1    89 241 A PILOT INVESTIGATION OF DIFFERENTIAL HYDROXYMETHYLATION LEVELS IN PATIENT-DERIVED NEURAL STEM CELLS IMPLICATES ALTERED CORTICAL DEVELOPMENT IN BIPOLAR DISORDER. INTRODUCTION: BIPOLAR DISORDER (BD) IS A CHRONIC MENTAL ILLNESS CHARACTERIZED BY RECURRENT EPISODES OF MANIA AND DEPRESSION AND ASSOCIATED WITH SOCIAL AND COGNITIVE DISTURBANCES. ENVIRONMENTAL FACTORS, SUCH AS MATERNAL SMOKING AND CHILDHOOD TRAUMA, ARE BELIEVED TO MODULATE RISK GENOTYPES AND CONTRIBUTE TO THE PATHOGENESIS OF BD, SUGGESTING A KEY ROLE IN EPIGENETIC REGULATION DURING NEURODEVELOPMENT. 5-HYDROXYMETHYLCYTOSINE (5HMC) IS AN EPIGENETIC VARIANT OF PARTICULAR INTEREST, AS IT IS HIGHLY EXPRESSED IN THE BRAIN AND IS IMPLICATED IN NEURODEVELOPMENT, AND PSYCHIATRIC AND NEUROLOGICAL DISORDERS. METHODS: INDUCED PLURIPOTENT STEM CELLS (IPSCS) WERE GENERATED FROM THE WHITE BLOOD CELLS OF TWO ADOLESCENT PATIENTS WITH BIPOLAR DISORDER AND THEIR SAME-SEX AGE-MATCHED UNAFFECTED SIBLINGS (N = 4). FURTHER, IPSCS WERE DIFFERENTIATED INTO NEURONAL STEM CELLS (NSCS) AND CHARACTERIZED FOR PURITY USING IMMUNO-FLUORESCENCE. WE USED REDUCED REPRESENTATION HYDROXYMETHYLATION PROFILING (RRHP) TO PERFORM GENOME-WIDE 5HMC PROFILING OF IPSCS AND NSCS, TO MODEL 5HMC CHANGES DURING NEURONAL DIFFERENTIATION AND ASSESS THEIR IMPACT ON BD RISK. FUNCTIONAL ANNOTATION AND ENRICHMENT TESTING OF GENES HARBORING DIFFERENTIATED 5HMC LOCI WERE PERFORMED WITH THE ONLINE TOOL DAVID. RESULTS: APPROXIMATELY 2 MILLION SITES WERE MAPPED AND QUANTIFIED, WITH THE MAJORITY (68.8%) LOCATED IN GENIC REGIONS, WITH ELEVATED 5HMC LEVELS PER SITE OBSERVED FOR 3' UTRS, EXONS, AND 2-KB SHORELINES OF CPG ISLANDS. PAIRED T-TESTS OF NORMALIZED 5HMC COUNTS BETWEEN IPSC AND NSC CELL LINES REVEALED GLOBAL HYPO-HYDROXYMETHYLATION IN NSCS AND ENRICHMENT OF DIFFERENTIALLY HYDROXYMETHYLATED SITES WITHIN GENES ASSOCIATED WITH PLASMA MEMBRANE (FDR = 9.1 X 10(-12)) AND AXON GUIDANCE (FDR = 2.1 X 10(-6)), AMONG OTHER NEURONAL PROCESSES. THE MOST SIGNIFICANT DIFFERENCE WAS OBSERVED FOR A TRANSCRIPTION FACTOR BINDING SITE FOR THE KCNK9 GENE (P = 8.8 X 10(-6)), ENCODING A POTASSIUM CHANNEL PROTEIN INVOLVED IN NEURONAL ACTIVITY AND MIGRATION. PROTEIN-PROTEIN-INTERACTION (PPI) NETWORKING SHOWED SIGNIFICANT CONNECTIVITY (P = 3.2 X 10(-10)) BETWEEN PROTEINS ENCODED BY GENES HARBORING HIGHLY DIFFERENTIATED 5HMC SITES, WITH GENES INVOLVED IN AXON GUIDANCE AND ION TRANSMEMBRANE TRANSPORT FORMING DISTINCT SUB-CLUSTERS. COMPARISON OF NSCS OF BD CASES AND UNAFFECTED SIBLINGS REVEALED ADDITIONAL PATTERNS OF DIFFERENTIATION IN HYDROXYMETHYLATION LEVELS, INCLUDING SITES IN GENES WITH FUNCTIONS RELATED TO SYNAPSE FORMATION AND REGULATION, SUCH AS CUX2 (P = 2.4 X 10(-5)) AND DOK-7 (P = 3.6 X 10(-3)), AS WELL AS AN ENRICHMENT OF GENES INVOLVED IN THE EXTRACELLULAR MATRIX (FDR = 1.0 X 10(-8)). DISCUSSION: TOGETHER, THESE PRELIMINARY RESULTS LEND EVIDENCE TOWARD A POTENTIAL ROLE FOR 5HMC IN BOTH EARLY NEURONAL DIFFERENTIATION AND BD RISK, WITH VALIDATION AND MORE COMPREHENSIVE CHARACTERIZATION TO BE ACHIEVED THROUGH FOLLOW-UP STUDY.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
2  3934  49 LIVER TUMOR INDUCTION. THE SIGNIFICANCE OF THE DEVELOPMENT OF NODULAR LIVER LESIONS IN RODENTS FOLLOWING THE ADMINISTRATION OF TEST AGENTS RAISES SEVERAL QUESTIONS WHICH COULD BE PLACED IN ONE OF TWO GENERAL CATEGORIES: DIAGNOSTIC AND INTERPRETATIONAL. FROM A DIAGNOSTIC POINT OF VIEW, THE PROPER CLASSIFICATION OF LIVER TUMORS INTO A BENIGN AND MALIGNANT CATEGORY HAS TO BE BASED ON THE DIRECT CORRELATION BETWEEN THE MORPHOLOGY AND THE BIOLOGIC BEHAVIOR OF THE LESIONS. THEREFORE, EXTREME CARE SHOULD BE TAKEN TO SEPARATE THE MALIGNANT TUMORS FROM THE BENIGN AND THE BENIGN NEOPLASIA FROM THE HYPERPLASIA. THE SUBSTITUTION OF THE TERM "NEOPLASTIC NODULE" FOR HYPERPLASTIC NODULE IN RATS IS MISLEADING. MOST OF THESE NODULES, WHEN INDUCED UNDER SPECIAL EXPERIMENTAL CONDITIONS, MAY REGRESS OR REMODEL AND THUS THEY ARE NOT NEOPLASTIC IN NATURE. CHRONIC CARCINOGENICITY BIOASSAYS SHOULD INCLUDE "STOP" TYPE OF TREATMENT LEAVING ENOUGH OF THE OBSERVATIONAL TIME TO ESTABLISH THE FATE OF INDUCED NODULAR LESIONS. THE INDUCTION OF HISTOCHEMICALLY CHANGED FOCI CAN SERVE ONLY AS AN INDICATION OF POTENTIAL HEPATOCARCINOGENICITY AND SHOULD NOT BE EQUATED WITH THE INDUCTION OF BONA FIDE CANCER. THE BIOLOGIC INTERPRETATION OF NODULAR LIVER LESIONS, ESPECIALLY IN MICE, NEEDS FURTHER SCRUTINY BECAUSE THESE LESIONS HAVE A TENDENCY TO DEVELOP SPONTANEOUSLY WITH HIGH INCIDENCE IN SOME STRAINS. THIS CHARACTERISTIC THEN RAISES THE QUESTION AS TO THE MECHANISM BY WHICH VARIOUS AGENTS AUGMENT AND/OR ACCELERATE THE DEVELOPMENT OF SUCH TUMORS. IS THIS ACTION PRIMARILY PROMOTING OR INITIATING IN NATURE OR DOES IT REPRESENT THE INDUCTION OF TUMORS DE NOVO? THE ANSWER TO THIS DILEMMA MAY HAVE A DECISIVE BEARING ON CARCINOGENIC RISK ASSESSMENT AND THE TYPE OF REGULATORY ACTION, SINCE THE PROMOTING AGENTS POSSESS A THRESHOLD EFFECT AND THE PROMOTED CHANGES MAY REGRESS FOLLOWING WITHDRAWAL OF TREATMENT. THE INTERPRETATION OF HEPATOCARCINOGENESIS IS FURTHER COMPLICATED BY THE FACT THAT SEVERAL FACTORS, SUCH AS SEX HORMONAL ENVIRONMENT, INCREASED MITOTIC ACTIVITY FOLLOWING AN EXCESSIVE LOSS OF PARENCHYMAL CELLS, DEGREE OF CALORIC INTAKE, ENZYMATIC COMPLEMENT, AND ANIMALS' AGE AT THE TIME OF THE EXPOSURE TO A TEST AGENT, MAY INFLUENCE THE OUTCOME OF LIVER TUMOR DEVELOPMENT BY MODULATING "INITIATION" AND/OR "PROMOTION" OF CARCINOGENESIS. BROAD FLUCTUATION IN THE HISTORIC INCIDENCE OF LIVER TUMORS FURTHER COMPOUNDS THE COMPLEXITY OF THE PROPER BIOASSAY INTERPRETATION. THE