1 1820 115 EFFECTS OF CHRONIC RESTRAINT STRESS ON THE GLOBAL DNA METHYLATION PROFILE OF RAT LUNG CELLS: MODULATION BY PHYSICAL EXERCISE. THE POTENTIAL OF BEHAVIORAL STRESS TO AFFECT EPIGENETIC MECHANISMS OF NON-ENCEPHALIC TISSUES IS STILL UNDERESTIMATED. IN THE PRESENT STUDY WE EVALUATED THE EFFECTS OF CHRONIC BEHAVIORAL STRESS ON THE DNA METHYLATION PROFILE OF RAT LUNG CELLS. FURTHERMORE, WE EVALUATED THE POTENTIAL OF PHYSICAL EXERCISE TO MODULATE THE CHANGES EVOKED BY BEHAVIORAL STRESS IN LUNG CELLS. MALE WISTAR RATS WERE DIVIDED INTO FOUR EXPERIMENTAL GROUPS: (1) ANIMALS SUBMITTED TO CHRONIC RESTRAINT STRESS (CRS) (ST GROUP) DURING THE PERIOD OF THE 67TH-80TH POSTNATAL DAY (PND); (2) ANIMALS SUBMITTED TO PHYSICAL EXERCISE (EX GROUP) DURING THE 53RD-79TH PND; (3) ANIMALS SUBMITTED TO SWIMMING DURING THE 53RD-79TH PND AND TO CRS DURING THE 67TH-80TH PND (EX-ST GROUP); AND (4) ANIMALS NOT SUBMITTED TO STRESS OR SWIMMING PROTOCOLS (CTL). GLOBAL DNA METHYLATION WAS QUANTIFIED USING AN ELISA-BASED APPROACH AND GENE EXPRESSION WAS EVALUATED BY REAL TIME PCR. A DECREASED GLOBAL DNA METHYLATION PROFILE WAS OBSERVED IN THE ST GROUP, HOWEVER PHYSICAL EXERCISE DEMONSTRATED PROTECTION OF LUNG CELLS FROM THIS STRESS-RELATED HYPOMETHYLATION. INCREASED EXPRESSION OF THE DNMT1 GENE WAS EVIDENCED IN THE ST GROUP, WHEREAS PHYSICAL EXERCISE WAS SHOWN TO PROTECT LUNG CELLS FROM THIS STRESS-RELATED EFFECT IN THE EX-ST GROUP. COMPARATIVE ANALYSIS OF THE ST AND EX GROUPS REVEALED OPPOSITE EFFECTS ON THE EXPRESSION OF DNMT3A AND DNMT3B; HOWEVER, A STRESS-RELATED INCREASE IN EXPRESSION OF DNMT3A AND DNMT3B WAS NOT SEEN IN THE EX-ST GROUP. OUR DATA SHOWED THAT BEHAVIORAL STRESS INDUCED SIGNIFICANT CHANGES IN THE DNA METHYLATION PROFILE OF RAT LUNG CELLS AND THAT THIS COULD BE MODULATED BY PHYSICAL EXERCISE.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
2 1418  40 DIFFERENCES IN DNA METHYLATION REPROGRAMMING UNDERLIE THE SEXUAL DIMORPHISM OF BEHAVIORAL DISORDER CAUSED BY PRENATAL STRESS IN RATS. PRENATAL STRESS (PS) CAN LEAD TO NEUROENDOCRINE AND EMOTIONAL DISORDERS LATER IN ADOLESCENCE. SEXUAL DIMORPHISM IN THESE NEURODEVELOPMENTAL OUTCOMES HAVE BEEN OBSERVED; HOWEVER, THE UNDERLYING MECHANISMS ARE NOT FULLY UNDERSTOOD. TO ADDRESS THIS ISSUE, WE INVESTIGATED WHETHER THERE ARE SEX DIFFERENCES IN EPIGENETIC REPROGRAMMING IN RATS EXPOSED TO PS. PREGNANT FEMALE RATS WERE SUBJECTED TO CHRONIC RESTRAINT STRESS FROM GESTATIONAL DAY (G)12 TO G18. FROM POSTNATAL DAY (P)38 TO P45, SUBGROUPS OF OFFSPRING INCLUDING BOTH MALES AND FEMALES WERE SUBJECTED TO BEHAVIORAL TESTING AND BRAIN TISSUE SPECIMENS WERE ANALYZED BY DNA PYROSEQUENCING, WESTERN BLOTTING, AND GOLGI STAINING TO ASSESS CHANGES IN METHYLATION PATTERN OF GLUCOCORTICOID RECEPTOR (GR) GENE, EXPRESSION OF DNA METHYLTRANSFERASE (DNMT) AND DNA DEMETHYLASE, AND DENDRITE MORPHOLOGY, RESPECTIVELY. THE DNA METHYLTRANSFERASE INHIBITOR DECITABINE WAS ADMINISTERED TO RATS PRIOR TO PS TO FURTHER EVALUATE THE ROLE OF METHYLATION IN THE SEXUALLY DIMORPHIC EFFECTS OF PS. THE RESULTS SHOWED THAT PS INCREASED ANXIETY-LIKE BEHAVIOR IN OFFSPRING, ESPECIALLY IN FEMALES, WHILE DEPRESSION-LIKE BEHAVIOR WAS INCREASED IN MALE OFFSPRING COMPARED TO CONTROL LITTERMATES. THE METHYLATION PATTERN IN THE PROMOTER REGION OF THE GR GENE DIFFERED BETWEEN MALES AND FEMALES. SEX-SPECIFIC CHANGES IN THE EXPRESSION OF DNMTS (DNMT1 AND DNMT3A) AND DNA DEMETHYLASE (TET METHYLCYTOSINE DIOXYGENASE 2) WERE ALSO OBSERVED. INTERESTINGLY, DECITABINE ALLEVIATED THE BEHAVIORAL DISORDER CAUSED BY PS AND RESTORED DENDRITE DENSITY AND MORPHOLOGY IN FEMALE BUT NOT MALE RATS. THESE FINDINGS SUGGEST THAT DIFFERENT CHANGE PATTERNS OF DNMT AND DEMETHYLASE IN THE TWO SEXES AFTER PS ARE RESPONSIBLE FOR THE SEXUALLY DIMORPHISM, WHICH COULD HAVE IMPLICATIONS FOR THE CLINICAL MANAGEMENT OF STRESS-RELATED DISORDERS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
