EPIGENETIC CLOCK CAPABLE OF PREDICTING CHRONOLOGICAL AGE WITH A MEAN ERROR OF 61.1 DAYS (~8.4% OF AVERAGE LIFESPAN). TO TEST THE ROLE OF ENVIRONMENTAL FACTORS IN DRIVING EPIGENETIC AGE VARIATION, WE EXPOSED MEDAKA TO CHRONIC, ENVIRONMENTALLY RELEVANT DOSES OF IONIZING RADIATION. BECAUSE MOST ORGANISMS SHARE AN EVOLUTIONARY HISTORY WITH IONIZING RADIATION, WE HYPOTHESIZED THAT EXPOSURE WOULD REVEAL FUNDAMENTAL INSIGHTS INTO ENVIRONMENT-BY-EPIGENETIC AGING INTERACTIONS. RADIATION EXPOSURE DISRUPTED EPIGENETIC AGING BY ACCELERATING AND DECELERATING NORMAL AGE-ASSOCIATED PATTERNING AND WAS MOST PRONOUNCED IN CYTOSINES THAT WERE MODERATELY ASSOCIATED WITH AGE. THESE FINDINGS EMPIRICALLY DEMONSTRATE THE ROLE OF DNA METHYLATION IN INTEGRATING ENVIRONMENTAL FACTORS INTO AGING TRAJECTORIES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
13  2755  30 EXPRESSION OF CLASS II HISTONE DEACETYLASES IN TWO MOUSE MODELS OF TEMPORAL LOBE EPILEPSY. EPIGENETIC MECHANISMS LIKE ALTERED HISTONE ACETYLATION MAY HAVE A CRUCIAL ROLE IN EPILEPTOGENESIS. IN TWO MOUSE MODELS OF TEMPORAL LOBE EPILEPSY, WE INVESTIGATED CHANGES IN THE EXPRESSION OF CLASS II HISTONE DEACETYLASES (HDAC), A GROUP OF SIGNAL TRANSDUCERS THAT SHUTTLE BETWEEN NUCLEUS AND CYTOPLASM. INTRAHIPPOCAMPAL INJECTION OF KAINIC ACID (KA) INDUCED A STATUS EPILEPTICUS, DEVELOPMENT OF SPONTANEOUS SEIZURES (AFTER 3 DAYS), AND FINALLY CHRONIC EPILEPSY AND GRANULE CELL DISPERSION. EXPRESSION OF CLASS II HDAC MRNAS WAS INVESTIGATED AT DIFFERENT TIME INTERVALS AFTER KA INJECTION IN THE GRANULE CELL LAYERS AND IN SECTORS CA1 AND CA3 CONTRALATERAL TO THE SITE OF KA INJECTION LACKING NEURODEGENERATION. INCREASED EXPRESSION OF HDAC5 AND 9 MRNAS COINCIDED WITH PRONOUNCED GRANULE CELL DISPERSION IN THE KA-INJECTED HIPPOCAMPUS AT LATE INTERVALS (14-28 DAYS AFTER KA) AND EQUALLY AFFECTED BOTH HDAC9 SPLICE VARIANTS. IN CONTRAST, IN THE PILOCARPINE MODEL (SHOWING NO GRANULE CELL DISPERSION), WE OBSERVED DECREASES IN THE EXPRESSION OF HDAC5 AND 9 AT THE SAME TIME INTERVALS. BEYOND THIS, STRIKING SIMILARITIES BETWEEN BOTH TEMPORAL LOBE EPILEPSY MODELS SUCH AS FAST DECREASES IN HDAC7 AND 10 MRNAS DURING THE ACUTE STATUS EPILEPTICUS WERE OBSERVED, NOTABLY ALSO IN THE CONTRALATERAL HIPPOCAMPUS NOT AFFECTED BY NEURODEGENERATION. THE PARTICULAR PATTERNS OF HDAC MRNA EXPRESSION SUGGEST A ROLE IN EPILEPTOGENESIS AND GRANULE CELL DISPERSION. REDUCED EXPRESSION OF HDACS MAY RESULT IN INCREASED EXPRESSION OF PRO- AND ANTICONVULSIVE PROTEINS. ON