SPECIFICALLY DESIGNED EXPERIMENTS MAY HAVE THE OBJECTIVE TO EXPLORE PREDOMINANTLY THE INITIATING OR PROMOTING EFFECTS OF THE AGENT. SUCH PROTOCOLS SHOULD BE USED WHENEVER NECESSARY TO DIFFERENTIATE BETWEEN THESE TWO MECHANISMS OF ACTION. IN THE CAUCASIANS, THE "SPONTANEOUS" DEVELOPMENT OF THE PRIMARY HEPATOCELLULAR TUMORS IS RARE. THE MAJORITY OF THESE TUMORS ARE MALIGNANT AND RAPIDLY FATAL. ACCORDING TO SOME HUMAN PATHOLOGISTS, THE BENIGN VARIETY OF LIVER TUMORS IS RARE AND IT DOES NOT REPRESENT NECESSARILY A PREMALIGNANT STAGE IN TUMOR DEVELOPMENT. CARCINOMA OF THE LIVER MAY OCCUR IN INFANCY, ESPECIALLY IN MALES BEFORE THE AGE OF 2 YEARS. THIS SUGGESTS A GENETIC CAUSATION OR CARCINOGENIC EXPOSURE IN UTERO. ONE OF THE GEOGRAPHIC FACTORS WHICH SIGNIFICANTLY ENHANCES THE INCIDENCE OF HEPATOCELLULAR CARCINOMA IN HUMANS IS EXPOSURE TO AFLATOXIN B(1) WHICH IS APPARENTLY POTENTIATED BY CONCURRENT LIVER CIRRHOSIS. BECAUSE MANY MORE AGENTS HAVE BEEN FOUND TO BE HEPATOCARCINOGENIC IN MICE AND RATS THAN IN MEN, A QUESTION ARISES AS TO THE DIRECT RELEVANCE OF RODENT STUDIES TO HUMANS. A BALANCED ASSESSMENT OF THE CARCINOGENICITY OF THE AGENT COULD ONLY BE REACHED IN CONSIDERING BOTH THE PHARMACOKINETICS AND THE DEVELOPMENT OF MALIGNANT NEOPLASIA IN OTHER ORGANS. IN THE CASE OF POSITIVE CARCINOGENICITY ASSESSMENT, THE OUTCOME OF THE MUTAGENICITY BIOASSAYS CAN SUGGEST GENIC (GENOTOXIC) OR PARAGENIC (EPIGENETIC) MODE OF ACTION IN MAMMALIAN SYSTEMS.	1982	

3  1563  43 DNA METHYLATION OF METHYLATION COMPLEX GENES IN RELATION TO STRESS AND GENOME-WIDE METHYLATION IN MOTHER-NEWBORN DYADS. OBJECTIVES: EARLY LIFE STRESS IS KNOWN TO HAVE ENDURING BIOLOGICAL EFFECTS, PARTICULARLY WITH RESPECT TO HEALTH. EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLATION, ARE A POSSIBLE MECHANISM TO MEDIATE THE BIOLOGICAL EFFECT OF STRESS. WE PREVIOUSLY FOUND CORRELATIONS BETWEEN MATERNAL STRESS, NEWBORN BIRTHWEIGHT, AND GENOME-WIDE MEASURES OF DNA METHYLATION. HERE WE INVESTIGATE TEN GENES RELATED TO THE METHYLATION/DEMETHYLATION COMPLEX IN ORDER TO BETTER UNDERSTAND THE IMPACT OF STRESS ON HEALTH. MATERIALS AND METHODS: DNA METHYLATION AND GENETIC VARIANTS AT METHYLATION/DEMETHYLATION GENES WERE ASSAYED. MEAN METHYLATION MEASURES WERE CONSTRUCTED FOR EACH GENE AND TESTED, IN ADDITION TO GENETIC VARIANTS, FOR ASSOCIATION WITH MATERNAL STRESS MEASURES BASED ON INTERVIEW AND SURVEY DATA (CHRONIC STRESS AND WAR TRAUMA), MATERNAL VENOUS, AND NEWBORN CORD GENOME-WIDE MEAN METHYLATION (GMM), AND BIRTHWEIGHT. RESULTS: AFTER CELL TYPE CORRECTION, WE FOUND MULTIPLE PAIRWISE ASSOCIATIONS BETWEEN WAR TRAUMA, MATERNAL GMM, MATERNAL METHYLATION AT DNMT1, DNMT3A, TET3, AND MBD2, AND BIRTHWEIGHT. CONCLUSIONS: THE ASSOCIATION OF MATERNAL GMM AND MATERNAL METHYLATION AT DNMT1, DNMT3A, TET3, AND MBD2 IS CONSISTENT WITH THE ROLE OF THESE GENES IN ESTABLISHING, MAINTAINING AND ALTERING GENOME-WIDE METHYLATION PATTERNS, IN SOME CASES IN RESPONSE TO STRESS. DNMT1 PRODUCES ONE OF THE PRIMARY ENZYMES THAT REPRODUCES METHYLATION PATTERNS DURING DNA REPLICATION. DNMT3A AND TET3 HAVE BEEN IMPLICATED IN GENOME-WIDE HYPOMETHYLATION IN RESPONSE TO GLUCOCORTICOID HORMONES. ALTHOUGH WE CANNOT DETERMINE THE DIRECTIONALITY OF THE GENIC AND GENOME-WIDE CHANGES IN METHYLATION, OUR RESULTS SUGGEST THAT ALTERED METHYLATION OF SPECIFIC METHYLATION GENES MAY BE PART OF THE MOLECULAR MECHANISM UNDERLYING THE HUMAN BIOLOGICAL RESPONSE TO STRESS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
4   521  53 ASSOCIATIONS BETWEEN MATERNAL PSYCHOSOCIAL STRESS, DNA METHYLATION, AND NEWBORN BIRTH WEIGHT IDENTIFIED BY INVESTIGATING METHYLATION AT INDIVIDUAL, REGIONAL, AND GENOME LEVELS. STRESS IS KNOWN TO AFFECT HEALTH THROUGHOUT LIFE AND INTO FUTURE GENERATIONS, BUT THE UNDERLYING MOLECULAR MECHANISMS ARE UNKNOWN. WE TESTED THE HYPOTHESIS THAT MATERNAL PSYCHOSOCIAL STRESS INFLUENCES DNA METHYLATION (DNAM), WHICH IN TURN IMPACTS NEWBORN HEALTH OUTCOMES. SPECIFICALLY, WE ANALYZED DNAM AT INDIVIDUAL, REGIONAL, AND GENOME-WIDE LEVELS TO TEST FOR ASSOCIATIONS WITH MATERNAL STRESS AND NEWBORN BIRTH WEIGHT. MATERNAL VENOUS BLOOD AND NEWBORN CORD BLOOD (N = 24 AND 22, RESPECTIVELY) WERE ASSAYED FOR METHYLATION AT APPROXIMATELY 450,000 CPG SITES. METHYLATION WAS ANALYZED BY EXAMINING CPG SITES INDIVIDUALLY IN AN EPIGENOME-WIDE ASSOCIATION STUDY (EWAS), AS REGIONAL GROUPS USING VARIABLY METHYLATED REGION (VMR) ANALYSIS IN MATERNAL BLOOD ONLY, AND THROUGH THE EPIGENOME-WIDE MEASURES USING GENOME-WIDE MEAN METHYLATION (GMM), HORVATH'S EPIGENETIC CLOCK, AND MITOTIC AGE. THESE METHYLATION MEASURES WERE TESTED FOR ASSOCIATION WITH THREE MEASURES OF MATERNAL STRESS (MATERNAL WAR TRAUMA, CHRONIC STRESS, AND EXPERIENCE OF SEXUAL VIOLENCE) AND ONE HEALTH OUTCOME (NEWBORN BIRTH WEIGHT). WE OBSERVED THAT MATERNAL EXPERIENCES OF WAR TRAUMA, CHRONIC STRESS, AND SEXUAL ASSAULT WERE EACH ASSOCIATED WITH DECREASED NEWBORN BIRTH WEIGHT (P < 1.95 X 10(-7) IN ALL CASES). TESTING INDIVIDUAL CPG SITES USING EWAS, WE OBSERVED NO ASSOCIATIONS BETWEEN DNAM AND ANY MEASURE OF MATERNAL STRESS OR NEWBORN BIRTH WEIGHT IN EITHER MATERNAL OR CORD BLOOD, AFTER BONFERRONI MULTIPLE TESTING CORRECTION. HOWEVER, THE TOP-RANKED CPG SITE IN MATERNAL BLOOD THAT ASSOCIATED WITH MATERNAL CHRONIC STRESS AND SEXUAL VIOLENCE BEFORE MULTIPLE TESTING CORRECTION IS LOCATED NEAR THE SPON1 GENE. TESTING AT A REGIONAL LEVEL, WE FOUND INCREASED METHYLATION OF A VMR IN MATERNAL BLOOD NEAR SPON1 THAT WAS ASSOCIATED WITH CHRONIC STRESS AND SEXUAL VIOLENCE AFTER BONFERRONI MULTIPLE TESTING CORRECTION (P = 1.95 X 10(-7) AND 8.3 X 10(-6), RESPECTIVELY). AT