3 6794  36 [EFFECT OF BENZO(A)PYRENE ON THE EXPRESSION OF AHR-REGULATED MICRORNA IN FEMALE AND MALE RAT LUNGS]. SMOKING IS THE MAIN RISK FACTOR FOR LUNG CANCER, MAINLY DUE TO PRESENCE OF NITROSAMINES AND POLYCYCLIC AROMATIC HYDROCARBONS, INCLUDING BENZO[A]PYRENE (BP) IN TOBACCO SMOKE COMPOSITION. THE GENOTOXIC EFFECT OF BP IS BASED ON THE HIGH DNA-BINDING ABILITY OF ITS METABOLITES, WHILE THE EPIGENETIC EFFECTS ARE MEDIATED BY A CHANGE IN THE EXPRESSION OF CANCER RELATED GENES OR REGULATORY RNAS. IT HAS BEEN SHOWN THAT WOMEN HAVE A HIGHER RISK TO DEVELOP LUNG CANCER UPON SMOKING RATHER THAN MEN. WE HYPOTHESIZED THAT CROSSTALK BETWEEN SIGNALING PATHWAYS ACTIVATED BY BP AND ESTROGENS COULD UNDERLIE THE SEX-DEPENDENT DIFFERENCES IN MIRNAS EXPRESSION. TO TEST THIS HYPOTHESIS, MALE AND FEMALE RATS WERE SUBJECTED TO SHORT-TERM OR LONG-TERM BP EXPOSURE. USING IN SILICO ANALYSIS, MIRNAS CONTAINING THE ER- AND AHR-BINDING SITES IN THE PROMOTERS OF THE GENES (OR HOST GENES) WERE SELECTED. DURING CHRONIC EXPOSURE OF BP THE EXPRESSION OF MIR-22-3P, -29A-3P, -126A-3P, -193B-5P IN THE LUNGS OF MALE RATS WERE SIGNIFICANTLY INCREASED, WHILE THE LEVEL OF MIRNA-483-3P WERE DECREASED. EXPRESSION OF MIRNA-483-3P WAS UP-REGULATED DURING CHRONIC BP EXPOSURE IN THE LUNGS OF FEMALE RATS AND THE LEVELS OF OTHER STUDIED MIRNAS WERE UNCHANGED. IN TURN, CHANGES IN THE EXPRESSION OF MIRNAS WERE FOLLOWED BY CHANGES IN THE EXPRESSION OF THEIR TARGET GENES, INCLUDING PTEN, EMP2, IGF1, ITGA6, SLC34A2, AND THE OBSERVED CHANGES IN FEMALE AND MALE RAT LUNGS WERE VARIED. THUS, OUR RESULTS SUGGEST THAT SEX-DEPENDENT EPIGENETIC EFFECTS OF BP MAY BE BASED ON DIFFERENT EXPRESSION OF AHR- AND ER- REGULATED MIRNAS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
4 2297  33 EPIGENETIC REGULATION OF ACUTE INFLAMMATORY PAIN. ACUTE PAIN IS ASSOCIATED WITH TISSUE DAMAGE, WHICH RESULTS IN THE RELEASE OF INFLAMMATORY MEDIATORS. RECENT STUDIES POINT TO THE INVOLVEMENT OF EPIGENETIC MECHANISMS (DNA METHYLATION) IN THE DEVELOPMENT OF PAIN. WE HAVE FOUND THAT DURING ACUTE INFLAMMATORY PAIN INDUCED BY THE APPLICATION OF 10% MUSTARD OIL ON THE TONGUES OF RATS, LEVELS OF DNMT3A AND 3B WERE ELEVATED MARKEDLY (36 AND 42 % RESPECTIVELY), WHEREAS THE LEVEL OF DNMT1 WAS NOT CHANGED SIGNIFICANTLY. PREVIOUS INJECTION OF XEFOCAM WITH 0,4 MG/KG DOSE DECREASED LEVELS OF DNMT3A AND 3B (25 AND 24% RESPECTIVELY). THE LEVEL OF DNMT1 WAS NOT CHANGED SIGNIFICANTLY COMPARED TO THE CONTROL GROUP. THE FINDINGS SUPPORT THE IDEA THAT INHIBITORS OF DNA-METHYLTRANSFERASES COULD BE USEFUL FOR PAIN MANAGEMENT. OUR DATA SUGGEST THAT NSAIDS (ALONE OR IN COMBINATION WITH DNMT INHIBITORS) MAY BE PROPOSED AS POSSIBLE EPIGENETIC REGULATORY AGENTS, WHICH MAY PLAY A ROLE IN EPIGENETIC MECHANISMS INDIRECTLY THROUGH ALTERING THE ACTIVITY OF INFLAMMATORY MEDIATORS INVOLVED IN PAIN DEVELOPMENT.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
5 2716  26 EXERCISE-MODULATED EPIGENETIC MARKERS AND INFLAMMATORY RESPONSE IN COPD INDIVIDUALS: A PILOT STUDY. THE STUDY INVESTIGATED THE EFFECTS OF EXERCISE ON EPIGENETIC SIGNALS AND SYSTEMIC CYTOKINE LEVELS IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) INDIVIDUALS. TEN PARTICIPANTS OF A PULMONARY REHABILITATION PROGRAM WERE SUBMITTED TO 24 SESSIONS OF A SUPERVISIONED EXERCISE PROTOCOL THRICE-WEEKLY (90MIN/SESSION). BLOOD SAMPLES WERE COLLECTED AT BASELINE, AFTER THE 1ST SESSION, BEFORE AND AFTER THE 24TH SESSION. A DNA HYPOMETHYLATION STATUS WAS OBSERVED AFTER THE 1ST SESSION WHEN COMPARED AT BASELINE, WHILE GLOBAL HISTONE H4 ACETYLATION STATUS WAS UNALTERED IN ANY TIME-POINTS EVALUATED. NO SIGNIFICANT CHANGES WERE OBSERVED ON CYTOKINE LEVELS AFTER THE 1ST SESSION. A SIGNIFICANT ENHANCEMENT ON INTERLEUKIN 6 (IL-6) AND A DECREASE ON TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA) LEVELS WERE FOUND AFTER THE 24TH SESSION WHEN COMPARED TO THE PRE 24TH SESSION. MOREOVER, 23 SESSIONS OF EXERCISE WERE ABLE TO DIMINISH SIGNIFICANTLY THE BASAL LEVELS OF IL-6 AND INTERLEUKIN 8 (IL-8). THESE DATA SUGGEST A POTENTIAL ROLE OF EPIGENETIC MACHINERY IN MEDIATING THE ANTI-INFLAMMATORY EFFECTS OF EXERCISE IN COPD PATIENTS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
6 5188  40 PRENATAL ALCOHOL EXPOSURE ALTERS EXPRESSION OF NEUROGENESIS-RELATED GENES IN AN EX VIVO CELL CULTURE MODEL. PRENATAL ALCOHOL EXPOSURE CAN LEAD TO LONG-LASTING CHANGES IN FUNCTIONAL AND GENETIC PROGRAMS OF THE BRAIN, WHICH MAY UNDERLIE BEHAVIORAL ALTERATIONS SEEN IN FETAL ALCOHOL SPECTRUM DISORDER (FASD). ABERRANT FETAL PROGRAMMING DURING GESTATIONAL ALCOHOL EXPOSURE IS A POSSIBLE MECHANISM BY WHICH ALCOHOL IMPARTS TERATOGENIC EFFECTS ON THE BRAIN; HOWEVER, CURRENT METHODS USED TO INVESTIGATE THE EFFECTS OF ALCOHOL ON DEVELOPMENT OFTEN RELY ON EITHER DIRECT APPLICATION OF ALCOHOL IN VITRO OR ACUTE HIGH DOSES IN VIVO. IN THIS STUDY, WE USED OUR ESTABLISHED MODERATE PRENATAL ALCOHOL EXPOSURE (PAE) MODEL, RESULTING IN MATERNAL BLOOD ALCOHOL CONTENT OF APPROXIMATELY 20 MM, AND SUBSEQUENT EX VIVO CELL CULTURE TO ASSESS EXPRESSION OF GENES RELATED TO NEUROGENESIS. PROLIFERATING AND DIFFERENTIATING NEURAL PROGENITOR CELL CULTURE CONDITIONS WERE ESTABLISHED FROM TELENCEPHALIC TISSUE DERIVED FROM EMBRYONIC DAY (E) 15-17 TISSUE EXPOSED TO ALCOHOL VIA MATERNAL DRINKING