THE OTHER HAND, EXPORT OF HDACS FROM THE NUCLEUS INTO THE CYTOPLASM COULD ALLOW FOR DEACETYLATION OF CYTOPLASMATIC PROTEINS INVOLVED IN AXONAL AND DENDRITIC REMODELING, LIKE GRANULE CELL DISPERSION. HDAC 5 AND HDAC 9 EXPRESSION IS HIGHLY INCREASED IN GRANULE CELLS OF THE KA-INJECTED HIPPOCAMPUS AND PARALLELS GRANULE CELL DISPERSION. BOTH HDACS ARE THOUGHT TO BE TARGETED TO THE CYTOPLASM AND TO ACT THERE BY DEACETYLATING CYTOPLASMATIC (E.G. CYTOSCELETON-RELATED) PROTEINS.	2016	
                                                                                                                                                                                                                                                                                                                                                        
14  1503  31 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
15  1533  41 DNA METHYLATION DYNAMICS DURING B CELL MATURATION UNDERLIE A CONTINUUM OF DISEASE PHENOTYPES IN CHRONIC LYMPHOCYTIC LEUKEMIA. CHARTING DIFFERENCES BETWEEN TUMORS AND NORMAL TISSUE IS A MAINSTAY OF CANCER RESEARCH. HOWEVER, CLONAL TUMOR EXPANSION FROM COMPLEX NORMAL TISSUE ARCHITECTURES POTENTIALLY OBSCURES CANCER-SPECIFIC EVENTS, INCLUDING DIVERGENT EPIGENETIC PATTERNS. USING WHOLE-GENOME BISULFITE SEQUENCING OF NORMAL B CELL SUBSETS, WE OBSERVED BROAD EPIGENETIC PROGRAMMING OF SELECTIVE TRANSCRIPTION FACTOR BINDING SITES COINCIDENT WITH THE DEGREE OF B CELL MATURATION. BY COMPARING NORMAL B CELLS TO MALIGNANT B CELLS FROM 268 PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), WE SHOWED THAT TUMORS DERIVE LARGELY FROM A CONTINUUM OF MATURATION STATES REFLECTED IN NORMAL DEVELOPMENTAL STAGES. EPIGENETIC MATURATION IN CLL WAS ASSOCIATED WITH AN INDOLENT GENE EXPRESSION PATTERN AND INCREASINGLY FAVORABLE CLINICAL OUTCOMES. WE FURTHER UNCOVERED THAT MOST PREVIOUSLY REPORTED TUMOR-SPECIFIC METHYLATION EVENTS ARE NORMALLY PRESENT IN NON-MALIGNANT B CELLS. INSTEAD, WE IDENTIFIED A POTENTIAL PATHOGENIC ROLE FOR TRANSCRIPTION FACTOR DYSREGULATION IN CLL, WHERE EXCESS PROGRAMMING BY EGR AND NFAT WITH REDUCED EBF AND AP-1 PROGRAMMING IMBALANCES THE NORMAL B CELL EPIGENETIC PROGRAM.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