THE EPIGENOMIC LEVEL, CORD BLOOD GMM WAS ASSOCIATED WITH SIGNIFICANTLY HIGHER LEVELS OF WAR TRAUMA (P = 0.025) AND WAS SUGGESTIVELY ASSOCIATED WITH SEXUAL VIOLENCE (P = 0.053). THE OTHER TWO EPIGENOME-WIDE MEASURES WERE NOT ASSOCIATED WITH MATERNAL STRESS OR NEWBORN BIRTH WEIGHT IN EITHER TISSUE TYPE. DESPITE OUR SMALL SAMPLE SIZE, WE IDENTIFIED ASSOCIATIONS EVEN AFTER CONSERVATIVE MULTIPLE TESTING CORRECTION. SPECIFICALLY, WE FOUND ASSOCIATIONS BETWEEN DNAM AND THE THREE MEASURES OF MATERNAL STRESS ACROSS BOTH TISSUES; SPECIFICALLY, A VMR IN MATERNAL BLOOD AND GMM IN CORD BLOOD WERE BOTH ASSOCIATED WITH DIFFERENT MEASURES OF MATERNAL STRESS. THE ASSOCIATION OF CORD BLOOD GMM, BUT NOT MATERNAL BLOOD GMM, WITH MATERNAL STRESS MAY SUGGEST DIFFERENT RESPONSES TO STRESS IN MOTHER AND NEWBORN. IT IS NOTEWORTHY THAT WE FOUND ASSOCIATIONS ONLY WHEN CPG SITES WERE ANALYZED IN AGGREGATE, EITHER AS VMRS OR AS A BROAD SUMMARY MEASURE OF GMM.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
5  1468  33 DISTINCT EPIGENETIC PROGRAMS REGULATE CARDIAC MYOCYTE DEVELOPMENT AND DISEASE IN THE HUMAN HEART IN VIVO. EPIGENETIC MECHANISMS AND TRANSCRIPTION FACTOR NETWORKS ESSENTIAL FOR DIFFERENTIATION OF CARDIAC MYOCYTES HAVE BEEN UNCOVERED. HOWEVER, RESHAPING OF THE EPIGENOME OF THESE TERMINALLY DIFFERENTIATED CELLS DURING FETAL DEVELOPMENT, POSTNATAL MATURATION, AND IN DISEASE REMAINS UNKNOWN. HERE, WE INVESTIGATE THE DYNAMICS OF THE CARDIAC MYOCYTE EPIGENOME DURING DEVELOPMENT AND IN CHRONIC HEART FAILURE. WE FIND THAT PRENATAL DEVELOPMENT AND POSTNATAL MATURATION ARE CHARACTERIZED BY A COOPERATION OF ACTIVE CPG METHYLATION AND HISTONE MARKS AT CIS-REGULATORY AND GENIC REGIONS TO SHAPE THE CARDIAC MYOCYTE TRANSCRIPTOME. IN CONTRAST, PATHOLOGICAL GENE EXPRESSION IN TERMINAL HEART FAILURE IS ACCOMPANIED BY CHANGES IN ACTIVE HISTONE MARKS WITHOUT MAJOR ALTERATIONS IN CPG METHYLATION AND REPRESSIVE CHROMATIN MARKS. NOTABLY, CIS-REGULATORY REGIONS IN CARDIAC MYOCYTES ARE SIGNIFICANTLY ENRICHED FOR CARDIOVASCULAR DISEASE-ASSOCIATED VARIANTS. THIS STUDY UNCOVERS DISTINCT LAYERS OF EPIGENETIC REGULATION NOT ONLY DURING PRENATAL DEVELOPMENT AND POSTNATAL MATURATION BUT ALSO IN DISEASED HUMAN CARDIAC MYOCYTES.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
6  4491  45 MONOSOMY 7 MYELOPROLIFERATIVE DISEASE IN CHILDREN WITH NEUROFIBROMATOSIS, TYPE 1: EPIDEMIOLOGY AND MOLECULAR ANALYSIS. LOSS OF CONSTITUTIONAL HETEROZYGOSITY IS A COMMON MOLECULAR FEATURE OF CANCERS IN WHICH INACTIVATION OF ONE OR MORE TUMOR SUPPRESSOR GENES IS THOUGHT TO CONTRIBUTE TO TUMORIGENESIS. RECENT EVIDENCE SUGGESTS THAT THE GENE RESPONSIBLE FOR NEUROFIBROMATOSIS, TYPE 1 (NF-1), BELONGS TO THIS CLASS OF HERITABLE CANCER GENES. CHILDREN WITH NF-1 SHOW AN INCREASED INCIDENCE OF MYELOID LEUKEMIA, INCLUDING JUVENILE CHRONIC MYELOGENOUS LEUKEMIA (JCML) AND, PERHAPS, THE MYELOPROLIFERATIVE SYNDROME (MPS) ASSOCIATED WITH BONE MARROW MONOSOMY 7 (MO 7). WE HAVE INVESTIGATED FIVE CHILDREN WITH MO 7: THREE WITH NF-1 AND TWO OTHERS WITH SUGGESTIVE EVIDENCE OF NF-1. SOUTHERN BLOTTING EXPERIMENTS PERFORMED IN FOUR PATIENTS SHOWED NO LOSS OF HETEROZYGOSITY IN BONE MARROW SPECIMENS USING PROBES LINKED TO THE NF-1 LOCUS ON THE LONG ARM OF CHROMOSOME 17. BOTH OF OUR PATIENTS WITH FAMILIAL NF-1 INHERITED THE DISEASE FROM THEIR MOTHERS, AS DID 14 OF 19 OTHER CASES OF MYELOID LEUKEMIA IN CHILDREN WITH FAMILIAL NF-1. SEVENTEEN OF THESE 21 CHILDREN WERE BOYS. MYELOID LEUKEMIA DEVELOPED IN 12 BOYS AND FOUR GIRLS WHO INHERITED NF-1 FROM THEIR MOTHERS, AND IN FIVE BOYS WHO INHERITED THE DISEASE FROM THEIR FATHERS. FATHER-TO-DAUGHTER TRANSMISSION WAS NOT OBSERVED. TAKEN TOGETHER, THE PRESENCE OF CHROMOSOME 7 DELETIONS IN THE LEUKEMIAS OF CHILDREN WITH NF-1, A PATTERN OF INHERITANCE FAVORING MATERNAL TRANSMISSION OF NF-1, AND THE MARKED PREDILECTION FOR BOYS TO DEVELOP JCML AND MO 7 SUGGEST A MULTISTEP MECHANISM OF ONCOGENESIS IN WHICH EPIGENETIC FACTORS MIGHT PLAY A ROLE. FURTHER INVESTIGATION IS REQUIRED TO DETERMINE IF THE NF-1 GENES IN THE LEUKEMIC BONE MARROWS OF THESE PATIENTS HAVE ACQUIRED POINT MUTATIONS OR SMALL DELETIONS.	1992	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
7  1161  58 CONTINUOUS DEVELOPMENTAL AND EARLY LIFE TRICHLOROETHYLENE EXPOSURE PROMOTED DNA METHYLATION ALTERATIONS IN POLYCOMB PROTEIN BINDING SITES IN EFFECTOR/MEMORY CD4(+) T CELLS. TRICHLOROETHYLENE (TCE) IS AN INDUSTRIAL SOLVENT AND DRINKING WATER POLLUTANT ASSOCIATED WITH CD4(+) T CELL-MEDIATED AUTOIMMUNITY. IN OUR MOUSE MODEL, DISCONTINUATION OF TCE EXPOSURE DURING ADULTHOOD AFTER DEVELOPMENTAL EXPOSURE DID NOT PREVENT IMMUNOTOXICITY. TO DETERMINE WHETHER PERSISTENT EFFECTS WERE LINKED TO EPIGENETIC CHANGES WE CONDUCTED WHOLE GENOME REDUCED REPRESENTATION BISULFITE SEQUENCING (RRBS) TO EVALUATE METHYLATION OF CPG SITES IN AUTOSOMAL CHROMOSOMES IN ACTIVATED EFFECTOR/MEMORY CD4(+) T CELLS. FEMALE MRL+/+ MICE WERE EXPOSED TO VEHICLE CONTROL OR TCE IN THE DRINKING WATER FROM GESTATION UNTIL ~37 WEEKS OF AGE [POSTNATAL DAY (PND) 259]. IN A SUBSET OF MICE, TCE EXPOSURE WAS DISCONTINUED AT ~22 WEEKS OF AGE (PND 154). AT PND 259, RRBS ASSESSMENT REVEALED MORE GLOBAL METHYLATION CHANGES IN THE CONTINUOUS EXPOSURE GROUP VS. THE DISCONTINUOUS EXPOSURE GROUP. A MAJORITY OF THE DIFFERENTIALLY METHYLATED CPG REGIONS (DMRS) ACROSS PROMOTERS, ISLANDS, AND REGULATORY ELEMENTS WERE HYPERMETHYLATED (~90%). HOWEVER, CONTINUOUS DEVELOPMENTAL TCE EXPOSURE ALTERED THE METHYLATION OF 274 CPG SITES IN PROMOTERS AND CPG ISLANDS. IN CONTRAST, ONLY 4 CPG ISLAND REGIONS WERE DIFFERENTIALLY METHYLATED (HYPERMETHYLATED) IN