1 3612 170 IN UTERO PARTICULATE MATTER EXPOSURE PRODUCES HEART FAILURE, ELECTRICAL REMODELING, AND EPIGENETIC CHANGES AT ADULTHOOD. BACKGROUND: PARTICULATE MATTER (PM; PM(2.5) [PM WITH DIAMETERS OF <2.5 MUM]) EXPOSURE DURING DEVELOPMENT IS STRONGLY ASSOCIATED WITH ADVERSE CARDIOVASCULAR OUTCOMES AT ADULTHOOD. IN THE PRESENT STUDY, WE TESTED THE HYPOTHESIS THAT IN UTERO PM(2.5) EXPOSURE ALONE COULD ALTER CARDIAC STRUCTURE AND FUNCTION AT ADULTHOOD. METHODS AND RESULTS: FEMALE FVB MICE WERE EXPOSED EITHER TO FILTERED AIR OR PM(2.5) AT AN AVERAGE CONCENTRATION OF 73.61 MUG/M(3) FOR 6 H/DAY, 7 DAYS/WEEK THROUGHOUT PREGNANCY. AFTER BIRTH, ANIMALS WERE ANALYZED AT 12 WEEKS OF AGE. ECHOCARDIOGRAPHIC (N=9-10 MICE/GROUP) AND PRESSURE-VOLUME LOOP ANALYSES (N=5 MICE/GROUP) REVEALED REDUCED FRACTIONAL SHORTENING, INCREASED LEFT VENTRICULAR END-SYSTOLIC AND -DIASTOLIC DIAMETERS, REDUCED LEFT VENTRICULAR POSTERIOR WALL THICKNESS, END-SYSTOLIC ELASTANCE, CONTRACTILE RESERVE (DP/DT(MAX)/END-SYSTOLIC VOLUME), FREQUENCY-DEPENDENT ACCELERATION OF RELAXATION), AND BLUNTED CONTRACTILE RESPONSE TO BETA-ADRENERGIC STIMULATION IN PM(2.5)-EXPOSED MICE. ISOLATED CARDIOMYOCYTE (N=4-5 MICE/GROUP) FUNCTION ILLUSTRATED REDUCED PEAK SHORTENING, +/-DL/DT, AND PROLONGED ACTION POTENTIAL DURATION AT 90% REPOLARIZATION. HISTOLOGICAL LEFT VENTRICULAR ANALYSES (N=3 MICE/GROUP) SHOWED INCREASED COLLAGEN DEPOSITION IN IN UTERO PM(2.5)-EXPOSED MICE AT ADULTHOOD. CARDIAC INTERLEUKIN (IL)-6, IL-1SS, COLLAGEN-1, MATRIX METALLOPROTEINASE (MMP) 9, AND MMP13 GENE EXPRESSIONS WERE INCREASED AT BIRTH IN IN UTERO PM(2.5)-EXPOSED MICE (N=4 MICE/GROUP). IN ADULT HEARTS (N=5 MICE/GROUP), GENE EXPRESSIONS OF SIRTUIN (SIRT) 1 AND SIRT2 WERE DECREASED, DNA METHYLTRANSFERASE (DNMT) 1, DNMT3A, AND DNMT3B WERE INCREASED, AND PROTEIN EXPRESSION (N=6 MICE/GROUP) OF CA(2+)-ATPASE, PHOSPHORYLATED PHOSPHOLAMBAN, AND NA(+)/CA(2+) EXCHANGER WERE DECREASED. CONCLUSIONS: IN UTERO PM(2.5) EXPOSURE TRIGGERS AN ACUTE INFLAMMATORY RESPONSE, CHRONIC MATRIX REMODELING, AND ALTERATIONS IN CA(2+) HANDLING PROTEINS, RESULTING IN GLOBAL ADULT CARDIAC DYSFUNCTION. THESE RESULTS ALSO HIGHLIGHT THE POTENTIAL INVOLVEMENT OF EPIGENETICS IN PRIMING OF ADULT CARDIAC DISEASE.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
2 5205  25 PRENATAL STRESS CHANGES THE GLYCOPROTEIN GPM6A GENE EXPRESSION AND INDUCES EPIGENETIC CHANGES IN RAT OFFSPRING BRAIN. PRENATAL STRESS (PS) EXERTS STRONG IMPACT ON FETAL BRAIN DEVELOPMENT AND ON ADULT OFFSPRING BRAIN FUNCTIONS. PREVIOUS WORK DEMONSTRATED THAT CHRONIC STRESS ALTERS THE MRNA EXPRESSION OF GPM6A, A NEURONAL GLYCOPROTEIN INVOLVED IN FILOPODIUM EXTENSION. IN THIS WORK, WE ANALYZED THE EFFECT OF PS ON GPM6A EXPRESSION AND THE EPIGENETIC MECHANISMS INVOLVED. PREGNANT WISTAR RATS RECEIVED RESTRAINT STRESS DURING THE LAST WEEK OF GESTATION. MALE OFFSPRING WERE SACRIFICED ON POSTNATAL DAYS 28 AND 60. HIPPOCAMPUS AND PREFRONTAL CORTEX SAMPLES WERE ANALYZED FOR GENE EXPRESSION (QPCR FOR MRNAS AND MICRORNAS), METHYLATION STATUS (BISULFITE CONVERSION) AND PROTEIN LEVELS. HIPPOCAMPAL NEURONS IN CULTURE WERE USED TO ANALYZE MICRORNA OVEREXPRESSION EFFECTS. PRENATAL STRESS INDUCED CHANGES IN GPM6A LEVELS IN BOTH TISSUES AND AT BOTH AGES ANALYZED, INDICATING A PERSISTENT EFFECT. TWO CPG ISLANDS IN THE GPM6A GENE WERE IDENTIFIED. VARIATIONS IN THE METHYLATION PATTERN AT THREE SPECIFIC CPGS WERE FOUND IN HIPPOCAMPUS, BUT NOT IN PFC SAMPLES FROM PS OFFSPRING. MICRORNAS PREDICTED TO TARGET GPM6A WERE IDENTIFIED IN SILICO. QPCR MEASUREMENTS SHOWED THAT PS MODIFIED THE EXPRESSION OF SEVERAL MICRORNAS IN BOTH TISSUES, BEING MICRORNA-133B THE MOST SIGNIFICANTLY ALTERED. FURTHER STUDIES OVEREXPRESSING THIS MICRORNA IN NEURONAL CULTURES SHOWED A REDUCTION IN GMP6A MRNA AND PROTEIN LEVEL. MOREOVER FILOPODIUM DENSITY WAS ALSO REDUCED, SUGGESTING THAT GPM6A FUNCTION WAS AFFECTED. GESTATIONAL STRESS AFFECTED GPM6A GENE EXPRESSION IN OFFSPRING LIKELY THROUGH CHANGES IN METHYLATION STATUS AND IN POSTTRANSCRIPTIONAL REGULATION BY MICRORNAS. THUS, OUR FINDINGS PROPOSE GPM6A AS A NOVEL TARGET FOR EPIGENETIC REGULATION DURING PRENATAL STRESS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