THROUGHOUT PREGNANCY. GENE EXPRESSION ANALYSIS ON MRNA DERIVED IN VITRO WAS PERFORMED USING A MICROARRAY, AND QUANTITATIVE PCR WAS CONDUCTED FOR GENES TO VALIDATE THE MICROARRAY. STUDENT'S T TESTS WERE PERFORMED FOR STATISTICAL COMPARISON OF EACH EXPOSURE UNDER EACH CULTURE CONDITION USING A 95% CONFIDENCE INTERVAL. ELEVEN PERCENT OF GENES ON THE ARRAY HAD SIGNIFICANTLY ALTERED MRNA EXPRESSION IN THE PRENATAL ALCOHOL-EXPOSED NEURAL PROGENITOR CULTURE UNDER PROLIFERATING CONDITIONS. THESE INCLUDE REDUCED EXPRESSION OF ADORA2A, CXCL1, DLG4, HES1, NPTX1, AND VEGFA AND INCREASED EXPRESSION OF FGF13, NDN, AND SOX3; BIOINFORMATICS ANALYSIS INDICATED THAT THESE GENES ARE INVOLVED IN CELL GROWTH AND PROLIFERATION. DECREASED LEVELS OF DNMT1 AND DNMT3A WERE ALSO FOUND UNDER PROLIFERATING CONDITIONS. UNDER DIFFERENTIATING CONDITIONS, 7.3% OF GENES HAD DECREASED MRNA EXPRESSION; THESE INCLUDE CDK5RAP3, GDNF, HEY2, HEYL, PARD6B, AND PTN, WHICH ARE ASSOCIATED WITH SURVIVAL AND DIFFERENTIATION AS INDICATED BY BIOINFORMATICS ANALYSIS. THIS STUDY IS THE FIRST TO USE CHRONIC LOW TO MODERATE PAE, TO MORE ACCURATELY REFLECT MATERNAL ALCOHOL CONSUMPTION, AND SUBSEQUENT NEURAL PROGENITOR CELL CULTURE TO DEMONSTRATE THAT PAE THROUGHOUT GESTATION ALTERS EXPRESSION OF GENES INVOLVED IN NEURAL DEVELOPMENT AND EMBRYONIC NEUROGENESIS.	2014	
                                                                                                                                                                                                                                                                                                         
7 4528  20 MULTIGENERATIONAL EFFECTS OF CADMIUM ON THE LIFESPAN AND FERTILITY OF DROSOPHILA MELANOGASTER. ALTHOUGH THE DAMAGE AND TOLERANCE MECHANISMS OF CD STRESS ARE KNOWN, THE DATA ON GENETIC RISK ARE LIMITED. THE AIM OF THIS STUDY WAS TO ASSESS THE CHRONIC TOXICITY OF CD, GENETIC RESPONSES, AND MULTIGENERATIONAL EFFECTS IN FIVE GENERATIONS OF DROSOPHILA MELANOGASTER. FOR EACH GENERATION, LIFESPAN AND FERTILITY WERE STATISTICALLY ANALYSED AND THE EXPRESSION OF APOPTOSIS- (P53 AND CASPASE-3) AND EPIGENESIS-RELATED (DDNMT2 AND DMBD2/3) GENES WAS EXAMINED. LIFESPAN AND FERTILITY SIGNIFICANTLY DECLINED UNDER CD STRESS AND THESE EFFECTS WERE MAINTAINED FOR TWO GENERATIONS AND ONE GENERATION, RESPECTIVELY, WHEN CD STRESS WAS REMOVED. THE EXPRESSION OF P53 AND CASPASE-3 WAS SIGNIFICANTLY UP-REGULATED AFTER EXPOSURE, SUGGESTING THAT APOPTOSIS CONTRIBUTES TO THE RESISTANCE MECHANISM. THEIR ALTERED EXPRESSION WAS RETAINED FOR TWO GENERATIONS. FURTHERMORE, HIGH EXPRESSION OF DDNMT2 AND DMBD2/3 ACCOMPANIED CD EXPOSURE, WHICH WAS PASSED ON TO THREE GENERATIONS, SUGGESTING THAT GENETIC MODIFICATIONS IN APOPTOSIS-RELATED GENES ARE CARRIED TO THE OFFSPRING THROUGH EPIGENETIC REGULATION.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
8 1328  33 DEPRESSION AND STRESS LEVELS INCREASE RISK OF LIVER CANCER THROUGH EPIGENETIC DOWNREGULATION OF HYPOCRETIN. RECENT STUDIES SUGGEST THAT HYPOCRETIN (HCRT, OREXIN) ARE INVOLVED IN STRESS REGULATION OF DEPRESSION THROUGH THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS. HOWEVER, THE MOLECULAR MECHANISM BY WHICH HYPOCRETIN REGULATE NEUROBIOLOGICAL RESPONSES IS UNKNOWN. HEREIN, THE EFFECTS OF CHRONIC STRESS ON THE EPIGENETIC MODIFICATION OF HCRT AND ITS ASSOCIATION WITH DEPRESSION WERE EXPLORED WITH REGARD TO A POTENTIAL ROLE IN CANCER PROGRESSION. IN THE STUDY, SPRAGUE DAWLEY (SD) RATS WERE USED TO ESTABLISH AN ANIMAL MODEL OF CANCER WITH DEPRESSION BY ADMINISTRATING N-NITROSODIETHYLAMINE (DEN) AND CHRONIC UNPREDICTABLE MILD STRESS (CUMS). RNA-SEQUENCING WAS USED TO DETECT DIFFERENTIALLY EXPRESSED GENES IN THE HIPPOCAMPUS OF RATS AND QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION (QRT-PCR) WAS USED TO VALIDATE THE RESULTS OF RNA-SEQUENCING. THE STATUS OF HCRT PROMOTER METHYLATION WAS ASSESSED BY METHYLATION SPECIFIC POLYMERASE CHAIN REACTION. BEHAVIORAL TESTS SHOWED THAT RATS EXPOSED TO CUMS HAD SIGNIFICANT DEPRESSIVE-LIKE BEHAVIORS. THE NUMBER OF LIVER TUMORS AND TUMOR LOAD IN DEPRESSED RATS EXPOSED TO CUMS WAS HIGHER THAN IN SD RATS WITHOUT CUMS. RNA-SEQUENCING REVEALED THAT HCRT WAS ONE OF THE MOST SIGINIFICANTLY DOWNREGULATED GENE IN THE HIPPOCAMPUS OF SD RATS WITH CUMS COMPARED TO NON-STRESSED GROUP, WHICH WAS VALIDATED BY QRT-PCR. HCRT MRNA EXPRESSION WAS DOWNREGULATED AND THE PROMOTER FOR HCRT WAS HYPER-METHYLATED IN THOSE WITH DEPRESSION. THESE RESULTS IDENTIFIED A CRITICAL ROLE FOR CHRONIC PSYCHOLOGICAL STRESSORS IN TUMORIGENESIS AND CANCER PROGRESSION, VIA EPIGENETIC HCRT DOWNREGULATION. SUCH EPIGENETIC DOWNREGULATION MAY BE THE MOLECULAR BASIS FOR THE ASSOCIATION OF CANCER WITH DEPRESSION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