16  4008  28 LOW DOSE OF URANIUM INDUCES MULTIGENERATIONAL EPIGENETIC EFFECTS IN RAT KIDNEY. PURPOSE: A PROTOCOL OF CHRONIC EXPOSURE TO LOW DOSE OF URANIUM WAS ESTABLISHED IN ORDER TO DISTINGUISH THE SEXUAL DIFFERENCES AND THE DEVELOPMENTAL PROCESS THAT ARE CRITICAL WINDOWS FOR EPIGENETIC EFFECTS OVER GENERATIONS. METHODS: BOTH MALE AND FEMALE RATS WERE CONTAMINATED THROUGH THEIR DRINKING WATER WITH A NON-TOXIC SOLUTION OF URANYL NITRATE FOR 9 MONTHS. THE EXPOSED GENERATION (F0) AND THE FOLLOWING TWO GENERATIONS (F1 AND F2) WERE EXAMINED. CLINICAL MONITORING, GLOBAL DNA METHYLATION PROFILE AND DNA METHYLTRANSFERASES (DNMTS) GENE EXPRESSION WERE ANALYZED IN KIDNEYS. RESULTS: WHILE THE BODY WEIGHT OF F1 MALES INCREASED, A SMALL DECREASE IN KIDNEY AND BODY WEIGHT WAS OBSERVED IN F2 MALES. IN ADDITION, GLOBAL DNA HYPERMETHYLATION PROFILE IN KIDNEY CELLS WAS OBSERVED IN F1 AND F2 MALES. QPCR RESULTS REVEAL A SIGNIFICANT INCREASE OF METHYLTRANSFERASE GENES EXPRESSION (DNMT1 AND DNMT3A) FOR F2 FEMALES. CONCLUSIONS: IN THE FIELD OF PUBLIC HEALTH POLICY AND TO RAISE ATTENTION TO GENERATIONAL EFFECTS FOR THE RISK ASSESSMENT OF THE ENVIRONMENTAL EXPOSURES, LOW DOSES OF URANIUM DO NOT IMPLY CLINICAL EFFECTS ON ADULT EXPOSED RATS. HOWEVER, OUR RESULTS CONFIRM THE IMPORTANCE OF THE DEVELOPMENTAL WINDOWS' SENSITIVITY IN ADDITION TO THE SEXUAL DIMORPHISMS OF THE OFFSPRING.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
17  1511  38 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	
                                                                                                                                                                                                                                                                                                                                                                                                
18  5166  32 PRECONCEPTION PATERNAL ALCOHOL EXPOSURE EXERTS SEX-SPECIFIC EFFECTS ON OFFSPRING GROWTH AND LONG-TERM METABOLIC PROGRAMMING. BACKGROUND: ALTHOUGH CLINICAL DATA SUPPORT AN ASSOCIATION BETWEEN PATERNAL ALCOHOL USE AND DEFICITS IN CHILD NEUROCOGNITIVE DEVELOPMENT, THE RELATIONSHIP BETWEEN PATERNAL DRINKING AND ALCOHOL-INDUCED GROWTH PHENOTYPES REMAINS CHALLENGING TO DEFINE. USING AN ESTABLISHED MOUSE MODEL OF CHRONIC EXPOSURE, PREVIOUS WORK BY OUR GROUP HAS LINKED PRECONCEPTION PATERNAL ALCOHOL USE TO SEX-SPECIFIC PATTERNS OF FETAL GROWTH RESTRICTION AND PLACENTAL DYSFUNCTION. THE AIM OF THE PRESENT STUDY WAS TO INVESTIGATE THE LONG-TERM IMPACT OF CHRONIC PRECONCEPTION PATERNAL ALCOHOL USE ON OFFSPRING GROWTH AND METABOLIC PROGRAMMING. RESULTS: PRECONCEPTION PATERNAL ALCOHOL EXPOSURE INDUCED A PROLONGED PERIOD OF FETAL GESTATION