3  982  40 CHRONIC PRENATAL HYPOXIA INDUCES EPIGENETIC PROGRAMMING OF PKCEPSILON GENE REPRESSION IN RAT HEARTS. RATIONALE: EPIDEMIOLOGICAL STUDIES DEMONSTRATE A CLEAR ASSOCIATION OF ADVERSE INTRAUTERINE ENVIRONMENT WITH AN INCREASED RISK OF ISCHEMIC HEART DISEASE IN ADULTHOOD. HYPOXIA IS A COMMON STRESS TO THE FETUS AND RESULTS IN DECREASED PROTEIN KINASE C EPSILON (PKCEPSILON) EXPRESSION IN THE HEART AND INCREASED CARDIAC VULNERABILITY TO ISCHEMIA AND REPERFUSION INJURY IN ADULT OFFSPRING IN RATS. OBJECTIVES: THE PRESENT STUDY TESTED THE HYPOTHESIS THAT FETAL HYPOXIA-INDUCED METHYLATION OF CYTOSINE-PHOSPHATE-GUANINE DINUCLEOTIDES AT THE PKCEPSILON PROMOTER IS REPRESSIVE AND CONTRIBUTES TO PKCEPSILON GENE REPRESSION IN THE HEART OF ADULT OFFSPRING. METHODS AND RESULTS: HYPOXIC TREATMENT OF PREGNANT RATS FROM DAYS 15 TO 21 OF GESTATION RESULTED IN SIGNIFICANT DECREASES IN PKCEPSILON PROTEIN AND MRNA IN FETAL HEARTS. SIMILAR RESULTS WERE OBTAINED IN EX VIVO HYPOXIC TREATMENT OF ISOLATED FETAL HEARTS AND RAT EMBRYONIC VENTRICULAR MYOCYTE CELL LINE H9C2. INCREASED METHYLATION OF PKCEPSILON PROMOTER AT SP1 BINDING SITES, -346 AND -268, WERE DEMONSTRATED IN BOTH FETAL HEARTS OF MATERNAL HYPOXIA AND H9C2 CELLS TREATED WITH 1% O(2) FOR 24 HOURS. WHEREAS HYPOXIA HAD NO SIGNIFICANT EFFECT ON THE BINDING AFFINITY OF SP1 TO THE UNMETHYLATED SITES IN H9C2 CELLS, HEARTS OF FETUSES AND ADULT OFFSPRING, METHYLATION OF BOTH SP1 SITES REDUCED SP1 BINDING. THE ADDITION OF 5-AZA-2'-DEOXYCYTIDINE BLOCKED THE HYPOXIA-INDUCED INCREASE IN METHYLATION OF BOTH SP1 BINDING SITES AND RESTORED PKCEPSILON MRNA AND PROTEIN TO THE CONTROL LEVELS. IN HEARTS OF BOTH FETUSES AND ADULT OFFSPRING, HYPOXIA-INDUCED METHYLATION OF SP1 SITES WAS SIGNIFICANTLY GREATER IN MALES THAN IN FEMALES, AND DECREASED PKCEPSILON MRNA WAS SEEN ONLY IN MALES. IN FETAL HEARTS, THERE WAS SIGNIFICANTLY HIGHER ABUNDANCE OF ESTROGEN RECEPTOR ALPHA AND BETA ISOFORMS IN FEMALES THAN IN MALES. BOTH ESTROGEN RECEPTOR ALPHA AND BETA INTERACTED WITH THE SP1 BINDING SITES IN THE FETAL HEART, WHICH MAY EXPLAIN THE SEX DIFFERENCES IN SP1 METHYLATION IN THE FETAL HEART. ADDITIONALLY, SELECTIVE ACTIVATION OF PKCEPSILON RESTORED THE HYPOXIA-INDUCED CARDIAC VULNERABILITY TO ISCHEMIC INJURY IN OFFSPRING. CONCLUSIONS: THE FINDINGS DEMONSTRATE A DIRECT EFFECT OF HYPOXIA ON EPIGENETIC MODIFICATION OF DNA METHYLATION AND PROGRAMMING OF CARDIAC PKCEPSILON GENE REPRESSION IN A SEX-DEPENDENT MANNER, LINKING FETAL HYPOXIA AND PATHOPHYSIOLOGICAL CONSEQUENCES IN THE HEARTS OF ADULT OFFSPRING.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
4 2776  39 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
5 3122  29 GESTATIONAL VALPROIC ACID EXPOSURE INDUCES EPIGENETIC MODIFICATIONS IN MURINE DECIDUA. INTRODUCTION: VALPROIC ACID (VPA), A WIDELY PRESCRIBED ANTIEPILEPTIC DRUG AND AN EFFECTIVE TREATMENT FOR BIPOLAR DISORDER AND NEUROPATHIC PAIN, RESULTS IN MULTIPLE DEVELOPMENTAL DEFECTS FOLLOWING IN UTERO EXPOSURE. UTERINE DECIDUA PROVIDES NUTRITIONAL AND PHYSICAL SUPPORT DURING IMPLANTATION AND EARLY EMBRYONIC DEVELOPMENT. PERTURBATIONS IN THE MOLECULAR MECHANISMS WITHIN DECIDUAL TISSUE DURING EARLY PREGNANCY MIGHT AFFECT EARLY EMBRYONIC GROWTH, RESULT IN EARLY PREGNANCY LOSS OR CAUSE COMPLICATIONS IN THE LATER GESTATIONAL STAGE. VPA IS A KNOWN HISTONE DEACETYLASE INHIBITOR AND EPIGENETIC CHANGES SUCH AS HISTONE HYPERACETYLATION AND METHYLATION HAVE BEEN PROPOSED AS A MECHANISM OF VPA-INDUCED TERATOGENESIS. METHODS: THIS STUDY INVESTIGATED THE EFFECTS OF IN UTERO VPA EXPOSURE ON HISTONE MODIFICATIONS IN MURINE DECIDUAL TISSUE. PREGNANT CD-1 MICE WERE EXPOSED TO 400 MG/KG VPA OR SALINE ON GD9 VIA SUBCUTANEOUS INJECTION. DECIDUAL TISSUE FROM EACH GESTATIONAL SAC WAS HARVESTED AT 1, 3 AND 6 H FOLLOWING EXPOSURE. LEVELS OF ACETYLATED HISTONES H3, H4 AND H3K56, AS WELL AS METHYLATED HISTONES H3K9 AND H3K27 WERE ACID EXTRACTED AND ASSESSED BY WESTERN BLOTTING FOLLOWED BY ACID HISTONE EXTRACTION. RESULTS: VPA EXPOSURE INDUCED A SIGNIFICANT INCREASE (P < 0.05) IN THE LEVELS OF ACETYLATED H3 AT 1, 3 H; ACETYLATED H4 AT 1, 3 AND 6 H AND TRIMETHYLATED H3K9 AT 6 H. IN CONTRAST, NO SIGNIFICANT PERTURBATIONS WERE NOTED IN THE LEVELS OF MONOMETHYLATED H3K9, TRIMETHYLATED H3K27 AND ACETYLATED H3K56. DISCUSSION: THE RESULTS FROM THIS STUDY SUGGEST THAT VPA-INDUCED DECIDUAL HISTONE MODIFICATIONS MIGHT PLAY AN IMPORTANT ROLE AS A MECHANISM OF VPA-INDUCED TERATOGENESIS DURING EARLY EMBRYONIC GROWTH.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