9  989  29 CHRONIC SOCIAL DEFEAT STRESS DIFFERENTIALLY REGULATES THE EXPRESSION OF BDNF TRANSCRIPTS AND EPIGENETIC MODIFYING ENZYMES IN SUSCEPTIBLE AND RESILIENT MICE. OBJECTIVES: ALTHOUGH STRESS IS CONSIDERED A PRIMARY RISK FACTOR FOR NEUROPSYCHIATRIC DISORDERS, A MAJORITY OF INDIVIDUALS ARE RESILIENT TO THE EFFECTS OF STRESS EXPOSURE AND SUCCESSFULLY ADAPT TO ADVERSE LIFE EVENTS, WHILE OTHERS, THE SO-CALLED SUSCEPTIBLE INDIVIDUALS, MAY HAVE PROBLEMS TO PROPERLY ADAPT TO ENVIRONMENTAL CHANGES. HOWEVER, THE MECHANISMS UNDERLYING THESE DIFFERENT RESPONSES TO STRESS EXPOSURE ARE POORLY UNDERSTOOD.METHODS: ADULT MALE C57BL/6J MICE WERE EXPOSED TO CHRONIC SOCIAL DEFEAT STRESS PROTOCOL AND LEVELS OF BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) TRANSCRIPTS AND EPIGENETIC MODIFYING ENZYMES WERE ANALYSED BY REAL-TIME PCR IN THE HIPPOCAMPUS (HPC) AND PREFRONTAL CORTEX (PFC) OF SUSCEPTIBLE AND RESILIENT MICE.RESULTS: WE FOUND A SELECTIVE REDUCTION OF BDNF-6 TRANSCRIPT IN THE HPC AND AN INCREASE OF BDNF-4 TRANSCRIPT IN THE PFC OF SUSCEPTIBLE MICE. MOREOVER, SUSCEPTIBLE MICE SHOWED A SELECTIVE REDUCTION OF THE G9A MRNA LEVELS IN THE HPC, WHILE HDAC-5 AND DNMT3A MRNA LEVELS WERE SPECIFICALLY REDUCED IN THE PFC.CONCLUSIONS: OVERALL, OUR RESULTS, SHOWING A DIFFERENT EXPRESSION OF BDNF TRANSCRIPTS AND EPIGENETIC MODIFYING ENZYMES IN SUSCEPTIBLE AND RESILIENT MICE, SUGGEST THAT STRESS RESILIENCE IS NOT SIMPLY A LACK OF ACTIVATION OF STRESS-RELATED PATHWAYS, BUT IS RELATED TO THE ACTIVATION OF ADDITIONAL DIFFERENT SPECIFIC MECHANISMS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
10 1729  32 DYSREGULATION OF MIR-155 EXPRESSION IN PROFESSIONAL MIXED MARTIAL ARTS (MMA) FIGHTERS. PSYCHOLOGICAL AND PHYSICAL STRESS CAN INDUCE DYSREGULATION OF GENE EXPRESSION VIA CHANGES IN DNA METHYLATION AND MICRORNA (MIRNA) EXPRESSION. SUCH EPIGENETIC MODIFICATIONS ARE YET TO BE INVESTIGATED IN PROFESSIONAL MIXED MARTIAL ARTS (MMA) FIGHTERS SUBJECT TO HIGHLY STRESSFUL TRAINING INVOLVING REPETITIVE HEAD IMPACTS. THIS STUDY EXAMINED DIFFERENCES IN DNA METHYLATION AND MIRNA EXPRESSION IN ELITE MMA FIGHTERS COMPARED TO ACTIVE CONTROLS. GLOBAL METHYLATION DIFFERENCES BETWEEN GROUPS WERE ASSESSED VIA A LINE-1 ASSAY. AT THE SAME TIME, PCR ARRAYS WERE USED TO ESTIMATE DIFFERENTIAL EXPRESSION IN SAMPLES OF 21 FIGHTERS AND 15 CONTROLS FOR 192 DIFFERENT MIRNAS ASSOCIATED WITH INFLAMMATORY DISEASES. AN INDEPENDENT-SAMPLES T-TEST FOUND NO SIGNIFICANT DIFFERENCE IN LINE-1 METHYLATION BETWEEN GROUPS. HOWEVER, AN INDEPENDENT-SAMPLES MANN-WHITNEY U TEST REVEALED A SIGNIFICANT UPREGULATION IN THE EXPRESSION OF MIR-155 IN MMA FIGHTER PLASMA. SINCE MIR-155 HAS BEEN RECOGNIZED AS AN IMPORTANT REGULATOR OF NEUROINFLAMMATION, THIS DYSREGULATION SUGGESTS A POSSIBLE EPIGENETIC MECHANISM RESPONSIBLE FOR CHRONIC INFLAMMATION ASSOCIATED WITH PROFESSIONAL-LEVEL MMA TRAINING. CONSISTENT WITH OTHER PUBLISHED WORKS, THIS STUDY HIGHLIGHTS THE POTENTIAL OF MIR-155 NOT ONLY AS A BIOMARKER FOR MONITORING LONG-TERM HEALTH RISKS LINKED TO HEAD TRAUMA BUT ALSO AS A TARGET TO REMEDIATE THE IMPACT OF CHRONIC NEUROINFLAMMATION.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
11 1903  40 ENHANCED NEUROINFLAMMATION MEDIATED BY DNA METHYLATION OF THE GLUCOCORTICOID RECEPTOR TRIGGERS COGNITIVE DYSFUNCTION AFTER SEVOFLURANE ANESTHESIA IN ADULT RATS SUBJECTED TO MATERNAL SEPARATION DURING THE NEONATAL PERIOD. BACKGROUND: MOUNTING EVIDENCE INDICATES THAT CHILDREN WHO EXPERIENCE ABUSE AND NEGLECT ARE PRONE TO CHRONIC DISEASES AND PREMATURE MORTALITY LATER IN LIFE. ONE MECHANISTIC HYPOTHESIS FOR THIS PHENOMENON IS THAT EARLY LIFE ADVERSITY ALTERS THE EXPRESSION OR FUNCTIONING OF THE GLUCOCORTICOID RECEPTOR (GR) THROUGHOUT THE COURSE OF LIFE AND THEREBY INCREASES SENSITIVITY TO INFLAMMATORY STIMULATION. AN EXAGGERATED PRO-INFLAMMATORY RESPONSE IS GENERALLY CONSIDERED TO BE A KEY CAUSE OF POSTOPERATIVE COGNITIVE DYSFUNCTION (POCD). THE AIM OF THIS STUDY WAS TO EXAMINE THE EFFECTS OF EARLY LIFE ADVERSITY ON COGNITIVE FUNCTION AND NEUROINFLAMMATION AFTER SEVOFLURANE ANESTHESIA IN ADULT RATS AND TO DETERMINE WHETHER SUCH EFFECTS ARE ASSOCIATED WITH THE EPIGENETIC REGULATION OF GR. METHODS: WISTAR RAT PUPS WERE REPEATEDLY SUBJECTED TO INFANT MATERNAL SEPARATION (EARLY LIFE STRESS) FROM POSTNATAL DAYS 2-21. IN ADULTHOOD, THEIR BEHAVIOR AND THE SIGNALING OF HIPPOCAMPAL PRO-INFLAMMATORY FACTORS AND NUCLEAR