AND AN INCREASED INCIDENCE OF INTRAUTERINE GROWTH RESTRICTION, WHICH AFFECTED THE MALE OFFSPRING TO A GREATER EXTENT THAN THE FEMALES. WHILE THE FEMALE OFFSPRING OF ETHANOL-EXPOSED MALES WERE ABLE TO MATCH THE BODY WEIGHTS OF THE CONTROLS WITHIN THE FIRST 2 WEEKS OF POSTNATAL LIFE, MALE OFFSPRING CONTINUED TO DISPLAY AN 11% REDUCTION IN WEIGHT AT 5 WEEKS OF AGE AND A 6% REDUCTION AT 8 WEEKS OF AGE. THE OBSERVED GROWTH DEFICITS ASSOCIATED WITH INSULIN HYPERSENSITIVITY IN THE MALE OFFSPRING, WHILE IN CONTRAST, FEMALES DISPLAYED A MODEST LAG IN THEIR GLUCOSE TOLERANCE TEST. THESE METABOLIC DEFECTS WERE ASSOCIATED WITH AN UP-REGULATION OF GENES WITHIN THE PRO-FIBROTIC TGF-BETA SIGNALING PATHWAY AND INCREASED LEVELS OF CELLULAR HYDROXYPROLINE WITHIN THE LIVERS OF THE MALE OFFSPRING. WE OBSERVED SUPPRESSED CYTOKINE PROFILES WITHIN THE LIVER AND PANCREAS OF BOTH THE MALE AND FEMALE OFFSPRING, WHICH CORRELATED WITH THE UP-REGULATION OF GENES IN THE LIVERX/RETINOIDX/FARNESOIDX RECEPTOR PATHWAYS. HOWEVER, PATTERNS OF GENE EXPRESSION WERE HIGHLY VARIABLE BETWEEN THE OFFSPRING OF ALCOHOL-EXPOSED SIRES. IN THE ADULT OFFSPRING OF ALCOHOL-EXPOSED MALES, WE DID NOT OBSERVE ANY DIFFERENCES IN THE ALLELIC EXPRESSION OF IGF2 OR ANY OTHER IMPRINTED GENES. CONCLUSIONS: THE IMPACT OF PATERNAL ALCOHOL USE ON CHILD DEVELOPMENT IS POORLY EXPLORED AND REPRESENTS A SIGNIFICANT GAP IN OUR UNDERSTANDING OF THE TERATOGENIC EFFECTS OF ETHANOL. OUR STUDIES IMPLICATE PATERNAL EXPOSURE HISTORY AS AN ADDITIONAL AND IMPORTANT MODIFIER OF ALCOHOL-INDUCED GROWTH PHENOTYPES AND CHALLENGE THE CURRENT MATERNAL-CENTRIC EXPOSURE PARADIGM.	2019	

19  2467  34 EPIGENETIC TOXICITY OF TRICHLOROETHYLENE: A SINGLE-MOLECULE PERSPECTIVE. THE VOLATILE, WATER SOLUBLE TRICHLOROETHYLENE (TCE) IS A HAZARDOUS INDUSTRIAL WASTE AND COULD LEAD TO VARIOUS HEALTH PROBLEMS, INCLUDING CANCER, NEUROPATHY, CARDIOVASCULAR DEFECTS, AND IMMUNE DISEASES. TOXICOLOGICAL STUDIES TAKING USE OF IN VITRO AND IN VIVO MODELS HAVE BEEN CONDUCTED TO UNDERSTAND THE BIOLOGICAL IMPACTS OF TCE AT THE GENETIC, TRANSCRIPTOMIC, METABOLOMIC, AND SIGNALING LEVELS. THE EPIGENETIC ABERRATIONS INDUCED BY TCE HAVE ALSO BEEN REPORTED IN A NUMBER OF MODEL ORGANISMS, WHILE A DETAILED MECHANISTIC ELUCIDATION IS LACKING. IN THIS STUDY WE UNCOVER AN UNREPORTED MECHANISM ACCOUNTING FOR THE EPIGENETIC TOXICITY DUE TO TCE EXPOSURE BY MONITORING THE SINGLE-MOLECULE DYNAMICS OF DNA METHYLTRANSFERASE 3A (DNMT3A) IN LIVING CELLS. TCE-INDUCED GLOBAL DNA