6 1846  26 EFFECTS OF TWO TYPES OF ENERGY RESTRICTION ON METHYLATION LEVELS OF ADIPONECTIN RECEPTOR 1 AND LEPTIN RECEPTOR OVERLAPPING TRANSCRIPT IN A MOUSE MAMMARY TUMOUR VIRUS-TRANSFORMING GROWTH FACTOR-ALPHA BREAST CANCER MOUSE MODEL. THE ROLE OF ADIPONECTIN AND LEPTIN SIGNALLING PATHWAYS HAS BEEN SUGGESTED TO PLAY IMPORTANT ROLES IN THE PROTECTIVE EFFECTS OF ENERGY RESTRICTION (ER) ON MAMMARY TUMOUR (MT) DEVELOPMENT. TO STUDY THE EFFECTS OF ER ON THE METHYLATION LEVELS IN ADIPONECTIN RECEPTOR 1 (ADIPOR1) AND LEPTIN RECEPTOR OVERLAPPING TRANSCRIPT (LEPROT) GENES USING THE PYROSEQUENCING METHOD IN MAMMARY FAT PAD TISSUE, MOUSE MAMMARY TUMOUR VIRUS-TRANSFORMING GROWTH FACTOR-ALPHA (MMTV-TGF-ALPHA) FEMALE MICE WERE RANDOMLY ASSIGNED TO AD LIBITUM (AL), CHRONIC ER (CER, 15 % ER) OR INTERMITTENT ER (3 WEEKS AL AND 1 WEEK 60 % ER IN CYCLIC PERIODS) GROUPS AT 10 WEEKS OF AGE UNTIL 82 WEEKS OF AGE. THE METHYLATION LEVELS OF ADIPOR1 IN THE CER GROUP WERE HIGHER THAN THOSE IN THE AL GROUP AT WEEK 49/50 (P < 0.05), WHILE THE LEVELS OF METHYLATION FOR ADIPOR1 AND LEPROT GENES WERE SIMILAR AMONG THE OTHER GROUPS. ALSO, THE METHYLATION LEVELS AT CPG2 AND CPG3 REGIONS OF THE PROMOTER REGION OF THE ADIPOR1 GENE IN THE CER GROUP WERE THREE TIMES HIGHER (P < 0.05), WHILE CPG1 ISLAND OF LEPROT METHYLATION WAS SIGNIFICANTLY LOWER COMPARED WITH THE OTHER GROUPS (P < 0.05). ADIPONECTIN AND LEPTIN GENE EXPRESSION LEVELS WERE CONSISTENT WITH THE METHYLATION LEVELS. WE ALSO OBSERVED A CHANGE WITH AGEING IN METHYLATION LEVELS OF THESE GENES. THESE RESULTS INDICATE THAT DIFFERENT TYPES OF ER MODIFY METHYLATION LEVELS OF ADIPOR1 AND LEPROT IN DIFFERENT WAYS AND CER HAD A MORE SIGNIFICANT EFFECT ON METHYLATION LEVELS OF BOTH GENES. EPIGENETIC REGULATION OF THESE GENES MAY PLAY IMPORTANT ROLES IN THE PREVENTIVE EFFECTS OF ER AGAINST MT DEVELOPMENT AND AGEING PROCESSES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
7  749  38 CARDIAC EPIGENETIC CHANGES IN VEGF SIGNALING GENES ASSOCIATE WITH MYOCARDIAL MICROVASCULAR RAREFACTION IN EXPERIMENTAL CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS COMMON IN PATIENTS WITH HEART FAILURE AND OFTEN RESULTS IN LEFT VENTRICULAR DIASTOLIC DYSFUNCTION (LVDD). HOWEVER, THE MECHANISMS RESPONSIBLE FOR CARDIAC DAMAGE IN CKD-LVDD REMAIN TO BE ELUCIDATED. EPIGENETIC ALTERATIONS MAY IMPOSE LONG-LASTING EFFECTS ON CELLULAR TRANSCRIPTION AND FUNCTION, BUT THEIR EXACT ROLE IN CKD-LVDD IS UNKNOWN. WE INVESTIGATE WHETHER CHANGES IN CARDIAC SITE-SPECIFIC DNA METHYLATION PROFILES MIGHT BE IMPLICATED IN CARDIAC ABNORMALITIES IN CKD-LVDD. CKD-LVDD AND NORMAL CONTROL PIGS (N = 6 EACH) WERE STUDIED FOR 14 WK. RENAL AND CARDIAC HEMODYNAMICS WERE QUANTIFIED BY MULTIDETECTOR CT AND ECHOCARDIOGRAPHY. IN RANDOMLY SELECTED PIGS (N = 3/GROUP), CARDIAC SITE-SPECIFIC 5-METHYLCYTOSINE (5MC) IMMUNOPRECIPITATION (MEDIP)- AND MRNA-SEQUENCING (SEQ) WERE PERFORMED, FOLLOWED BY INTEGRATED (MEDIP-SEQ/MRNA-SEQ ANALYSIS), AND CONFIRMATORY EX VIVO STUDIES. MEDIP-SEQ ANALYSIS REVEALED 261 GENES WITH HIGHER (FOLD CHANGE > 1.4; P < 0.05) AND 162 GENES WITH LOWER (FOLD CHANGE < 0.7; P < 0.05) 5MC LEVELS IN CKD-LVDD VERSUS NORMAL PIGS, WHICH WERE PRIMARILY IMPLICATED IN VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF)-RELATED SIGNALING AND ANGIOGENESIS. INTEGRATED MEDIP-SEQ/MRNA-SEQ ANALYSIS IDENTIFIED A SELECT GROUP OF VEGF-RELATED GENES IN WHICH 5MC LEVELS WERE HIGHER, BUT MRNA EXPRESSION WAS LOWER IN CKD-LVDD VERSUS NORMAL PIGS. CARDIAC VEGF SIGNALING GENE AND VEGF PROTEIN EXPRESSION WERE BLUNTED IN CKD-LVDD COMPARED WITH CONTROLS AND WERE ASSOCIATED WITH DECREASED SUBENDOCARDIAL MICROVASCULAR DENSITY. CARDIAC EPIGENETIC CHANGES IN VEGF-RELATED GENES ARE ASSOCIATED WITH IMPAIRED ANGIOGENESIS AND CARDIAC MICROVASCULAR RAREFACTION IN SWINE CKD-LVDD. THESE OBSERVATIONS MAY ASSIST IN DEVELOPING NOVEL THERAPIES TO AMELIORATE CARDIAC DAMAGE IN CKD-LVDD.NEW & NOTEWORTHY CHRONIC KIDNEY DISEASE (CKD) OFTEN LEADS TO LEFT VENTRICULAR DIASTOLIC DYSFUNCTION (LVDD) AND HEART FAILURE. USING A NOVEL TRANSLATIONAL SWINE MODEL OF CKD-LVDD, WE CHARACTERIZE THE CARDIAC EPIGENETIC LANDSCAPE, IDENTIFYING SITE-SPECIFIC 5-METHYLCYTOSINE CHANGES IN VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF)-RELATED GENES ASSOCIATED WITH IMPAIRED ANGIOGENESIS AND CARDIAC MICROVASCULAR RAREFACTION. THESE OBSERVATIONS SHED LIGHT ON THE MECHANISMS OF CARDIAC MICROVASCULAR DAMAGE IN CKD-LVDD AND MAY ASSIST IN DEVELOPING NOVEL THERAPIES FOR THESE PATIENTS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