FACTOR-KAPPA B (NF-KAPPAB) AFTER SEVOFLURANE ANESTHESIA WERE EVALUATED. WE ALSO EXAMINED THE EFFECTS OF MATERNAL SEPARATION (MS) ON THE EXPRESSION OF GR AND THE DNA METHYLATION STATUS OF THE PROMOTER REGION OF EXON 1(7) OF GR AND WHETHER BEHAVIORAL CHANGES AND NEUROINFLAMMATION AFTER ANESTHESIA WERE REVERSIBLE WHEN THE EXPRESSION OF GR WAS INCREASED BY ALTERING DNA METHYLATION. RESULTS: MS INDUCED COGNITIVE DECLINE AFTER SEVOFLURANE INHALATION IN THE MORRIS WATER MAZE AND CONTEXT FEAR CONDITIONING TESTS AND ENHANCED THE RELEASE OF CYTOKINES AND THE ACTIVATION OF ASTROCYTE INTRACELLULAR NF-KAPPAB SIGNALING INDUCED BY SEVOFLURANE IN THE HIPPOCAMPUS OF ADULT RATS. BLOCKING NF-KAPPAB SIGNALING BY PYRROLIDINE DITHIOCARBAMATE (PDTC) INHIBITED THE RELEASE OF CYTOKINES. MS ALSO REDUCED THE EXPRESSION OF GR AND UPREGULATED THE METHYLATION LEVELS OF THE PROMOTER REGION OF GR EXON 1(7), AND SUCH EFFECTS WERE REVERSED BY TREATMENT WITH THE HISTONE DEACETYLASE INHIBITOR TRICHOSTATIN A (TSA) IN ADULT RATS. MOREOVER, TSA TREATMENT IN ADULT MS RATS INHIBITED THE OVERACTIVATION OF ASTROCYTE INTRACELLULAR NF-KAPPAB SIGNALING AND THE RELEASE OF CYTOKINES AND ALLEVIATED COGNITIVE DYSFUNCTION AFTER SEVOFLURANE ANESTHESIA. CONCLUSIONS: EARLY LIFE STRESS INDUCES COGNITIVE DYSFUNCTION AFTER SEVOFLURANE ANESTHESIA, PERHAPS DUE TO THE ABERRANT METHYLATION OF THE GR GENE PROMOTER, WHICH REDUCES THE EXPRESSION OF THE GR GENE AND FACILITATES EXAGGERATED INFLAMMATORY RESPONSES.	2017	

12 5273  25 PROMOTER METHYLATION AND BDNF AND DAT1 GENE EXPRESSION PROFILES IN PATIENTS WITH DRUG ADDICTION. BACKGROUND: DRUG ADDICTION IS A BRAIN DISORDER THAT HAS NEGATIVE CONSEQUENCES FOR INDIVIDUALS AND SOCIETY. ADDICTIONS ARE CHRONIC RELAPSING DISEASES OF THE BRAIN THAT ARE CAUSED BY DIRECT DRUG-INDUCED EFFECTS AND PERSEVERING NEUROADAPTATIONS AT THE EPIGENETIC, NEUROPEPTIDE AND NEUROTRANSMITTER LEVELS. BECAUSE THE DOPAMINERGIC SYSTEM HAS A SIGNIFICANT ROLE IN DRUG ABUSE, THE PURPOSE OF THIS STUDY WAS TO ANALYZE THE METHYLATION AND EXPRESSION PROFILE OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) AND DOPAMINE TRANSPORTER (DAT1) GENES IN INDIVIDUALS WITH DRUG ADDICTION. MATERIALS AND METHODS: BDNF AND DAT1 PROMOTER METHYLATION WERE INVESTIGATED WITH A METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (PCR) TECHNIQUE IN BLOOD SAMPLES FROM 75 INDIVIDUALS WITH DRUG ADDICTION AND 65 HEALTHY CONTROLS. THE EXPRESSION LEVELS OF BDNF AND DAT1 WERE ASSESSED IN 12 MRNA SAMPLES FROM THE BLOOD OF PATIENTS AND COMPARED TO THE SAMPLES OF HEALTHY CONTROLS (N = 12) WITH REAL-TIME QUANTITATIVE REVERSE TRANSCRIPTION PCR. RESULTS: NO SIGNIFICANT DIFFERENCES WERE FOUND IN THE METHYLATION OF BDNF AND DAT1 BETWEEN PATIENTS AND CONTROLS, BUT THE RELATIVE LEVELS OF EXPRESSION OF BDNF AND DAT1 MRNA DIFFERED SIGNIFICANTLY IN THE PATIENTS COMPARED TO CONTROLS (P < 0.0001). CONCLUSION: THESE RESULTS SHOWED THAT THE METHYLATION STATUS OF THE BDNF AND DAT1 GENES HAD NO SIGNIFICANT FUNCTION IN THE PROCESSES OF DRUG ADDICTION.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
13  887  28 CHRONIC CORTISOL EXPOSURE IN EARLY DEVELOPMENT LEADS TO NEUROENDOCRINE DYSREGULATION IN ADULTHOOD. OBJECTIVE: CHRONIC EARLY LIFE STRESS CAN AFFECT DEVELOPMENT OF THE NEUROENDOCRINE STRESS SYSTEM, LEADING TO ITS PERSISTENT DYSREGULATION AND CONSEQUENTLY INCREASED DISEASE RISK IN ADULTHOOD. ONE CONTRIBUTING FACTOR IS THOUGHT TO BE EPIGENETIC PROGRAMMING IN RESPONSE TO CHRONIC CORTISOL EXPOSURE DURING EARLY DEVELOPMENT. WE HAVE PREVIOUSLY SHOWN THAT ZEBRAFISH EMBRYOS TREATED CHRONICALLY WITH CORTISOL DEVELOP INTO ADULTS WITH CONSTITUTIVELY ELEVATED WHOLE-BODY CORTISOL AND ABERRANT IMMUNE GENE EXPRESSION. HERE WE FURTHER CHARACTERIZE THAT PHENOTYPE BY ASSESSING PERSISTENT EFFECTS OF THE TREATMENT ON CORTISOL TISSUE DISTRIBUTION AND DYNAMICS, CHROMATIN ACCESSIBILITY, AND ACTIVITIES OF GLUCOCORTICOID-RESPONSIVE REGULATORY GENES KLF9 AND FKBP5. TO THAT END CORTISOL LEVELS IN DIFFERENT TISSUES OF FED AND FASTED ADULTS WERE MEASURED USING ELISA, OPEN CHROMATIN IN ADULT BLOOD CELLS WAS MAPPED USING ATAC-SEQ, AND GENE ACTIVITY IN ADULT BLOOD AND BRAIN CELLS WAS MEASURED USING QRT-PCR. RESULTS: ADULTS DERIVED FROM CORTISOL-TREATED EMBRYOS HAVE ELEVATED WHOLE-BODY CORTISOL WITH ABERRANTLY REGULATED TISSUE DISTRIBUTION AND DYNAMICS THAT CORRELATE WITH DIFFERENTIAL ACTIVITY OF KLF9 AND FKBP5 IN BLOOD AND BRAIN.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