THE DISCONTINUOUS GROUP. INTERESTINGLY, 2 OF THESE 4 SITES WERE ALSO HYPERMETHYLATED IN THE CONTINUOUS EXPOSURE GROUP, AND BOTH OF THESE ISLAND REGIONS ARE ASSOCIATED WITH LYSINE 27 ON HISTONE H3 (H3K27) INVOLVED IN POLYCOMB COMPLEX-DEPENDENT TRANSCRIPTIONAL REPRESSION VIA H3K27 TRI-METHYLATION. CPG SITES WERE OVERLAPPED WITH THE OPEN REGULATORY ANNOTATION DATABASE. UNLIKE THE DISCONTINUOUS GROUP, CONTINUOUS TCE TREATMENT RESULTED IN 129 DMRS INCLUDING 12 UNIQUE TRANSCRIPTION FACTORS AND REGULATORY ELEMENTS; 80% OF WHICH WERE ENRICHED FOR ONE OR MORE POLYCOMB GROUP (PCG) PROTEIN BINDING REGIONS (I.E., SUZ12, EZH2, JARID2, AND MTF2). PATHWAY ANALYSIS OF THE DMRS INDICATED THAT TCE PRIMARILY ALTERED THE METHYLATION OF GENES ASSOCIATED WITH REGULATION OF CELLULAR METABOLISM AND CELL SIGNALING. THE RESULTS DEMONSTRATED THAT CONTINUOUS DEVELOPMENTAL EXPOSURE TO TCE DIFFERENTIALLY METHYLATED BINDING SITES OF PCG PROTEINS IN EFFECTOR/MEMORY CD4(+) CELLS. THERE WERE MINIMAL YET POTENTIALLY BIOLOGICALLY SIGNIFICANT EFFECTS THAT OCCURRED WHEN EXPOSURE WAS DISCONTINUED. THESE RESULTS POINT TOWARD A NOVEL MECHANISM BY WHICH CHRONIC DEVELOPMENTAL TCE EXPOSURE MAY ALTER TERMINALLY DIFFERENTIATED CD4(+) T CELL FUNCTION IN ADULTHOOD.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
8  3455  53 HYPOMETHYLATION COORDINATES ANTAGONISTICALLY WITH HYPERMETHYLATION IN CANCER DEVELOPMENT: A CASE STUDY OF LEUKEMIA. BACKGROUND: METHYLATION CHANGES ARE FREQUENT IN CANCERS, BUT UNDERSTANDING HOW HYPER- AND HYPOMETHYLATED REGION CHANGES COORDINATE, ASSOCIATE WITH GENOMIC FEATURES, AND AFFECT GENE EXPRESSION IS NEEDED TO BETTER UNDERSTAND THEIR BIOLOGICAL SIGNIFICANCE. THE FUNCTIONAL SIGNIFICANCE OF HYPERMETHYLATION IS WELL STUDIED, BUT THAT OF HYPOMETHYLATION REMAINS LIMITED. HERE, WITH PAIRED EXPRESSION AND METHYLATION SAMPLES GATHERED FROM A PATIENT/CONTROL COHORT, WE ATTEMPT TO BETTER CHARACTERIZE THE GENE EXPRESSION AND METHYLATION CHANGES THAT TAKE PLACE IN CANCER FROM B CELL CHRONIC LYMPHOCYTE LEUKEMIA (B-CLL) SAMPLES. RESULTS: ACROSS THE DATASET, WE FOUND THAT CONSISTENT DIFFERENTIALLY HYPOMETHYLATED REGIONS (C-DMRS) ACROSS SAMPLES WERE RELATIVELY FEW COMPARED TO THE MANY POORLY CONSISTENT HYPO- AND HIGHLY CONSERVED HYPER-DMRS. HOWEVER, GENES IN THE HYPO-C-DMRS TENDED TO BE ASSOCIATED WITH FUNCTIONS ANTAGONISTIC TO THOSE IN THE HYPER-C-DMRS, LIKE DIFFERENTIATION, CELL-CYCLE REGULATION AND PROLIFERATION, SUGGESTING COORDINATED REGULATION OF METHYLATION CHANGES. HYPO-C-DMRS IN B-CLL WERE FOUND ENRICHED IN KEY SIGNALING PATHWAYS LIKE B CELL RECEPTOR AND P53 PATHWAYS AND GENES/MOTIFS ESSENTIAL FOR B LYMPHOPOIESIS. HYPO-C-DMRS TENDED TO BE PROXIMAL TO GENES WITH ELEVATED EXPRESSION IN CONTRAST TO THE TRANSCRIPTION SILENCING-MECHANISM IMPOSED BY HYPERMETHYLATION. HYPO-C-DMRS TENDED TO BE ENRICHED IN THE REGIONS OF ACTIVATING H4K4ME1/2/3, H3K79ME2, AND H3K27AC HISTONE MODIFICATIONS. IN COMPARISON, THE POLYCOMB REPRESSIVE COMPLEX 2 (PRC2) SIGNATURE, MARKED BY EZH2, SUZ12, CTCF BINDING-SITES, REPRESSIVE H3K27ME3 MARKS, AND "REPRESSED/POISED PROMOTER" STATES WERE ASSOCIATED WITH HYPER-C-DMRS. MOST HYPO-C-DMRS WERE FOUND IN INTRONS (36 %), 3' UNTRANSLATED REGIONS (29 %), AND INTERGENIC REGIONS (24 %). MANY OF THESE GENIC REGIONS ALSO OVERLAPPED WITH ENHANCERS. THE METHYLATION OF CPGS FROM 3'UTR EXONS WAS FOUND TO HAVE WEAK BUT POSITIVE CORRELATION WITH GENE EXPRESSION. IN CONTRAST, METHYLATION IN THE 5'UTR WAS NEGATIVELY CORRELATED WITH EXPRESSION. TO BETTER CHARACTERIZE THE OVERLAP BETWEEN METHYLATION AND EXPRESSION CHANGES, WE IDENTIFIED CORRELATION MODULES THAT ASSOCIATE WITH "APOPTOSIS" AND "LEUKOCYTE ACTIVATION". CONCLUSIONS: DESPITE CLINICAL HETEROGENEITY IN DISEASE PRESENTATION, A NUMBER OF METHYLATION CHANGES, BOTH HYPO AND HYPER, APPEAR TO BE COMMON IN B-CLL. HYPOMETHYLATION APPEARS TO PLAY AN ACTIVE, TARGETED, AND COMPLEMENTARY ROLE IN CANCER PROGRESSION, AND IT INTERPLAYS WITH HYPERMETHYLATION IN A COORDINATED FASHION IN THE CANCER PROCESS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
9  4015  42 LOW-DOSE EXPOSURE TO BISPHENOLS A, F AND S OF HUMAN PRIMARY ADIPOCYTE IMPACTS CODING AND NON-CODING RNA PROFILES. BISPHENOL A (BPA) EXPOSURE HAS BEEN SUSPECTED TO BE ASSOCIATED WITH DELETERIOUS EFFECTS ON HEALTH INCLUDING OBESITY AND METABOLICALLY-LINKED DISEASES. ALTHOUGH BISPHENOLS F (BPF) AND S (BPS) ARE BPA STRUCTURAL ANALOGS COMMONLY USED IN MANY MARKETED PRODUCTS AS A REPLACEMENT FOR BPA, ONLY SPARSE TOXICOLOGICAL DATA ARE AVAILABLE YET. OUR OBJECTIVE WAS TO COMPREHENSIVELY CHARACTERIZE BISPHENOLS GENE TARGETS IN A HUMAN PRIMARY ADIPOCYTE MODEL, IN ORDER TO DETERMINE WHETHER THEY MAY INDUCE CELLULAR DYSFUNCTION, USING CHRONIC EXPOSURE AT TWO CONCENTRATIONS: A "LOW-DOSE" SIMILAR TO THE DOSE USUALLY ENCOUNTERED IN HUMAN BIOLOGICAL FLUIDS AND A HIGHER DOSE. THEREFORE, BPA, BPF AND BPS HAVE BEEN ADDED AT 10 NM OR 10 MUM DURING THE DIFFERENTIATION OF HUMAN PRIMARY ADIPOCYTES FROM SUBCUTANEOUS FAT OF THREE NON-DIABETIC CAUCASIAN FEMALE PATIENTS. GENE EXPRESSION (MRNA/LNCRNA) ARRAYS AND MICRORNA ARRAYS, HAVE BEEN USED TO ASSESS CODING AND NON-CODING RNA CHANGES. WE DETECTED SIGNIFICANTLY DEREGULATED MRNA/LNCRNA AND MIRNA AT LOW AND HIGH DOSES. ENRICHMENT IN "CANCER" AND "ORGANISMAL INJURY AND ABNORMALITIES" RELATED PATHWAYS WAS FOUND IN RESPONSE TO THE THREE PRODUCTS. SOME LONG INTERGENIC NON-CODING RNAS AND SMALL NUCLEOLAR RNAS WERE DIFFERENTIALLY EXPRESSED SUGGESTING THAT BISPHENOLS MAY ALSO ACTIVATE MULTIPLE CELLULAR PROCESSES AND EPIGENETIC MODIFICATIONS. THE ANALYSIS OF UPSTREAM REGULATORS OF DEREGULATED GENES HIGHLIGHTED HORMONES OR HORMONE-LIKE CHEMICALS SUGGESTING THAT BPS AND BPF CAN BE SUSPECTED TO INTERFERE, JUST LIKE BPA, WITH HORMONAL REGULATION AND HAVE TO BE CONSIDERED AS ENDOCRINE DISRUPTORS. ALL THESE RESULTS SUGGEST THAT AS BPA, ITS SUBSTITUTES BPS AND BPF SHOULD BE USED WITH THE SAME RESTRICTIONS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