8 1368  45 DEVELOPMENTAL ORIGINS OF DISEASE AND DETERMINANTS OF CHROMATIN STRUCTURE: MATERNAL DIET MODIFIES THE PRIMATE FETAL EPIGENOME. CHROMATIN STRUCTURE IS EPIGENETICALLY ALTERED VIA COVALENT MODIFICATIONS OF HISTONES TO ALLOW FOR HERITABLE GENE REGULATION WITHOUT ALTERING THE NUCLEOTIDE SEQUENCE. MULTIPLE LINES OF EVIDENCE FROM RODENTS HAVE ESTABLISHED A ROLE FOR EPIGENETIC REMODELING IN REGULATING GENE TRANSCRIPTION IN RESPONSE TO AN ALTERED GESTATIONAL MILIEU. HOWEVER, TO DATE, IT IS UNKNOWN WHETHER VARIATIONS IN THE INTRAUTERINE ENVIRONMENT IN PRIMATES SIMILARLY INDUCE CHANGES IN KEY DETERMINANTS OF HEPATIC CHROMATIN STRUCTURE. WE HYPOTHESIZED THAT A MATERNAL HIGH-FAT DIET WOULD ALTER THE EPIGENOMIC PROFILE OF THE DEVELOPING OFFSPRING, WHICH WOULD RESULT IN ALTERATIONS IN FETAL GENE EXPRESSION. AGE- AND WEIGHT-MATCHED ADULT FEMALE JAPANESE MACAQUES WERE PLACED ON CONTROL (13% FAT) OR HIGH-FAT (35% FAT) BREEDER DIETS AND MATED ANNUALLY OVER A 4-YEAR INTERVAL. FETUSES IN SUCCESSIVE YEARS WERE DELIVERED NEAR TERM (E130 OF 167 DAYS) AND UNDERWENT NECROPSY WITH TISSUE HARVEST. FETAL HISTONES WERE ACID EXTRACTED FOR CHARACTERIZATION OF H3 MODIFICATION AND CHROMATIN IMMUNOPRECIPITATION (CHIP) WITH DIFFERENTIAL DISPLAY PCR; FETAL RNA, DNA, AND CYTOPLASMIC AND NUCLEAR PROTEIN EXTRACTS WERE SIMILARLY EXTRACTED FOR COMPARISON. CHRONIC CONSUMPTION OF A MATERNAL HIGH-FAT DIET RESULTS IN A THREEFOLD INCREASE IN FETAL LIVER TRIGLYCERIDES AND HISTOLOGIC CORRELATES OF NON-ALCOHOLIC FATTY LIVER DISEASE. THESE GROSS CHANGES IN THE FETAL LIVER ARE ACCOMPANIED BY A STATISTICALLY SIGNIFICANT HYPERACETYLATION OF FETAL HEPATIC TISSUE AT H3K14 (199.85+/-9.64 VS 88.8+/-45.4; P=0.038) WITH A TREND TOWARDS THE INCREASED ACETYLATION AT H3K9 (140.9+/-38.7 VS 46.6+/-6.53; P=0.097) AND AT H3K18 (69.0+/-3.54 VS 58.0+/-4.04; P=0.096). HOWEVER, EPIGENETIC MODIFICATIONS ON FETAL HEPATIC H3 ASSOCIATED WITH GENE REPRESSION WERE ABSENT OR SUBTLE (P>0.05). SUBSEQUENT CHARACTERIZATION OF KEY EPIGENETIC DETERMINANTS ASSOCIATED WITH H3 ACETYLATION MARKS REVEALED SIMILAR SIGNIFICANT ALTERATIONS IN ASSOCIATION WITH A HIGH-FAT MATERNAL DIET (E.G., RELATIVE FETAL HISTONE DEACETYLASE 1 (HDAC1) GENE EXPRESSION 0.61+/-0.25; P=0.011). CONSISTENT WITH OUR MRNA EXPRESSION PROFILE, FETAL NUCLEAR EXTRACTS FROM OFFSPRING OF HIGH-FAT DIET ANIMALS WERE OBSERVED TO BE SIGNIFICANTLY RELATIVELY DEPLETE OF HDAC1 PROTEIN (36.07+/-6.73 VS 83.18+/-7.51; P=0.006) AND IN VITRO HDAC FUNCTIONAL ACTIVITY (0.252+/-0.03 VS 0.698+/-0.02; P<0.001). WE EMPLOY THESE OBSERVATIONS IN CHIP DIFFERENTIAL DISPLAY PCR TO ATTEMPT TO IDENTIFY POTENTIAL FETAL GENES WHOSE EXPRESSION IS REPROGRAMED UNDER CONDITIONS OF A HIGH-FAT MATERNAL DIET. WE QUANTITATIVELY CONFIRM A MINIMUM OF A 40% ALTERATION IN THE EXPRESSION OF SEVERAL GENES OF INTEREST: GLUTAMIC PYRUVATE TRANSAMINASE (ALANINE AMINOTRANSFERASE) 2 (GPT2) (1.59+/-0.23-FOLD; P=0.08), DNAJA2 (1.36+/-0.21; P=0.09), AND RDH12 (1.88+/-0.15; P=0.01) ARE APPRECIABLY INCREASED IN FETAL HEPATIC TISSUE FROM MATERNAL CALORIC-DENSE DIET ANIMALS WHEN COMPARED WITH CONTROL WHILE NPAS2, A PERIPHERAL CIRCADIAN REGULATOR, WAS SIGNIFICANTLY DOWNMODULATED IN THE OFFSPRING OF HIGH-FAT DIET ANIMALS (0.66+/-0.08; P=0.03). IN THIS STUDY, WE SHOW THAT A CURRENT SIGNIFICANT IN UTERO EXPOSURE (CALORIC-DENSE HIGH-FAT MATERNAL DIET) INDUCES SITE-SPECIFIC ALTERATIONS IN FETAL HEPATIC H3 ACETYLATION. EMPLOYING CHIP, WE EXTEND THESE OBSERVATIONS TO LINK MODIFICATIONS OF H3 ACETYLATION WITH ALTERATIONS IN GENE-SPECIFIC EXPRESSION. THESE RESULTS SUGGEST THAT A CALORIC-DENSE MATERNAL DIET LEADING TO OBESITY EPIGENETICALLY ALTERS FETAL CHROMATIN STRUCTURE IN PRIMATES VIA COVALENT MODIFICATIONS OF HISTONES AND HENCE LENDS A MOLECULAR BASIS TO THE FETAL ORIGINS OF ADULT DISEASE HYPOTHESIS.	2008	