14 3991  31 LONGITUDINAL EFFECTS OF DEVELOPMENTAL BISPHENOL A, VARIABLE DIET, AND PHYSICAL ACTIVITY ON AGE-RELATED METHYLATION IN BLOOD. RESEARCH INDICATES THAT ENVIRONMENTAL FACTORS CAN ALTER DNA METHYLATION, BUT THE SPECIFIC EFFECTS OF ENVIRONMENTAL EXPOSURES ON EPIGENETIC AGING REMAIN UNCLEAR. HERE, USING A MOUSE MODEL OF HUMAN-RELEVANT EXPOSURES, WE TESTED THE HYPOTHESIS THAT EARLY-LIFE EXPOSURE TO BISPHENOL A (BPA), VARIABLE DIET, AND/OR CHANGES IN PHYSICAL ACTIVITY WOULD MODIFY RATES OF AGE-RELATED METHYLATION AT SEVERAL TARGET REGIONS, AS MEASURED FROM LONGITUDINAL BLOOD SAMPLES (2, 4, AND 10 MONTHS OLD). DNA METHYLATION WAS QUANTIFIED AT TWO REPETITIVE ELEMENTS (LINE-1, IAP), TWO IMPRINTED GENES (IGF2, H19), AND ONE NON-IMPRINTED GENE (ESR1) IN ISOGENIC MICE DEVELOPMENTALLY EXPOSED TO CONTROL, CONTROL + BPA (50 MICROG/KG DIET), WESTERN HIGH-FAT DIET (WHFD), OR WESTERN + BPA DIETS. IN BLOOD SAMPLES, ESR1 DNA METHYLATION INCREASED SIGNIFICANTLY WITH AGE, BUT NO OTHER INVESTIGATED LOCI SHOWED SIGNIFICANT AGE-RELATED METHYLATION. LINE-1 AND IAP BOTH SHOWED SIGNIFICANT NEGATIVE ENVIRONMENTAL DEFLECTION BY WHFD EXPOSURE (P < 0.05). ESR1ALSO SHOWED SIGNIFICANT NEGATIVE ENVIRONMENTAL DEFLECTION BY WHFD EXPOSURE IN FEMALE MICE (P = 0.02), BUT NOT MALE MICE. PHYSICAL ACTIVITY HAD A NON-SIGNIFICANT POSITIVE EFFECT ON AGE-RELATED ESR1 METHYLATION IN FEMALE BLOOD, SUGGESTING THAT IT MAY PARTIALLY ABROGATE THE EFFECTS OF WHFD ON THE AGING EPIGENOME. THESE RESULTS SUGGEST THAT DEVELOPMENTAL NUTRITIONAL EXPOSURES CAN MODIFY AGE-RELATED DNA METHYLATION PATTERNS AT A GENE RELATED TO GROWTH AND DEVELOPMENT. AS SUCH, ENVIRONMENTAL DEFLECTION OF THE AGING EPIGENOME MAY HELP TO EXPLAIN THE GROWING PREVALENCE OF CHRONIC DISEASES IN HUMAN POPULATIONS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
15 1537  37 DNA METHYLATION IN ADOLESCENTS WITH ANXIETY DISORDER: A LONGITUDINAL STUDY. ANXIETY DISORDERS (AD) TYPICALLY MANIFEST IN CHILDREN AND ADOLESCENTS AND MIGHT PERSIST INTO ADULTHOOD. HOWEVER, THERE ARE STILL FEW DATA CONCERNING EPIGENETIC MECHANISMS ASSOCIATED WITH ONSET, PERSISTENCE OR REMISSION OF AD OVER TIME. WE INVESTIGATED A COHORT OF ADOLESCENTS AND YOUNG ADULTS AT BASELINE (AGE; 13.19 +/- 2.38) AND AFTER 5 YEARS AND CLASSIFIED THEM ACCORDING TO THE AD DIAGNOSIS AND THEIR LONGITUDINAL TRAJECTORIES INTO 4 GROUPS: (1) TYPICALLY DEVELOPING COMPARISONS (TDC; CONTROL GROUP, N = 14); (2) INCIDENT (AD IN THE SECOND EVALUATION ONLY, N = 11); (3) PERSISTENT (AD IN BOTH EVALUATIONS, N = 14) AND (4) REMITTENT (AD IN THE FIRST EVALUATION ONLY, N = 8). DNA METHYLATION WAS EVALUATED WITH THE INFINIUM HUMANMETHYLATION450 BEADCHIP FROM SALIVA SAMPLES COLLECTED AT BOTH EVALUATIONS. GENE SET ENRICHMENT ANALYSIS WAS APPLIED TO CONSIDER BIOLOGICAL PATHWAYS. WE FOUND DECREASED DNA METHYLATION IN TDC GROUP WHILE THE CHRONIC CASES OF AD PRESENTED HYPERMETHYLATION IN CENTRAL NERVOUS SYSTEM DEVELOPMENT PATHWAYS. MOREOVER, WE SHOWED THAT THIS PERSISTENT GROUP ALSO PRESENTED HYPERMETHYLATION WHILE THE OTHER THREE GROUPS WERE ASSOCIATED WITH HYPOMETHYLATION IN NERVOUS SYSTEM DEVELOPMENT PATHWAY. INCIDENCE AND REMISSION GROUPS WERE ASSOCIATED WITH INCREASED AND DECREASED METHYLATION IN NEURON DEVELOPMENT PATHWAYS, RESPECTIVELY. LARGER STUDIES ARE LIKELY TO DETECT SPECIFIC GENES RELEVANT TO AD.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
16 5189  34 PRENATAL ARSENIC EXPOSURE INDUCES IMMUNOMETABOLIC ALTERATION AND RENAL INJURY IN RATS. ARSENIC (AS) EXPOSURE IS PROGRESSIVELY ASSOCIATED WITH CHRONIC KIDNEY DISEASE (CKD), A LEADING PUBLIC HEALTH CONCERN PRESENT WORLDWIDE. THE ADVERSE EFFECT OF AS EXPOSURE ON THE KIDNEYS OF PEOPLE LIVING IN AS ENDEMIC AREAS HAVE NOT BEEN EXTENSIVELY STUDIED. FURTHERMORE, THE IMPACT OF ONLY PRENATAL EXPOSURE TO AS ON THE PROGRESSION OF CKD ALSO HAS NOT BEEN FULLY CHARACTERIZED. IN THE PRESENT STUDY, WE EXAMINED THE EFFECT OF PRENATAL EXPOSURE TO LOW DOSES OF AS 0.04 AND 0.4 MG/KG BODY WEIGHT (0.04 AND 0.4 PPM, RESPECTIVELY) ON THE PROGRESSION OF CKD IN MALE OFFSPRING USING A WISTAR RAT MODEL. INTERESTINGLY, ONLY PRENATAL AS EXPOSURE WAS SUFFICIENT TO ELEVATE THE EXPRESSION OF PROFIBROTIC (TGF-BETA1) AND PROINFLAMMATORY (IL-1ALPHA, MIP-2ALPHA, RANTES, AND TNF-ALPHA) CYTOKINES AT 2-DAY, 12- AND 38-WEEK TIME POINTS IN THE EXPOSED PROGENY. FURTHER, ALTERATION IN ADIPOGENIC FACTORS (GHRELIN, LEPTIN, AND GLUCAGON) WAS ALSO OBSERVED IN 12- AND 38-WEEK OLD MALE OFFSPRING PRENATALLY EXPOSED TO AS. AN ALTERED LEVEL OF THESE FACTORS COINCIDES WITH IMPAIRED GLUCOSE METABOLISM AND HOMEOSTASIS ACCOMPANIED BY PROGRESSIVE KIDNEY DAMAGE. WE OBSERVED A SIGNIFICANT INCREASE IN THE DEPOSITION OF EXTRACELLULAR MATRIX COMPONENTS AND GLOMERULAR AND TUBULAR DAMAGE IN THE KIDNEYS OF 38-WEEK-OLD MALE OFFSPRING PRENATALLY EXPOSED TO AS. FURTHERMORE, THE OVEREXPRESSION OF TGF-BETA1 IN KIDNEYS CORRESPONDS WITH HYPERMETHYLATION OF THE TGF-BETA1 GENE-BODY, INDICATING A POSSIBLE INVOLVEMENT OF PRENATAL AS EXPOSURE-DRIVEN EPIGENETIC MODULATIONS OF TGF-BETA1 EXPRESSION. OUR STUDY PROVIDES EVIDENCE THAT PRENATAL AS EXPOSURE TO MALES CAN ADVERSELY AFFECT THE IMMUNOMETABOLISM OF OFFSPRING WHICH CAN PROMOTE KIDNEY DAMAGE LATER IN LIFE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