10  5200  42 PRENATAL MATERNAL STRESS PREDICTS METHYLATION OF GENES REGULATING THE HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL SYSTEM IN MOTHERS AND NEWBORNS IN THE DEMOCRATIC REPUBLIC OF CONGO. EXPOSURE TO STRESS EARLY IN LIFE PERMANENTLY SHAPES ACTIVITY OF THE HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL (HPA) AXIS AND THE BRAIN. PRENATALLY, GLUCOCORTICOIDS PASS THROUGH THE PLACENTA TO THE FETUS WITH POSTNATAL IMPACTS ON BRAIN DEVELOPMENT, BIRTH WEIGHT (BW), AND HPA AXIS FUNCTIONING. LITTLE IS KNOWN ABOUT THE BIOLOGICAL MECHANISMS BY WHICH PRENATAL STRESS AFFECTS POSTNATAL FUNCTIONING. THIS STUDY ADDRESSES THIS GAP BY EXAMINING THE EFFECT OF CHRONIC STRESS AND TRAUMATIC WAR-RELATED STRESS ON EPIGENETIC CHANGES IN FOUR KEY GENES REGULATING THE HPA AXIS IN NEONATAL CORD BLOOD, PLACENTA, AND MATERNAL BLOOD: CRH, CRHBP, NR3C1, AND FKBP5. PARTICIPANTS WERE 24 MOTHER-NEWBORN DYADS IN THE CONFLICT-RIDDEN REGION OF THE EASTERN DEMOCRATIC REPUBLIC OF CONGO. BW DATA WERE COLLECTED AT DELIVERY AND MATERNAL INTERVIEWS WERE CONDUCTED TO ASSESS CULTURALLY RELEVANT CHRONIC AND WAR-RELATED STRESSORS. CHRONIC STRESS AND WAR TRAUMA HAD WIDESPREAD EFFECTS ON HPA AXIS GENE METHYLATION, WITH SIGNIFICANT EFFECTS OBSERVED AT TRANSCRIPTION FACTOR BINDING (TFB) SITES IN ALL TARGET GENES TESTED. SOME CHANGES IN METHYLATION WERE UNIQUE TO CHRONIC OR WAR STRESS, WHEREAS OTHERS WERE OBSERVED ACROSS BOTH STRESSOR TYPES. MOREOVER, STRESS EXPOSURES IMPACTED MATERNAL AND FETAL TISSUES DIFFERENTLY, SUPPORTING THEORETICAL MODELS THAT STRESS IMPACTS VARY ACCORDING TO LIFE PHASE. METHYLATION IN SEVERAL NR3C1 AND CRH CPG SITES, ALL LOCATED AT TFB SITES, WAS ASSOCIATED WITH BW. THESE FINDINGS SUGGEST THAT PRENATAL STRESS EXPOSURE IMPACTS DEVELOPMENT VIA EPIGENETIC CHANGES IN HPA AXIS GENES.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
11  1784  59 EFFECT OF ALCOHOL CONSUMPTION ON CPG METHYLATION IN THE DIFFERENTIALLY METHYLATED REGIONS OF H19 AND IG-DMR IN MALE GAMETES: IMPLICATIONS FOR FETAL ALCOHOL SPECTRUM DISORDERS. BACKGROUND: EXPOSURE TO ALCOHOL IN UTERO IS THE MAIN ATTRIBUTABLE CAUSE OF FETAL ALCOHOL SPECTRUM DISORDERS (FASD) WHICH IN ITS MOST SEVERE FORM IS CHARACTERIZED BY IRREVERSIBLE BEHAVIORAL AND COGNITIVE DISABILITY. PATERNAL PRECONCEPTION DRINKING IS NOT CONSIDERED TO BE A SIGNIFICANT RISK FACTOR, EVEN THOUGH ANIMAL STUDIES HAVE DEMONSTRATED THAT CHRONIC PATERNAL ALCOHOL CONSUMPTION HAS A DETRIMENTAL EFFECT ON THE PHYSICAL AND MENTAL DEVELOPMENT OF OFFSPRING EVEN IN THE ABSENCE OF IN UTERO ALCOHOL EXPOSURE. IT HAS BEEN DOCUMENTED THAT ALCOHOL CAN REDUCE THE LEVELS AND ACTIVITY OF DNA METHYLTRANSFERASES RESULTING IN DNA HYPOMETHYLATION AND THAT REDUCED METHYLTRANSFERASE ACTIVITY CAN CAUSE ACTIVATION OF NORMALLY SILENCED GENES. THE AIM OF THIS STUDY WAS TO ESTABLISH A LINK BETWEEN ALCOHOL USE IN MEN AND HYPOMETHYLATION OF PATERNALLY IMPRINTED LOCI IN SPERM DNA IN GENOMIC REGIONS CRITICAL FOR EMBRYONIC DEVELOPMENT, THUS PROVIDING A MECHANISM FOR PATERNAL EFFECTS IN THE AETIOLOGY OF FASD. METHODS: SPERM DNA FROM MALE VOLUNTEERS WAS BISULFITE TREATED AND THE METHYLATION PATTERNS OF 2 DIFFERENTIALLY METHYLATED REGIONS (DMRS), H19 AND IG-DMR, ANALYZED FOLLOWING SEQUENCING OF INDIVIDUAL CLONES. THE METHYLATION PATTERNS WERE CORRELATED WITH THE ALCOHOL CONSUMPTION LEVELS OF THE VOLUNTEER MALES. RESULTS: THERE WAS A PATTERN OF INCREASED DEMETHYLATION WITH ALCOHOL CONSUMPTION AT THE 2 IMPRINTED LOCI WITH A SIGNIFICANT DIFFERENCE OBSERVED AT THE IG-DMR BETWEEN THE NONDRINKING AND HEAVY ALCOHOL CONSUMING GROUPS. GREATER INTER-INDIVIDUAL VARIATION IN AVERAGE METHYLATION WAS OBSERVED AT THE H19 DMR AND INDIVIDUAL CLONES WERE MORE EXTENSIVELY DEMETHYLATED THAN THOSE OF THE IG-DMR. CPG SITE #4 IN THE IG-DMR WAS PREFERENTIALLY DEMETHYLATED AMONG ALL INDIVIDUALS AND ALONG WITH THE H19 DMR CPG SITE #7 LOCATED WITHIN THE CTCF BINDING SITE 6 SHOWED SIGNIFICANT DEMETHYLATION IN THE ALCOHOL CONSUMING GROUPS COMPARED WITH THE CONTROL GROUP. CONCLUSION: THIS STUDY DEMONSTRATES A CORRELATION BETWEEN CHRONIC ALCOHOL USE AND DEMETHYLATION OF NORMALLY HYPERMETHYLATED IMPRINTED REGIONS IN SPERM DNA. WE HYPOTHESIZE THAT, SHOULD THESE EPIGENETIC CHANGES IN IMPRINTED GENES BE TRANSMITTED THROUGH FERTILIZATION, THEY WOULD ALTER THE CRITICAL GENE EXPRESSION DOSAGES REQUIRED FOR NORMAL PRENATAL DEVELOPMENT RESULTING IN OFFSPRING WITH FEATURES OF FASD.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