9 2714  38 EXERCISE-CONDITIONED PLASMA ATTENUATES NUCLEAR CONCENTRATIONS OF DNA METHYLTRANSFERASE 3B IN HUMAN PERIPHERAL BLOOD MONONUCLEAR CELLS. DNA METHYLATION IS MODIFIABLE BY ACUTE AND CHRONIC EXERCISE. DNA METHYLTRANSFERASES (DNMT) CATALYZE THIS PROCESS; HOWEVER, THERE IS A LACK OF LITERATURE CONCERNING THE SPECIFIC MECHANISMS BY WHICH EXERCISE-INDUCED MODIFICATIONS OCCUR. INTERLEUKIN 6 (IL-6) STIMULATION OF VARIOUS CELL LINES HAS BEEN SHOWN TO AUGMENT DNMT EXPRESSION AND NUCLEAR TRANSLOCATION, WHICH SUGGESTS A POSSIBLE PATHWAY BY WHICH EXERCISE IS ABLE TO ELICIT CHANGES IN EPIGENETIC ENZYMES. THE PRESENT STUDY SOUGHT TO ELUCIDATE THE RESPONSE OF THE DE NOVO METHYLTRANSFERASES DNMT3A AND DNMT3B TO CIRCULATORY FACTORS FOUND IN PLASMA ISOLATED FROM WHOLE BLOOD BEFORE AND AFTER 120-MIN OF TREADMILL RUNNING AT AN INTENSITY OF 60% OF INDIVIDUAL VELOCITY AT V O2MAX (VV O2MAX) INTERSPERSED WITH 30-SEC SPRINTS AT 90% OF VV O2MAX EVERY 10-MIN. PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) ISOLATED FROM A RESTING PARTICIPANT WERE INCUBATED WITH PLASMA ISOLATED FROM EXERCISING PARTICIPANTS (N = 10) OR RECOMBINANT IL-6 (RIL-6), FOLLOWED BY NUCLEAR PROTEIN EXTRACTION AND QUANTIFICATION OF DNMT3A AND DNMT3B CONCENTRATIONS. NUCLEAR CONCENTRATIONS OF DNMT3B SIGNIFICANTLY DECREASED FOLLOWING THE EXPERIMENTAL PROTOCOL (P = 0.03), WITH NO CHANGE OBSERVED IN DNMT3A (P = 0.514).VARIOUS CONCENTRATIONS OF RIL-6 CAUSED AN ELEVATION IN BOTH DNMT3A AND DNMT3B NUCLEAR CONCENTRATION COMPARED WITH THE BLANK CONTROL. THE CONFLICTING RESULTS BETWEEN EXERCISING AND RIL-6 CONDITIONS SUGGESTS THAT IL-6 DOES REGULATE DNMT NUCLEAR TRANSPORT, HOWEVER, OTHER PLASMA MEDIATORS MAY ALSO EXERT SIGNIFICANT INFLUENCE ON THE NUCLEAR CONCENTRATIONS OF THESE ENZYMES.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
10 5468  32 RESISTANCE TRAINING AND REDOX HOMEOSTASIS: CORRELATION WITH AGE-ASSOCIATED GENOMIC CHANGES. REGULAR PHYSICAL ACTIVITY IS EFFECTIVE AS PREVENTION AND TREATMENT FOR DIFFERENT CHRONIC CONDITIONS RELATED TO THE AGEING PROCESSES. IN FACT, A SEDENTARY LIFESTYLE HAS BEEN LINKED TO A WORSENING OF CELLULAR AGEING BIOMARKERS SUCH AS TELOMERE LENGTH (TL) AND/OR SPECIFIC EPIGENETIC CHANGES (E.G. DNA METHYLATION), WITH INCREASE OF THE PROPENSITY TO AGING-RELATED DISEASES AND PREMATURE DEATH. EXTENDING OUR PREVIOUS FINDINGS, WE AIMED TO TEST THE HYPOTHESIS THAT 12 WEEKS OF LOW FREQUENCY, MODERATE INTENSITY, EXPLOSIVE-TYPE RESISTANCE TRAINING (EMRT) MAY ATTENUATE AGE-ASSOCIATED GENOMIC CHANGES. TO THIS AIM, TL, GLOBAL DNA METHYLATION, TRF2, KU80, SIRT1, SIRT2 AND GLOBAL PROTEIN ACETYLATION, AS WELL AS OTHER PROTEINS INVOLVED IN APOPTOTIC PATHWAY (BCL-2, BAX AND CASPASE-3), ANTIOXIDANT RESPONSE (TRXR1 AND MNSOD) AND OXIDATIVE DAMAGE (MYELOPEROXIDASE) WERE EVALUATED BEFORE AND AFTER EMRT IN WHOLE BLOOD OR PERIPHERAL MONONUCLEAR CELLS (PBMCS) OF ELDERLY SUBJECTS. OUR FINDINGS CONFIRM THE POTENTIAL OF EMRT TO INDUCE AN ADAPTIVE CHANGE IN THE ANTIOXIDANT PROTEIN SYSTEMS AT SYSTEMIC LEVEL AND SUGGEST A PUTATIVE ROLE OF RESISTANCE TRAINING IN THE REDUCTION OF GLOBAL DNA METHYLATION. MOREOVER, WE OBSERVED THAT EMRT COUNTERACTS THE TELOMERES' SHORTENING IN A MANNER THAT PROVED TO BE DIRECTLY CORRELATED WITH THE AMELIORATION OF REDOX HOMEOSTASIS AND EFFICACY OF TRAINING REGIME, EVALUATED AS IMPROVEMENT OF BOTH MUSCLE'S POWER/STRENGTH AND FUNCTIONAL PARAMETERS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
11 3390  30 HOPX PLAYS A CRITICAL ROLE IN ANTIRETROVIRAL DRUGS INDUCED EPIGENETIC MODIFICATION AND CARDIAC HYPERTROPHY. PEOPLE LIVING WITH HIV (PLWH) HAVE TO TAKE AN ANTIRETROVIRAL THERAPY (ART) FOR LIFE AND SHOW NONCOMMUNICABLE ILLNESSES SUCH AS CHRONIC INFLAMMATION, IMMUNE ACTIVATION, AND MULTIORGAN DYSREGULATION. RECENT STUDIES SUGGEST THAT LONG-TERM USE OF ART INDUCES COMORBID CONDITIONS AND IS ONE OF THE LEADING CAUSES OF HEART FAILURE IN PLWH. HOWEVER, THE MOLECULAR MECHANISM OF ANTIRETROVIRAL DRUGS (ARVS) INDUCED HEART FAILURE IS UNCLEAR. TO DETERMINE THE MECHANISM OF ARVS INDUCED CARDIAC DYSFUNCTION, WE PERFORMED GLOBAL TRANSCRIPTOMIC PROFILING OF ARVS