HYPOMETHYLATION COULD BE PARTLY ATTRIBUTED TO THE DISRUPTED DNMT3A-DNA ASSOCIATION. BY ANALYZING THE COMPONENTS OF DETACHED DNMT3A, WE FOUND THAT THE DNMT3A OLIGOMERS (E.G., DIMER, TRIMER, AND HIGH-ORDER OLIGOMERS) DISSOCIATED FROM HETEROCHROMATIN IN A DOSE-DEPENDENT MANNER UPON EXPOSURE. THEREAFTER THE DIMINISHED DNA-BINDING AFFINITY OF DNMT3A RESULTED IN A SIGNIFICANT DECREASE IN 5-METHYLCYTOSINE (5MC) UNDER BOTH ACUTE HIGH-DOSAGE AND CHRONIC LOW-DOSAGE TCE EXPOSURE. THE RESULTING DNA DEMETHYLATION MIGHT ALSO BE CONTRIBUTED BY THE ELEVATED EXPRESSION OF TEN-ELEVEN-TRANSLOCATION (TET) ENZYMES AND REFORMED CYSTEINE CYCLE. BESIDES THE GLOBAL EFFECT, WE FURTHER IDENTIFIED THAT A GROUP OF HETEROCHROMATIN-LOCATED, CANCER-RELATED MICRORNAS (MIRNAS) EXPERIENCED PROMOTER DEMETHYLATION UPON TCE EXPOSURE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
20  2266  33 EPIGENETIC PROGRAMMING OF MU-OPIOID RECEPTOR GENE IN MOUSE BRAIN IS REGULATED BY MECP2 AND BRG1 CHROMATIN REMODELLING FACTOR. THE PHARMACOLOGICAL ACTION OF MORPHINE AS A PAIN MEDICATION IS MEDIATED PRIMARILY THROUGH THE MU-OPIOID RECEPTOR (MOR). WITH FEW EXCEPTIONS, MOR IS EXPRESSED IN BRAIN REGIONS WHERE OPIOID ACTIONS TAKE PLACE. THE BASIS FOR THIS UNIQUE SPATIAL EXPRESSION OF MOR REMAINS UNDETERMINED. RECENTLY, WE REPORTED THAT DNA METHYLATION OF THE MOR PROMOTER PLAYS AN IMPORTANT ROLE IN REGULATING MOR IN P19 CELLS. IN THIS STUDY, WE SHOW THAT THE DIFFERENTIAL EXPRESSION OF MOR IN MICRODISSECTED MOUSE BRAIN REGIONS COINCIDES WITH DNA METHYLATION AND HISTONE MODIFICATIONS. MOR EXPRESSION COULD BE INDUCED BY A DEMETHYLATING AGENT OR A HISTONE DEACETYLASE INHIBITOR IN MOR-NEGATIVE CELLS, SUGGESTING THAT THE MOR GENE CAN BE SILENCED UNDER EPIGENETIC CONTROL. INCREASES IN THE IN VIVO INTERACTION OF METHYL-CPG-BINDING PROTEIN 2 (MECP2) WERE OBSERVED IN THE CEREBELLUM, IN WHICH THE MOR PROMOTER WAS HYPERMETHYLATED AND MOR EXPRESSION WAS THE LOWEST AMONG ALL BRAIN REGIONS TESTED. MECP2 IS ASSOCIATED CLOSELY WITH RETT SYNDROME, A NEURODEVELOPMENTAL DISORDER. WE ALSO ESTABLISHED NOVEL EVIDENCE FOR A FUNCTIONAL ROLE FOR MECP2'S ASSOCIATION WITH THE CHROMATIN-REMODELLING FACTOR BRG1 AND DNA METHYLTRANSFERASE DNMT1, SUGGESTING A POSSIBLE ROLE FOR MECP2 IN CHROMATIN REMODELLING DURING MOR GENE REGULATION. WE CONCLUDE THAT MOR GENE EXPRESSION IS EPIGENETICALLY PROGRAMMED IN VARIOUS BRAIN REGIONS AND THAT MECP2 ASSISTS THE EPIGENETIC PROGRAM DURING DNA METHYLATION AND CHROMATIN REMODELLING OF THE MOR PROMOTER.	2009