12  2842  38 FREQUENT CONCOMITANT EPIGENETIC SILENCING OF SOX1 AND SECRETED FRIZZLED-RELATED PROTEINS (SFRPS) IN HUMAN HEPATOCELLULAR CARCINOMA. BACKGROUND AND AIM: EXCEPT FOR GENETIC MUTATIONS, EPIGENETIC CHANGES ARE ALSO INVOLVED IN THE DEVELOPMENT OF HUMAN CANCERS. RECENTLY, WE HAVE IDENTIFIED SOX1, SRY (SEX DETERMINING REGION Y)-BOX 1, IS HYPERMETHYLATED IN CERVICAL CANCER AND OVARIAN CANCER. THEREFORE, WE INVESTIGATED WHETHER PROMOTER HYPERMETHYLATION OF SOX1 IS COMMON IN HEPATOCELLULAR CARCINOMA (HCC). METHODS: WE USED METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MS-PCR) AND BISULFITE SEQUENCING TO ANALYZE THE METHYALTION LEVEL OF THE SOX1 PROMOTER IN SEVEN HCC CELL LINES, 54 CLINICAL HCCS, 42 CIRRHOTIC LIVERS, 21 LIVERS WITH CHRONIC HEPATITIS, AND 15 CONTROL LIVERS. THEN, WE EMPLOYED QUANTITATIVE MS-PCR (QMSP) TO VALIDATE IN AN INDEPENDENT SET OF SAMPLES (60 PAIRED HCCS AND 30 CONTROL LIVERS). FINALLY, WE USED LUCIFERASE REPORTER AND COLONY FORMATION ASSAY TO CHECK THE EFFECT OF SOX1 IN HCC. RESULTS: PROMOTER METHYLATION OF SOX1 WAS SIGNIFICANTLY FREQUENT IN HCC CELL LINES AND CLINICAL HCCS, CIRRHOTIC LIVERS, BUT NOT IN CONTROL LIVERS (P < 0.0001). THERE IS A SIGNIFICANT CORRELATION BETWEEN DOWNREGULATION OF SOX1 EXPRESSION AND PROMOTER METHYLATION. QMSP RESULTS CONFIRMED THAT PROMOTER HYPERMETHYLATION OF SOX1 IS SIGNIFICANTLY MORE FREQUENT IN HCCS THAN CONTROL LIVERS (P < 0.0001). THE FREQUENCY OF SOX1 METHYLATION IN PATIENTS WITH SECRETED FRIZZLED-RELATED PROTEINS (SFRPS) METHYLATION IS SIGNIFICANTLY HIGHER THAN IN PATIENTS WITHOUT SFRPS METHYLATION (P < 0.0001). FURTHERMORE, ECTOPIC EXPRESSION OF SOX1 COULD SUPPRESS T-CELL FACTOR-DEPENDENT TRANSCRIPTIONAL ACTIVITY AND COLONY FORMATION NUMBER IN HCCS. CONCLUSIONS: CONCOMITANT EPIGENETIC SILENCING OF SOX1 AND SFRPS THROUGH PROMOTER HYPERMETHYLATION IS FREQUENT IN HCCS, AND THIS MIGHT CONTRIBUTE TO ABNORMAL ACTIVATION OF CANONICAL WNT SIGNAL PATHWAY.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
13  4010  40 LOW MATERNAL ADHERENCE TO A MEDITERRANEAN DIET IS ASSOCIATED WITH INCREASE IN METHYLATION AT THE MEG3-IG DIFFERENTIALLY METHYLATED REGION IN FEMALE INFANTS. DIET IS DICTATED BY THE SURROUNDING ENVIRONMENT, AS FOOD ACCESS AND AVAILABILITY MAY CHANGE DEPENDING ON WHERE ONE LIVES. MATERNAL DIET DURING PREGNANCY IS AN IMPORTANT PART OF THE IN UTERO ENVIRONMENT, AND MAY AFFECT THE EPIGENOME. STUDIES LOOKING AT OVERALL DIET PATTERN IN RELATION TO DNA METHYLATION HAVE BEEN LACKING. THE MEDITERRANEAN DIET IS KNOWN FOR ITS HEALTH BENEFITS, INCLUDING DECREASED INFLAMMATION, WEIGHT LOSS, AND MANAGEMENT OF CHRONIC DISEASES. THIS STUDY ASSESSES THE ASSOCIATION BETWEEN MATERNAL ADHERENCE TO A MEDITERRANEAN DIET PATTERN DURING PREGNANCY AND INFANT DNA METHYLATION AT BIRTH. MEDITERRANEAN DIET ADHERENCE IN EARLY PREGNANCY WAS MEASURED IN 390 WOMEN ENROLLED IN THE NEWBORN EPIGENETIC STUDY, AND DNA METHYLATION WAS ASSESSED IN THEIR INFANTS AT BIRTH. MULTINOMIAL LOGISTIC REGRESSION WAS USED TO ASSESS THE ASSOCIATION BETWEEN ADHERENCE TO A MEDITERRANEAN DIET AND INFANT METHYLATION AT THE MEG3, MEG3-IG, PLEIOMORPHIC ADENOMA GENE-LIKE 1, INSULIN-LIKE GROWTH FACTOR 2 GENE, H19, MESODERM-SPECIFIC TRANSCRIPT, NEURONATIN, PATERNALLY EXPRESSED GENE 3, SARCOGLYCAN AND PATERNALLY EXPRESSED GENE 10 REGIONS, MEASURED BY PYROSEQUENCING. INFANTS OF MOTHERS WITH A LOW ADHERENCE TO A MEDITERRANEAN DIET HAD A GREATER ODDS OF HYPO-METHYLATION AT THE MEG3-IG DIFFERENTIALLY METHYLATED REGION (DMR). SEX-STRATIFIED MODELS SHOWED THAT THIS ASSOCIATION WAS PRESENT IN GIRLS ONLY. THIS STUDY PROVIDES EARLY EVIDENCE ON THE ASSOCIATION BETWEEN OVERALL DIET PATTERN AND METHYLATION AT THE 9 DMRS INCLUDED IN THIS STUDY, AND SUGGESTS THAT MATERNAL DIET CAN HAVE A SEX-SPECIFIC IMPACT ON INFANT DNA METHYLATION AT SPECIFIC IMPRINTED DMRS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
14  3493  49 IDENTIFICATION OF KEY GENES, PATHWAYS, AND MIRNA/MRNA REGULATORY NETWORKS OF CUMS-INDUCED DEPRESSION IN NUCLEUS ACCUMBENS BY INTEGRATED BIOINFORMATICS ANALYSIS. INTRODUCTION: MAJOR DEPRESSIVE DISORDER (MDD) IS A RECURRENT, DEVASTATING MENTAL DISORDER, WHICH AFFECTS >350 MILLION PEOPLE WORLDWIDE, AND EXERTS SUBSTANTIAL PUBLIC HEALTH AND FINANCIAL COSTS TO SOCIETY. THUS, THERE IS A SIGNIFICANT NEED TO DISCOVER INNOVATIVE THERAPEUTICS TO TREAT DEPRESSION EFFICIENTLY. STRESS-INDUCED DYSFUNCTION IN THE SUBTYPE OF NEURONAL CELLS AND THE CHANGE OF SYNAPTIC PLASTICITY AND STRUCTURAL PLASTICITY OF NUCLEUS ACCUMBENS (NAC) ARE IMPLICATED IN DEPRESSION SYMPTOMOLOGY. HOWEVER, THE MOLECULAR AND EPIGENETIC MECHANISMS AND STRESSES TO THE NAC PATHOLOGICAL CHANGES IN DEPRESSION REMAIN ELUSIVE. MATERIALS AND METHODS: IN THIS STUDY, TREATMENT GROUP MICE WERE TREATED CONTINUALLY WITH THE CHRONIC UNPREDICTABLE MILD STRESS (CUMS) UNTIL EXPRESSION OF DEPRESSION-LIKE BEHAVIORS WERE FOUND. DEPRESSION WAS CONFIRMED WITH SUCROSE PREFERENCE, NOVELTY-SUPPRESSED FEEDING, FORCED SWIMMING, AND TAIL SUSPENSION TESTS. WE APPLIED HIGH-THROUGHPUT RNA SEQUENCING TO ASSESS MICRORNA EXPRESSION AND TRANSCRIPTIONAL PROFILES IN THE NAC TISSUE FROM DEPRESSION-LIKE BEHAVIORS MICE AND CONTROL MICE. THE REGULATORY NETWORK OF MIRNAS/MRNAS WAS CONSTRUCTED BASED ON THE HIGH-THROUGHPUT RNA SEQUENCE AND BIOINFORMATICS SOFTWARE PREDICTIONS. RESULTS: A TOTAL OF 17 MIRNAS AND 10 MRNAS WERE SIGNIFICANTLY UPREGULATED IN THE NAC OF CUMS-INDUCED MICE WITH DEPRESSION-LIKE BEHAVIORS, AND 12 MIRNAS AND 29 MRNAS WERE DOWNREGULATED. A SERIES OF BIOINFORMATICS ANALYSES SHOWED THAT THESE ALTERED MIRNAS PREDICTED TARGET MRNA AND DIFFERENTIALLY EXPRESSED MRNAS WERE SIGNIFICANTLY ENRICHED IN THE MAPK SIGNALING PATHWAY, GABAERGIC SYNAPSE, DOPAMINERGIC SYNAPSE, CYTOKINE-CYTOKINE RECEPTOR INTERACTION, AXON GUIDANCE, REGULATION OF AUTOPHAGY, AND SO ON. FURTHERMORE, DUAL LUCIFERASE REPORT ASSAY AND QRT-PCR RESULTS VALIDATED THE MIRNA/MRNA REGULATORY NETWORK. CONCLUSION: THE DETERIORATIONS OF GABAERGIC SYNAPSES, DOPAMINERGIC SYNAPSES, NEUROTRANSMITTER SYNTHESIS, AS WELL AS AUTOPHAGY-ASSOCIATED APOPTOTIC PATHWAY ARE ASSOCIATED WITH THE MOLECULAR PATHOLOGICAL MECHANISM OF CUMS-INDUCED DEPRESSION.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