TREATED NEONATAL RAT VENTRICULAR CARDIOMYOCYTES IN CULTURE. DIFFERENTIALLY EXPRESSED GENES WERE IDENTIFIED BY RNA-SEQUENCING. OUR DATA SHOW THAT ARVS TREATMENT CAUSES UPREGULATION OF SEVERAL BIOLOGICAL FUNCTIONS ASSOCIATED WITH CARDIOTOXICITY, HYPERTROPHY, AND HEART FAILURE. GLOBAL GENE EXPRESSION DATA WERE VALIDATED IN CARDIAC TISSUE ISOLATED FROM HIV PATIENTS HAVING A HISTORY OF ART. INTERESTINGLY, WE FOUND THAT HOMEODOMAIN-ONLY PROTEIN HOMEOBOX (HOPX) EXPRESSION WAS SIGNIFICANTLY INCREASED IN CARDIOMYOCYTES TREATED WITH ARVS AND IN THE HEART TISSUE OF HIV PATIENTS. FURTHERMORE, WE FOUND THAT HOPX PLAYS A CRUCIAL ROLE IN ARVS MEDIATED CELLULAR HYPERTROPHY. MECHANISTICALLY, WE FOUND THAT HOPX PLAYS A CRITICAL ROLE IN EPIGENETIC REGULATION, THROUGH DEACETYLATION OF HISTONE, WHILE THE HDAC INHIBITOR, TRICHOSTATIN A, CAN RESTORE THE ACETYLATION LEVEL OF HISTONE 3 IN THE PRESENCE OF ARVS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
12 4736  29 NOVEL EPIGENETIC BIOMARKERS MEDIATING BISPHENOL A EXPOSURE AND METABOLIC PHENOTYPES IN FEMALE MICE. THERE IS COMPELLING EVIDENCE THAT EPIGENETIC MODIFICATIONS LINK DEVELOPMENTAL ENVIRONMENTAL INSULTS TO ADULT DISEASE SUSCEPTIBILITY. ANIMAL STUDIES HAVE ASSOCIATED PERINATAL BISPHENOL A (BPA) EXPOSURE TO ALTERED DNA METHYLATION, BUT THESE STUDIES ARE OFTEN LIMITED TO CANDIDATE GENE AND GLOBAL NON-LOCI-SPECIFIC APPROACHES. BY USING AN EPIGENOME-WIDE DISCOVERY PLATFORM, WE ELUCIDATED EPIGENETIC ALTERATIONS IN LIVER TISSUE FROM ADULT MICE OFFSPRING (10 MONTHS) FOLLOWING PERINATAL BPA EXPOSURE AT HUMAN PHYSIOLOGICALLY RELEVANT DOSES (50-NG, 50-MUG, AND 50-MG BPA/KG DIET). BIOLOGICAL PATHWAY ANALYSIS IDENTIFIED AN ENRICHMENT OF SIGNIFICANT DIFFERENTIALLY METHYLATED REGIONS IN METABOLIC PATHWAYS AMONG FEMALES. FURTHERMORE, THROUGH THE USE OF TOP ENRICHED BIOLOGICAL PATHWAYS, 4 CANDIDATE GENES WERE CHOSEN TO ASSESS DNA METHYLATION AS A MEDIATING FACTOR LINKING THE ASSOCIATION OF PERINATAL BPA EXPOSURE TO METABOLIC PHENOTYPES PREVIOUSLY OBSERVED IN FEMALE OFFSPRING. DNA METHYLATION STATUS AT JANUS KINASE-2 (JAK-2), RETINOID X RECEPTOR (RXR), REGULATORY FACTOR X-ASSOCIATED PROTEIN (RFXAP), AND TRANSMEMBRANE PROTEIN 238 (TMEM238) WAS USED WITHIN A MEDIATIONAL REGRESSION ANALYSIS. DNA METHYLATION IN ALL FOUR OF THE CANDIDATE GENES WAS IDENTIFIED AS A MEDIATOR IN THE MECHANISTIC PATHWAY OF DEVELOPMENTAL BPA EXPOSURE AND FEMALE-SPECIFIC ENERGY EXPENDITURE, BODY WEIGHT, AND BODY FAT PHENOTYPES. DATA GENERATED FROM THIS STUDY ARE CRUCIAL FOR DECIPHERING THE MECHANISTIC ROLE OF EPIGENETICS IN THE PATHOGENESIS OF CHRONIC DISEASE AND THE DEVELOPMENT OF EPIGENETIC-BASED PREVENTION AND THERAPEUTIC STRATEGIES FOR COMPLEX HUMAN DISEASE.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
13 3206  30 HDAC9 IS AN EPIGENETIC REPRESSOR OF KIDNEY ANGIOTENSINOGEN ESTABLISHING A SEX DIFFERENCE. BACKGROUND: SEXUAL DIFFERENCE HAS BEEN SHOWN IN THE PATHOGENESIS OF CHRONIC KIDNEY DISEASE INDUCED BY HYPERTENSION. FEMALES ARE PROTECTED FROM HYPERTENSION AND RELATED END-ORGAN DAMAGE. AUGMENTATION OF RENAL PROXIMAL TUBULAR ANGIOTENSINOGEN (AGT) EXPRESSION CAN PROMOTE INTRARENAL ANGIOTENSIN FORMATION AND THE DEVELOPMENT OF ASSOCIATED HYPERTENSION AND KIDNEY INJURY. FEMALE RODENTS EXHIBIT LOWER INTRARENAL AGT LEVELS THAN MALES UNDER NORMAL CONDITIONS, SUGGESTING THAT THE SUPPRESSED INTRARENAL AGT PRODUCTION BY PROGRAMMED MECHANISMS IN FEMALES MAY PROVIDE PROTECTION FROM THESE DISEASES. THIS STUDY WAS PERFORMED TO EXAMINE WHETHER EPIGENETIC MECHANISMS SERVE AS REPRESSORS OF AGT. METHODS: MALE AND FEMALE SPRAGUE DAWLEY RATS WERE USED TO INVESTIGATE SEX DIFFERENCES OF SYSTEMIC, HEPATIC, AND INTRARENAL AGT LEVELS. ALL HISTONE DEACETYLASE (HDAC) MRNA LEVELS IN THE KIDNEYS WERE DETERMINED USING A PCR ARRAY. HDAC9 PROTEIN EXPRESSION IN THE KIDNEYS AND CULTURED RENAL PROXIMAL TUBULAR CELLS (PTC) WAS ANALYZED BY WESTERN BLOT ANALYSIS AND IMMUNOHISTOCHEMISTRY. THE EFFECTS OF HDAC9 ON AGT EXPRESSION WERE EVALUATED BY USING AN INHIBITOR AND SIRNA. CHIP ASSAY WAS PERFORMED TO INVESTIGATE THE INTERACTION BETWEEN THE AGT PROMOTER AND HDAC9. RESULTS: PLASMA AND LIVER AGT LEVELS DID NOT SHOW DIFFERENCES BETWEEN MALE AND FEMALE SPRAGUE-DAWLEY RATS. IN CONTRAST, FEMALES EXHIBITED