17 2776  43 EXTRAUTERINE GROWTH RESTRICTION ON PULMONARY VASCULAR ENDOTHELIAL DYSFUNCTION IN ADULT MALE RATS: THE ROLE OF EPIGENETIC MECHANISMS. OBJECTIVE: EARLY POSTNATAL LIFE IS CONSIDERED AS A CRITICAL TIME WINDOW FOR THE DETERMINATION OF LONG-TERM METABOLIC STATES AND ORGAN FUNCTIONS. EXTRAUTERINE GROWTH RESTRICTION (EUGR) CAUSES THE DEVELOPMENT OF ADULT-ONSET CHRONIC DISEASES, INCLUDING PULMONARY HYPERTENSION. HOWEVER, THE EFFECTS OF NUTRITIONAL DISADVANTAGES DURING THE EARLY POSTNATAL PERIOD ON PULMONARY VASCULAR CONSEQUENCES IN LATER LIFE ARE NOT FULLY UNDERSTOOD. OUR STUDY WAS DESIGNED TO TEST WHETHER EPIGENETICS DYSREGULATION MEDIATES THE CELLULAR MEMORY OF THIS EARLY POSTNATAL EVENT. METHODS AND RESULTS: TO TEST THIS HYPOTHESIS, WE ISOLATED PULMONARY VASCULAR ENDOTHELIAL CELLS BY MAGNETIC-ACTIVATED CELL SORTING FROM EUGR AND CONTROL RATS. A POSTNATAL INSULT, NUTRITIONAL RESTRICTION-INDUCED EUGR CAUSED DEVELOPMENT OF AN INCREASED PULMONARY ARTERY PRESSURE AT 9 WEEKS OF AGE IN MALE SPRAGUE-DAWLEY RATS. METHYL-DNA IMMUNE PRECIPITATION CHIP, GENOME-SCALE MAPPING STUDIES TO SEARCH FOR DIFFERENTIALLY METHYLATED LOCI BETWEEN CONTROL AND EUGR RATS, REVEALED SIGNIFICANT DIFFERENCE IN CYTOSINE METHYLATION BETWEEN EUGR AND CONTROL RATS. EUGR CHANGES THE CYTOSINE METHYLATION AT APPROXIMATELY 500 LOCI IN MALE RATS AT 9 WEEKS OF AGE, PRECEDING THE DEVELOPMENT OF PULMONARY HYPERTENSION AND THESE REPRESENT THE CANDIDATE LOCI FOR MEDIATING THE PATHOGENESIS OF PULMONARY VASCULAR DISEASE THAT OCCURS LATER IN LIFE. GENE ONTOLOGY ANALYSIS ON DIFFERENTIALLY METHYLATED GENES SHOWED THAT HYPERMETHYLATED GENES IN EUGR ARE VASCULAR DEVELOPMENT-ASSOCIATED GENES AND HYPOMETHYLATED GENES IN EUGR ARE LATE-DIFFERENTIATION-ASSOCIATED AND SIGNAL TRANSDUCTION GENES. WE VALIDATED CANDIDATE DYSREGULATED LOCI WITH THE QUANTITATIVE ASSAYS OF CYTOSINE METHYLATION AND GENE EXPRESSIONS. CONCLUSION: THESE RESULTS DEMONSTRATE THAT EPIGENETICS DYSREGULATION IS A STRONG MECHANISM FOR PROPAGATING THE CELLULAR MEMORY OF EARLY POSTNATAL EVENTS, CAUSING CHANGES IN THE EXPRESSION OF GENES AND LONG-TERM SUSCEPTIBILITY TO PULMONARY HYPERTENSION, AND FURTHER PROVIDING A NEW INSIGHT INTO THE PREVENTION AND TREATMENT OF EUGR-RELATED PULMONARY HYPERTENSION.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
18 1186  34 COORDINATED DYNAMIC GENE EXPRESSION CHANGES IN THE CENTRAL NUCLEUS OF THE AMYGDALA DURING ALCOHOL WITHDRAWAL. BACKGROUND: CHRONIC ALCOHOL USE CAUSES WIDESPREAD CHANGES IN THE CELLULAR BIOLOGY OF THE AMYGDALA'S CENTRAL NUCLEUS (CEA), A GABAERGIC CENTER THAT INTEGRATES AUTONOMIC PHYSIOLOGY WITH THE EMOTIONAL ASPECTS OF MOTIVATION AND LEARNING. WHILE ALCOHOL-INDUCED NEUROCHEMICAL CHANGES PLAY A ROLE IN DEPENDENCE AND DRINKING BEHAVIOR, LITTLE IS KNOWN ABOUT THE CEA'S DYNAMIC CHANGES DURING WITHDRAWAL, A PERIOD OF EMOTIONAL AND PHYSIOLOGIC DISTURBANCE. METHODS: WE USED A QRT-PCR PLATFORM TO MEASURE 139 TRANSCRIPTS IN 92 RAT CEA SAMPLES FROM CONTROL (N = 33), CHRONICALLY ALCOHOL EXPOSED (N = 26), AND WITHDRAWN RATS (T = 4, 8, 18, 32, AND 48 HOURS; N = 5, 10, 7, 6, 5). THIS FOCUSED TRANSCRIPT SET ALLOWED US TO IDENTIFY SIGNIFICANT DYNAMIC EXPRESSION PATTERNS DURING THE FIRST 48 HOURS OF WITHDRAWAL AND PROPOSE POTENTIAL REGULATORY MECHANISMS. RESULTS: CHRONIC ALCOHOL EXPOSURE CAUSES A LIMITED NUMBER OF SMALL MAGNITUDE EXPRESSION CHANGES. IN CONTRAST, WITHDRAWAL RESULTS IN A GREATER NUMBER OF LARGE CHANGES WITHIN 4 HOURS OF REMOVAL OF THE ALCOHOL DIET. SIXTY-FIVE OF THE 139 MEASURED TRANSCRIPTS (47%) SHOWED DIFFERENTIAL REGULATION DURING WITHDRAWAL. OVER THE 48-HOUR PERIOD, DYNAMIC CHANGES IN THE EXPRESSION OF GAMMA-AMINOBUTYRIC ACID TYPE A (GABA(A) ), IONOTROPIC GLUTAMATE AND NEUROPEPTIDE SYSTEM-RELATED G-PROTEIN-COUPLED RECEPTOR SUBUNITS, AND THE RAS/RAF SIGNALING PATHWAY WERE SEEN AS WELL AS DOWNSTREAM TRANSCRIPTION FACTORS (TFS) AND EPIGENETIC REGULATORS. FOUR TEMPORALLY CORRELATED GENE CLUSTERS WERE IDENTIFIED WITH SHARED FUNCTIONAL ROLES INCLUDING NMDA RECEPTORS, MAPKKK AND CHEMOKINE SIGNALING CASCADES, AND MEDIATORS OF LONG-TERM POTENTIATION, AMONG OTHERS. CLUSTER PROMOTER REGIONS SHARED OVERREPRESENTED BINDING SITES FOR MULTIPLE TFS INCLUDING CEBP, USF-1, SMAD3, AP-2, AND C-ETS, SUGGESTING A POTENTIAL REGULATORY ROLE. CONCLUSIONS: DURING ALCOHOL WITHDRAWAL, THE CEA EXPERIENCES RAPID CHANGES IN MRNA EXPRESSION OF THESE FUNCTIONALLY RELATED TRANSCRIPTS THAT WERE NOT PREDICTED BY MEASUREMENT DURING CHRONIC EXPOSURE. THIS STUDY PROVIDES NEW INSIGHT INTO DYNAMIC EXPRESSION CHANGES DURING ALCOHOL WITHDRAWAL AND SUGGESTS NOVEL REGULATORY RELATIONSHIPS THAT POTENTIALLY IMPACT THE ASPECTS OF EMOTIONAL MODULATION.	