15    66  40 A KEY ROLE FOR EZH2 IN EPIGENETIC SILENCING OF HOX GENES IN MANTLE CELL LYMPHOMA. THE CHROMATIN MODIFIER EZH2 IS OVEREXPRESSED AND ASSOCIATED WITH INFERIOR OUTCOME IN MANTLE CELL LYMPHOMA (MCL). RECENTLY, WE DEMONSTRATED PREFERENTIAL DNA METHYLATION OF HOX GENES IN MCL COMPARED WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), DESPITE THESE GENES NOT BEING EXPRESSED IN EITHER ENTITY. SINCE EZH2 HAS BEEN SHOWN TO REGULATE HOX GENE EXPRESSION, TO GAIN FURTHER INSIGHT INTO ITS POSSIBLE ROLE IN DIFFERENTIAL SILENCING OF HOX GENES IN MCL VS. CLL, WE PERFORMED DETAILED EPIGENETIC CHARACTERIZATION USING REPRESENTATIVE CELL LINES AND PRIMARY SAMPLES. WE OBSERVED SIGNIFICANT OVEREXPRESSION OF EZH2 IN MCL VS. CLL. CHROMATIN IMMUNE PRECIPITATION (CHIP) ASSAYS REVEALED THAT EZH2 CATALYZED REPRESSIVE H3 LYSINE 27 TRIMETHYLATION (H3K27ME3), WHICH WAS SUFFICIENT TO SILENCE HOX GENES IN CLL, WHEREAS IN MCL H3K27ME3 IS ACCOMPANIED BY DNA METHYLATION FOR A MORE STABLE REPRESSION. MORE IMPORTANTLY, HYPERMETHYLATION OF THE HOX GENES IN MCL RESULTED FROM EZH2 OVEREXPRESSION AND SUBSEQUENT RECRUITMENT OF THE DNA METHYLATION MACHINERY ONTO HOX GENE PROMOTERS. THE IMPORTANCE OF EZH2 UPREGULATION IN THIS PROCESS WAS FURTHER UNDERSCORED BY SIRNA TRANSFECTION AND EZH2 INHIBITOR EXPERIMENTS. ALTOGETHER, THESE OBSERVATIONS IMPLICATE EZH2 IN THE LONG-TERM SILENCING OF HOX GENES IN MCL, AND ALLUDE TO ITS POTENTIAL AS A THERAPEUTIC TARGET WITH CLINICAL IMPACT.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
16   520  35 ASSOCIATIONS BETWEEN MATERNAL PRENATAL STRESS, METHYLATION CHANGES IN IGF1 AND IGF2, AND BIRTH WEIGHT. MATERNAL STRESS HAS BEEN LINKED TO LOW BIRTH WEIGHT IN NEWBORNS. ONE POTENTIAL PATHWAY INVOLVES EPIGENETIC CHANGES AT CANDIDATE GENES THAT MAY MEDIATE THE EFFECTS OF PRENATAL MATERNAL STRESS ON BIRTH WEIGHT. THIS RELATIONSHIP HAS BEEN DOCUMENTED IN STRESS-RELATED GENES, SUCH AS NR3C1. THERE IS LESS LITERATURE EXPLORING THE EFFECT OF STRESS ON GROWTH-RELATED GENES. IGF1 AND IGF2 HAVE BEEN IMPLICATED IN FETAL GROWTH AND DEVELOPMENT, THOUGH VIA DIFFERENT MECHANISMS AS IGF2 IS UNDER IMPRINTING CONTROL. IN THIS STUDY, WE TESTED FOR ASSOCIATIONS BETWEEN PRENATAL STRESS, METHYLATION OF IGF1 AND IGF2, AND BIRTH WEIGHT. A TOTAL OF 24 MOTHER-NEWBORN DYADS IN THE DEMOCRATIC REPUBLIC OF CONGO WERE ENROLLED. ETHNOGRAPHIC INTERVIEWS WERE CONDUCTED WITH MOTHERS AT DELIVERY TO GATHER CULTURALLY RELEVANT WAR-RELATED AND CHRONIC STRESSORS. DNA METHYLATION DATA WERE GENERATED FROM MATERNAL VENOUS, CORD BLOOD AND PLACENTAL TISSUE SAMPLES. MULTIVARIATE REGRESSIONS WERE USED TO TEST FOR ASSOCIATIONS BETWEEN STRESS MEASURES, DNA METHYLATION AND BIRTH WEIGHT IN EACH OF THE THREE TISSUE TYPES. WE FOUND AN ASSOCIATION BETWEEN IGF2 METHYLATION IN MATERNAL BLOOD AND BIRTH WEIGHT. PREVIOUS LITERATURE ON THE RELATIONSHIP BETWEEN IGF2 METHYLATION AND BIRTH WEIGHT HAS FOCUSED ON METHYLATION AT KNOWN DIFFERENTIALLY METHYLATED REGIONS IN CORD BLOOD OR PLACENTAL SAMPLES. OUR FINDINGS INDICATE THERE MAY BE LINKS BETWEEN THE MATERNAL EPIGENOME AND LOW BIRTH WEIGHT THAT RELY ON MECHANISMS OUTSIDE KNOWN IMPRINTING PATHWAYS. IT THUS MAY BE IMPORTANT TO CONSIDER THE EFFECT OF MATERNAL EXPOSURES AND EPIGENETIC PROFILES ON BIRTH WEIGHT EVEN IN THE SETTING OF MATERNALLY IMPRINTED GENES SUCH AS IGF2.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
17  3410  44 HOXA5 UNDERGOES DYNAMIC DNA METHYLATION AND TRANSCRIPTIONAL REPRESSION IN THE ADIPOSE TISSUE OF MICE EXPOSED TO HIGH-FAT DIET. BACKGROUND/OBJECTIVES: THE GENOMIC BASES OF THE ADIPOSE TISSUE ABNORMALITIES INDUCED BY CHRONIC POSITIVE CALORIE EXCESS HAVE BEEN ONLY PARTIALLY ELUCIDATED. WE ADOPTED A GENOME-WIDE APPROACH TO DIRECTLY TEST WHETHER LONG-TERM HIGH-FAT DIET (HFD) EXPOSURE AFFECTS THE DNA METHYLATION PROFILE OF THE MOUSE ADIPOSE TISSUE AND TO IDENTIFY THE FUNCTIONAL CONSEQUENCES OF THESE CHANGES. SUBJECTS/METHODS: WE HAVE USED EPIDIDYMAL FAT OF MICE FED EITHER HIGH-FAT (HFD) OR REGULAR CHOW (STD) DIET FOR 5 MONTHS AND PERFORMED GENOME-WIDE DNA METHYLATION ANALYSES BY METHYLATED DNA IMMUNOPRECIPITATION SEQUENCING (MEDIP-SEQ). MOUSE HOMEOBOX (HOX) GENE DNA METHYLATION PCR, RT-QPCR AND BISULPHITE SEQUENCING ANALYSES WERE THEN PERFORMED. RESULTS: MICE FED THE HFD PROGRESSIVELY EXPANDED THEIR ADIPOSE MASS ACCOMPANIED BY A SIGNIFICANT DECREASE IN GLUCOSE TOLERANCE (P<0.001) AND INSULIN SENSITIVITY (P<0.05). MEDIP-SEQ DATA ANALYSIS REVEALED A UNIFORM DISTRIBUTION OF DIFFERENTIALLY METHYLATED REGIONS (DMR) THROUGH THE ENTIRE ADIPOCYTE GENOME, WITH A HIGHER NUMBER OF HYPERMETHYLATED REGIONS IN HFD MICE (P<0.005). THIS DIFFERENT METHYLATION PROFILE WAS ACCOMPANIED BY INCREASED EXPRESSION OF THE DNMT3A DNA METHYLTRANSFERASE (DNMT; P<0.05) AND THE METHYL-CPG-BINDING DOMAIN PROTEIN MBD3 (P<0.05) GENES IN HFD MICE. GENE ONTOLOGY ANALYSIS REVEALED THAT, IN THE HFD-TREATED MICE, THE HOX FAMILY OF DEVELOPMENT GENES WAS HIGHLY ENRICHED IN DIFFERENTIALLY METHYLATED GENES (P=0.008). TO VALIDATE THIS FINDING, HOXA5, WHICH IS IMPLICATED IN FAT TISSUE DIFFERENTIATION AND REMODELING, HAS BEEN SELECTED AND ANALYZED BY BISULPHITE SEQUENCING, CONFIRMING HYPERMETHYLATION IN THE ADIPOSE TISSUE FROM THE HFD MICE. HOXA5 HYPERMETHYLATION WAS ASSOCIATED WITH DOWNREGULATION OF HOXA5 MRNA AND PROTEIN EXPRESSION. FEEDING ANIMALS PREVIOUSLY EXPOSED TO THE HFD WITH A STANDARD CHOW DIET FOR TWO FURTHER MONTHS IMPROVED THE METABOLIC PHENOTYPE OF THE ANIMALS, ACCOMPANIED BY RETURN OF HOXA5 METHYLATION AND EXPRESSION LEVELS (P<0.05) TO VALUES SIMILAR TO THOSE OF THE CONTROL MICE MAINTAINED UNDER STANDARD CHOW. CONCLUSIONS: HFD INDUCES ADIPOSE TISSUE ABNORMALITIES ACCOMPANIED BY EPIGENETIC CHANGES AT THE HOXA5 ADIPOSE TISSUE REMODELING GENE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