LOWER AGT LEVELS THAN MALES IN THE RENAL CORTEX AND URINE. IN THE ABSENCE OF SUPPLEMENTED SEX HORMONES, PRIMARY CULTURED RENAL CORTICAL CELLS ISOLATED FROM FEMALE RATS SUSTAINED LOWER AGT LEVELS THAN THOSE FROM MALES, SUGGESTING THAT THE KIDNEYS HAVE A UNIQUE MECHANISM OF AGT REGULATION CONTROLLED BY EPIGENETIC FACTORS RATHER THAN SEX HORMONES. HDAC9 MRNA AND PROTEIN LEVELS WERE HIGHER IN THE RENAL CORTEX OF FEMALE RATS VERSUS MALE RATS (7.09 +/- 0.88, RATIO TO MALE) WHILE OTHER HDACS DID NOT EXHIBIT A SEX DIFFERENCE. HDAC9 EXPRESSION WAS LOCALIZED IN PTC WHICH ARE THE PRIMARY SOURCE OF INTRARENAL AGT. IMPORTANTLY, HDAC9 KNOCKDOWN AUGMENTED AGT MRNA (1.92 +/- 0.35-FOLD) AND PROTEIN (2.25 +/- 0.50-FOLD) LEVELS, SIMILAR TO AN HDAC9 INHIBITOR. FURTHERMORE, AN INTERACTION BETWEEN HDAC9 AND A DISTAL 5' FLANKING REGION OF AGT VIA A HISTONE COMPLEX CONTAINING H3 AND H4 WAS DEMONSTRATED. CONCLUSIONS: THESE RESULTS INDICATE THAT HDAC9 IS A NOVEL SUPPRESSING FACTOR INVOLVED IN AGT REGULATION IN PTC, LEADING TO LOW LEVELS OF INTRARENAL AGT IN FEMALES. THESE FINDINGS WILL HELP TO DELINEATE MECHANISMS UNDERLYING SEX DIFFERENCES IN THE DEVELOPMENT OF HYPERTENSION AND RENIN-ANGIOTENSIN SYSTEM (RAS) ASSOCIATED KIDNEY INJURY.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
14 3468  40 HYPOXIA-INDUCED DNA HYPERMETHYLATION IN HUMAN PULMONARY FIBROBLASTS IS ASSOCIATED WITH THY-1 PROMOTER METHYLATION AND THE DEVELOPMENT OF A PRO-FIBROTIC PHENOTYPE. BACKGROUND: PULMONARY FIBROSIS IS A DEBILITATING AND LETHAL DISEASE WITH NO EFFECTIVE TREATMENT OPTIONS. UNDERSTANDING THE PATHOLOGICAL PROCESSES AT PLAY WILL DIRECT THE APPLICATION OF NOVEL THERAPEUTIC AVENUES. HYPOXIA HAS BEEN IMPLICATED IN THE PATHOGENESIS OF PULMONARY FIBROSIS YET THE PRECISE MECHANISM BY WHICH IT CONTRIBUTES TO DISEASE PROGRESSION REMAINS TO BE FULLY ELUCIDATED. IT HAS BEEN SHOWN THAT CHRONIC HYPOXIA CAN ALTER DNA METHYLATION PATTERNS IN TUMOUR-DERIVED CELL LINES. THIS EPIGENETIC ALTERATION CAN INDUCE CHANGES IN CELLULAR PHENOTYPE WITH PROMOTER METHYLATION BEING ASSOCIATED WITH GENE SILENCING. OF PARTICULAR RELEVANCE TO IDIOPATHIC PULMONARY FIBROSIS (IPF) IS THE OBSERVATION THAT THY-1 PROMOTER METHYLATION IS ASSOCIATED WITH A MYOFIBROBLAST PHENOTYPE WHERE LOSS OF THY-1 OCCURS ALONGSIDE INCREASED ALPHA SMOOTH MUSCLE ACTIN (ALPHA-SMA) EXPRESSION. THE INITIAL AIM OF THIS STUDY WAS TO DETERMINE WHETHER HYPOXIA REGULATES DNA METHYLATION IN NORMAL HUMAN LUNG FIBROBLASTS (CCD19LU). AS IT HAS BEEN REPORTED THAT HYPOXIA SUPPRESSES THY-1 EXPRESSION DURING LUNG DEVELOPMENT WE ALSO STUDIED THE EFFECT OF HYPOXIA ON THY-1 PROMOTER METHYLATION AND GENE EXPRESSION. METHODS: CCD19LU WERE GROWN FOR UP TO 8 DAYS IN HYPOXIA AND ASSESSED FOR GLOBAL CHANGES IN DNA METHYLATION USING FLOW CYTOMETRY. REAL-TIME PCR WAS USED TO QUANTIFY EXPRESSION OF THY-1, ALPHA-SMA, COLLAGEN I AND III. GENOMIC DNA WAS BISULPHITE TREATED AND METHYLATION SPECIFIC PCR (MSPCR) WAS USED TO EXAMINE THE METHYLATION STATUS OF THE THY-1 PROMOTER. RESULTS: SIGNIFICANT GLOBAL HYPERMETHYLATION WAS DETECTED IN HYPOXIC FIBROBLASTS RELATIVE TO NORMOXIC CONTROLS AND WAS ACCOMPANIED BY INCREASED EXPRESSION OF MYOFIBROBLAST MARKERS. THY-1 MRNA EXPRESSION WAS SUPPRESSED IN HYPOXIC CELLS, WHICH WAS RESTORED WITH THE DEMETHYLATING AGENT 5-AZA-2'-DEOXYCYTIDINE. MSPCR REVEALED THAT THY-1 BECAME METHYLATED FOLLOWING FIBROBLAST EXPOSURE TO 1% O2. CONCLUSION: THESE DATA SUGGEST THAT GLOBAL AND GENE-SPECIFIC CHANGES IN DNA METHYLATION MAY PLAY AN IMPORTANT ROLE IN FIBROBLAST FUNCTION IN HYPOXIA.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
15 2032  39 EPIGENETIC CHANGES IN P21 EXPRESSION IN RENAL CELLS AFTER EXPOSURE TO BROMATE. THIS STUDY TESTED THE HYPOTHESIS THAT BROMATE (KBRO3)-INDUCED RENAL CELL DEATH IS MEDIATED BY EPIGENETIC MECHANISMS. GLOBAL DNA METHYLATION, AS ASSESSED BY 5-METHYLCYTOSINE STAINING, WAS NOT CHANGED IN NORMAL RAT KIDNEY CELLS TREATED WITH ACUTE CYTOTOXIC DOSES OF KBRO3 (100 AND 200 PPM), AS COMPARED WITH CONTROLS. HOWEVER, KBRO3 TREATMENT DID INCREASE P38, P53 AND HISTONE 2AX (H2AX) PHOSPHORYLATION, AND P21 EXPRESSION. TREATMENT OF CELLS WITH INHIBITORS OF DNA METHYLTRANSFERASE (5-AZACYTIDINE OR 5-AZA) AND HISTONE DEACETYLASE (TRICHOSTATIN A OR TSA) IN ADDITION TO KBRO3 INCREASED CYTOTOXICITY, AS COMPARED WITH CELLS EXPOSED TO KBRO3 ALONE. 