2013	
                                                                                                                                                                                                                                                                                                                                                                 
19 2740  32 EXPOSURE TO EARLY LIFE STRESS RESULTS IN EPIGENETIC CHANGES IN NEUROTROPHIC FACTOR GENE EXPRESSION IN A PARKINSONIAN RAT MODEL. EARLY LIFE ADVERSITY INCREASES THE RISK OF MENTAL DISORDERS LATER IN LIFE. CHRONIC EARLY LIFE STRESS MAY ALTER NEUROTROPHIC FACTOR GENE EXPRESSION INCLUDING THOSE FOR BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) AND GLIAL CELL DERIVED NEUROTROPHIC FACTOR (GDNF) THAT ARE IMPORTANT IN NEURONAL GROWTH, SURVIVAL, AND MAINTENANCE. MATERNAL SEPARATION WAS USED IN THIS STUDY TO MODEL EARLY LIFE STRESS. FOLLOWING UNILATERAL INJECTION OF A MILD DOSE OF 6-HYDROXYDOPAMINE (6-OHDA), WE MEASURED CORTICOSTERONE (CORT) IN THE BLOOD AND STRIATUM OF STRESSED AND NONSTRESSED RATS; WE ALSO MEASURED DNA METHYLATION AND BDNF AND GDNF GENE EXPRESSION IN THE STRIATUM USING REAL TIME PCR. IN THE PRESENCE OF STRESS, WE FOUND THAT THERE WAS INCREASED CORTICOSTERONE CONCENTRATION IN BOTH BLOOD AND STRIATAL TISSUE. FURTHER TO THIS, WE FOUND HIGHER DNA METHYLATION AND DECREASED NEUROTROPHIC FACTOR GENE EXPRESSION. 6-OHDA LESION INCREASED NEUROTROPHIC FACTOR GENE EXPRESSION IN BOTH STRESSED AND NONSTRESSED RATS BUT THIS INCREASE WAS HIGHER IN THE NONSTRESSED RATS. OUR RESULTS SUGGEST THAT EXPOSURE TO EARLY POSTNATAL STRESS INCREASES CORTICOSTERONE CONCENTRATION WHICH LEADS TO INCREASED DNA METHYLATION. THIS EFFECT RESULTS IN DECREASED BDNF AND GDNF GENE EXPRESSION IN THE STRIATUM LEADING TO DECREASED PROTECTION AGAINST SUBSEQUENT INSULTS LATER IN LIFE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
20  344  28 ALTERED BDNF METHYLATION IN PATIENTS WITH CHRONIC MUSCULOSKELETAL PAIN AND HIGH BIOPSYCHOSOCIAL COMPLEXITY. PURPOSE: THE INTERMED INSTRUMENT, WHICH WAS DEVELOPED TO MEASURE PATIENT'S BIOPSYCHOSOCIAL (BPS) COMPLEXITY, REPRESENTS A POWERFUL DIAGNOSTIC AND THERAPEUTIC TOOL. EPIGENETIC CHANGES ARE THE INTERFACE BETWEEN SIGNALS FROM THE ENVIRONMENT AND GENETIC MODIFICATIONS, AFFECTING GENE EXPRESSION, IN PARTICULAR, BY DNA METHYLATION OF CPG DINUCLEOTIDES IN PROMOTOR REGIONS OF THE CORRESPONDING GENES. THE BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) GENE PLAYS A CRUCIAL ROLE IN THE CENTRAL SENSITIZATION (CS) OF PAIN. IN THIS STUDY, WE HYPOTHESIZED THAT CHRONIC PAIN MODIFIES THE METHYLATION LEVELS OF THE BDNF GENE IN A MANNER THAT IS INTERCONNECTED WITH THE BPS STATUS. PATIENTS AND METHODS: FIFTY-EIGHT CHRONIC MUSCULOSKELETAL PAIN PATIENTS (CMSP) WERE ENROLLED IN THE STUDY. DNA WAS EXTRACTED FROM BLOOD SAMPLES, THE METHYLATION LEVELS OF 13 CPG SITES IN THE BDNF PROMOTER WERE MEASURED BY PYROSEQUENCING, AND ASSOCIATION STUDIES WITH VARIOUS PATIENT PARAMETERS AND THE INTERMED SCORES WERE PERFORMED. RESULTS: INTERESTINGLY, A NEGATIVE CORRELATION (-0.40) WAS FOUND BETWEEN THE TOTAL INTERMED SCORES AND THE AVERAGE CPG METHYLATION VALUES OF THE BDNF GENE, BUT NO CORRELATION WAS OBSERVED WITH THE SEVERITY OF PAIN, DEGREE OF ANXIETY, DEPRESSION, OR KINESIOPHOBIA AND CATASTROPHISM. MOREOVER, THE ASSOCIATION WAS INDEPENDENT OF AGE, SEX AND LEVEL OF COMORBIDITIES. CONCLUSION: THIS RESULT SHOWS THAT CMSP, IN ASSOCIATION WITH ITS BIOPSYCHOSOCIAL CONTEXT, EPIGENETICALLY DECREASES THE DEGREE OF METHYLATION OF THE BDNF PROMOTER AND SHOULD THEREFORE INCREASE THE LEVEL OF BDNF TRANSCRIPTION. IT ALSO SUGGESTS A ROLE OF THE INTERMED TOOL TO DETECT A RELATIONSHIP BETWEEN THE BPS COMPLEXITY AND THE EPIGENETIC CONTROL OF A TARGET GENE. THE POSSIBLE UPREGULATION OF BDNF EXPRESSION MIGHT BE, AT LEAST IN PART, THE SIGNAL FOR CHRONIC PAIN-INDUCED CENTRAL SENSITIZATION (CS). THIS COULD PARTLY EXPLAIN WHY PATIENTS WITH A HIGHER LEVEL OF COMPLEXITY FEEL MORE PAIN THAN THOSE WITH LOWER COMPLEXITY.	2020