18   219  35 ACUTE IMMOBILIZATION STRESS FOLLOWING CONTEXTUAL FEAR CONDITIONING REDUCES FEAR MEMORY: TIMING IS ESSENTIAL. BACKGROUND: HISTONE ACETYLATION IS REGULATED IN RESPONSE TO STRESS AND PLAYS AN IMPORTANT ROLE IN LEARNING AND MEMORY. CHRONIC STRESS IS KNOWN TO DETERIORATE COGNITION, WHEREAS ACUTE STRESS FACILITATES MEMORY FORMATION. HOWEVER, WHETHER ACUTE STRESS FACILITATES MEMORY FORMATION WHEN IT IS APPLIED AFTER FEAR STIMULATION IS NOT YET KNOWN. THEREFORE, THIS STUDY AIMED TO INVESTIGATE THE EFFECT OF ACUTE STRESS APPLIED AFTER FEAR TRAINING ON MEMORY FORMATION, MRNA EXPRESSION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), EPIGENETIC REGULATION OF BDNF EXPRESSION, AND CORTICOSTERONE LEVEL IN MICE IN VIVO. METHODS: MICE WERE SUBJECTED TO ACUTE IMMOBILIZATION STRESS FOR 30 MIN AT 60 OR 90 MIN AFTER CONTEXTUAL FEAR CONDITIONING TRAINING, AND ACETYLATION OF HISTONE 3 AT LYSINE 14 (H3K14) AND LEVEL OF CORTICOSTERONE WERE MEASURED USING WESTERN BLOT ANALYSIS AND ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA), RESPECTIVELY. A FREEZING BEHAVIOR TEST WAS PERFORMED 24 H AFTER TRAINING, AND MRNA EXPRESSION OF BDNF WAS MEASURED USING REAL-TIME POLYMERASE CHAIN REACTIONS. DIFFERENT GROUPS OF MICE WERE USED FOR EACH TEST. RESULTS: FREEZING BEHAVIOR SIGNIFICANTLY DECREASED WITH THE DOWN-REGULATION OF BDNF MRNA EXPRESSION CAUSED BY ACUTE IMMOBILIZATION STRESS AT 60 MIN AFTER FEAR CONDITIONING TRAINING OWING TO THE REDUCTION OF H3K14 ACETYLATION. HOWEVER, BDNF MRNA EXPRESSION AND H3K14 ACETYLATION WERE NOT REDUCED IN ANIMALS SUBJECTED TO IMMOBILIZATION STRESS AT 90 MIN AFTER THE TRAINING. FURTHER, THE CORTICOSTERONE LEVEL WAS SIGNIFICANTLY HIGH IN MICE SUBJECTED TO IMMOBILIZATION STRESS AT 60 MIN AFTER THE TRAINING. CONCLUSION: ACUTE IMMOBILIZATION STRESS FOR 30 MIN AT 60 MIN AFTER FEAR CONDITIONING TRAINING IMPAIRED MEMORY FORMATION AND REDUCED BDNF MRNA EXPRESSION AND H3K14 ACETYLATION IN THE HIPPOCAMPUS OF MICE OWING TO THE HIGH LEVEL OF CORTICOSTERONE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
19  3064  39 GENOME-WIDE DNA METHYLATION ENCODES CARDIAC TRANSCRIPTIONAL REPROGRAMMING IN HUMAN ISCHEMIC HEART FAILURE. ISCHEMIC CARDIOMYOPATHY (ICM) IS THE CLINICAL ENDPOINT OF CORONARY HEART DISEASE AND A LEADING CAUSE OF HEART FAILURE. DESPITE GROWING DEMANDS TO DEVELOP PERSONALIZED APPROACHES TO TREAT ICM, PROGRESS IS LIMITED BY INADEQUATE KNOWLEDGE OF ITS PATHOGENESIS. SINCE EPIGENETICS HAS BEEN IMPLICATED IN THE DEVELOPMENT OF OTHER CHRONIC DISEASES, THE CURRENT STUDY WAS DESIGNED TO DETERMINE WHETHER TRANSCRIPTIONAL AND/OR EPIGENETIC CHANGES ARE SUFFICIENT TO DISTINGUISH ICM FROM OTHER ETIOLOGIES OF HEART FAILURE. SPECIFICALLY, WE HYPOTHESIZE THAT GENOME-WIDE DNA METHYLATION ENCODES TRANSCRIPTIONAL REPROGRAMMING IN ICM. RNA-SEQUENCING ANALYSIS WAS PERFORMED ON HUMAN ISCHEMIC LEFT VENTRICULAR TISSUE OBTAINED FROM PATIENTS WITH END-STAGE HEART FAILURE, WHICH ENRICHED KNOWN TARGETS OF THE POLYCOMB METHYLTRANSFERASE EZH2 COMPARED TO NON-ISCHEMIC HEARTS. COMBINED RNA SEQUENCING AND GENOME-WIDE DNA METHYLATION ANALYSIS REVEALED A ROBUST GENE EXPRESSION PATTERN CONSISTENT WITH SUPPRESSION OF OXIDATIVE METABOLISM, INDUCED ANAEROBIC GLYCOLYSIS, AND ALTERED CELLULAR REMODELING. LASTLY, KLF15 WAS IDENTIFIED AS A PUTATIVE UPSTREAM REGULATOR OF METABOLIC GENE EXPRESSION THAT WAS ITSELF REGULATED BY EZH2 IN A SET DOMAIN-DEPENDENT MANNER. OUR OBSERVATIONS THEREFORE DEFINE A NOVEL ROLE OF DNA METHYLATION IN THE METABOLIC REPROGRAMMING OF ICM. FURTHERMORE, WE IDENTIFY EZH2 AS AN EPIGENETIC REGULATOR OF KLF15 ALONG WITH DNA HYPERMETHYLATION, AND WE PROPOSE A NOVEL MECHANISM THROUGH WHICH CORONARY HEART DISEASE REPROGRAMS THE EXPRESSION OF BOTH INTERMEDIATE ENZYMES AND UPSTREAM REGULATORS OF CARDIAC METABOLISM SUCH AS KLF15.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
20   668  44 BNDF METHYLATION IN MOTHERS AND NEWBORNS IS ASSOCIATED WITH MATERNAL EXPOSURE TO WAR TRAUMA. BACKGROUND: THE BDNF GENE CODES FOR BRAIN-DERIVED NEUROTROPHIC FACTOR, A GROWTH FACTOR INVOLVED IN NEURAL DEVELOPMENT, CELL DIFFERENTIATION, AND SYNAPTIC PLASTICITY. PRESENT IN BOTH THE BRAIN AND PERIPHERY, BDNF PLAYS CRITICAL ROLES THROUGHOUT THE BODY AND IS ESSENTIAL FOR PLACENTAL AND FETAL DEVELOPMENT. RODENT STUDIES SHOW THAT EARLY LIFE STRESS, INCLUDING PRENATAL STRESS, BROADLY ALTERS BDNF METHYLATION, WITH PRESUMED CHANGES IN GENE EXPRESSION. NO STUDIES HAVE ASSESSED PRENATAL EXPOSURE TO MATERNAL TRAUMATIC STRESS AND BDNF METHYLATION IN HUMANS. THIS STUDY EXAMINED ASSOCIATIONS OF PRENATAL EXPOSURE TO MATERNAL STRESS AND BDNF METHYLATION AT CPG SITES ACROSS THE BDNF GENE. RESULTS: AMONG 24 MOTHERS AND NEWBORNS IN THE EASTERN DEMOCRATIC REPUBLIC OF CONGO, A REGION WITH EXTREME CONFLICT AND VIOLENCE TO WOMEN, MATERNAL EXPERIENCES OF WAR TRAUMA AND CHRONIC STRESS WERE ASSOCIATED WITH BDNF METHYLATION IN UMBILICAL CORD BLOOD, PLACENTAL TISSUE, AND MATERNAL VENOUS BLOOD. ASSOCIATIONS OF MATERNAL STRESS AND BDNF METHYLATION SHOWED HIGH TISSUE SPECIFICITY. THE MAJORITY OF SIGNIFICANT ASSOCIATIONS WERE OBSERVED IN PUTATIVE TRANSCRIPTION FACTOR BINDING REGIONS. CONCLUSIONS: THIS IS THE FIRST STUDY IN HUMANS TO EXAMINE BDNF METHYLATION IN RELATION TO PRENATAL EXPOSURE TO MATERNAL STRESS IN THREE TISSUES SIMULTANEOUSLY AND THE FIRST IN ANY MAMMALIAN SPECIES TO REPORT ASSOCIATIONS OF PRENATAL STRESS AND BDNF METHYLATION IN PLACENTAL TISSUE. THE FINDINGS ADD TO THE GROWING BODY OF EVIDENCE HIGHLIGHTING THE IMPORTANCE OF CONSIDERING EPIGENETIC EFFECTS WHEN EXAMINING THE IMPACTS OF TRAUMA AND STRESS, NOT ONLY FOR ADULTS BUT ALSO FOR OFFSPRING EXPOSED VIA EFFECTS TRANSMITTED BEFORE BIRTH.	2017