5-AZA AND TSA CO-TREATMENT DID NOT ALTER P38 OR P53 PHOSPHORYLATION, BUT SLIGHTLY DECREASED H2AX PHOSPHORYLATION AND SIGNIFICANTLY DECREASED P21 EXPRESSION. WE ALSO ASSESSED EPIGENETIC CHANGES IN CELLS TREATED UNDER SUB-CHRONIC CONDITIONS WITH ENVIRONMENTALLY RELEVANT CONCENTRATIONS OF KBRO3. UNDER THESE CONDITIONS (0-10PPM KBRO3 FOR UP TO 18 DAYS), WE DETECTED NO INCREASES IN CELL DEATH OR DNA DAMAGE. IN CONTRAST, SLIGHT ALTERATIONS WERE DETECTED IN THE PHOSPHORYLATION OF H2AX, P38, AND P53. SUB-CHRONIC LOW-DOSE KBRO3 TREATMENT ALSO INDUCED A BIPHASIC RESPONSE IN P21 EXPRESSION, WITH LOWER CONCENTRATIONS INCREASING EXPRESSION, BUT HIGHER CONCENTRATIONS DECREASING EXPRESSION. METHYLATION-SPECIFIC PCR DEMONSTRATED THAT SUB-CHRONIC KBRO3 TREATMENT ALTERED THE METHYLATION OF CYTOSINE BASES IN THE P21 GENE, AS COMPARED WITH CONTROLS, CORRELATING TO ALTERATIONS IN P21 PROTEIN EXPRESSION. COLLECTIVELY, THESE DATA SHOW THE NOVEL FINDING THAT KBRO3-INDUCED RENAL CELL DEATH IS ALTERED BY INHIBITORS OF EPIGENETIC MODIFYING ENZYMES AND THAT KBRO3 ITSELF INDUCES EPIGENETIC CHANGES IN THE P21 GENE.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
16 1182  37 CONVERGING AND DIFFERENTIAL BRAIN PHOSPHOLIPID DYSREGULATION IN THE PATHOGENESIS OF REPETITIVE MILD TRAUMATIC BRAIN INJURY AND ALZHEIMER'S DISEASE. REPETITIVE MILD TRAUMATIC BRAIN INJURY (RMTBI) IS A MAJOR EPIGENETIC RISK FACTOR FOR ALZHEIMER'S DISEASE (AD). THE PRECISE NATURE OF HOW RMTBI LEADS TO OR PRECIPITATES AD PATHOLOGY IS CURRENTLY UNKNOWN. NUMEROUS NEUROLOGICAL CONDITIONS HAVE SHOWN AN IMPORTANT ROLE FOR DYSFUNCTIONAL PHOSPHOLIPID METABOLISM AS A DRIVING FACTOR FOR THE PATHOGENESIS OF NEURODEGENERATIVE DISEASES. HOWEVER, THE PRECISE ROLE IN RMTBI AND AD REMAINS ELUSIVE. WE HYPOTHESIZED THAT A DETAILED PHOSPHOLIPID CHARACTERIZATION WOULD REVEAL PROFILES OF RESPONSE TO INJURY IN TBI THAT OVERLAP WITH AGE-DEPENDENT CHANGES IN AD AND THUS PROVIDE INSIGHTS INTO THE TBI-AD RELATIONSHIP. WE EMPLOYED A LIPIDOMIC APPROACH EXAMINING BRAIN PHOSPHOLIPID PROFILES FROM MOUSE MODELS OF RMTBI AND AD. CORTEX AND HIPPOCAMPAL TISSUE WERE COLLECTED AT 24 H, 3, 6, 9, AND 12 MONTHS POST-RMTBI, AND AT AGES REPRESENTING 'PRE', 'PERI' AND 'POST' ONSET OF AMYLOID PATHOLOGY (I.E., 3, 9, 15 MONTHS-OLD). TOTAL LEVELS OF PHOSPHATIDYLCHOLINE (PC), PHOSPHATIDYLETHANOLAMINE (PE), LYSOPE, AND PHOSPHATIDYLINOSITOL (PI), INCLUDING THEIR MONOUNSATURATED, POLYUNSATURATED AND SATURATED FATTY ACID (FA) CONTAINING SPECIES WERE SIGNIFICANTLY INCREASED AT ACUTE AND/OR CHRONIC TIME POINTS POST-INJURY IN BOTH BRAIN REGIONS. HOWEVER, LEVELS OF MOST PHOSPHOLIPID SPECIES IN PS1/APP MICE WERE NOMINAL IN THE HIPPOCAMPUS, WHILE IN THE CORTEX, LEVELS WERE SIGNIFICANTLY DECREASED AT AGES POST-ONSET OF AMYLOID PATHOLOGY. SPHINGOMYELIN AND LYSOPC LEVELS SHOWED COINCIDENTAL TRENDS IN OUR RMTBI AND AD MODELS WITHIN THE HIPPOCAMPUS, AN INCREASE AT ACUTE AND/OR CHRONIC TIME POINTS EXAMINED. THE RATIO OF ARACHIDONIC ACID (OMEGA-6 FA) TO DOCOSAHEXAENOIC ACID (OMEGA-3 FA)-CONTAINING PE SPECIES WAS INCREASED AT EARLY TIME POINTS IN THE HIPPOCAMPUS OF INJURED VERSUS SHAM MICE, AND IN PS1/APP MICE THERE WAS A COINCIDENTAL INCREASE COMPARED TO WILD TYPE LITTERMATES AT ALL TIME POINTS. THIS STUDY DEMONSTRATES SOME OVERLAPPING AND DIVERSE PHOSPHOLIPID PROFILES IN RMTBI AND AD MODELS. FUTURE STUDIES ARE REQUIRED TO CORROBORATE OUR FINDINGS IN HUMAN POST-MORTEM TISSUE. INVESTIGATION OF SECONDARY MECHANISMS TRIGGERED BY ABERRANT DOWNSTREAM ALTERATIONS IN BIOACTIVE METABOLITES OF THESE PHOSPHOLIPIDS, AND THEIR MODULATION AT THE APPROPRIATE TIME-WINDOWS OF OPPORTUNITY COULD HELP FACILITATE DEVELOPMENT OF NOVEL THERAPEUTIC STRATEGIES TO AMELIORATE THE NEURODEGENERATIVE CONSEQUENCES OF RMTBI OR THE POTENTIAL TRIGGERING OF AD PATHOGENESIS BY RMTBI.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
17 3813  22 INTRAUTERINE GROWTH RESTRICTION INHIBITS EXPRESSION OF EUKARYOTIC ELONGATION FACTOR 2 KINASE, A REGULATOR OF PROTEIN TRANSLATION. NUTRIENT DEPRIVATION SUPPRESSES PROTEIN SYNTHESIS BY BLOCKING PEPTIDE ELONGATION. TRANSCRIPTIONAL UPREGULATION AND ACTIVATION OF EUKARYOTIC ELONGATION FACTOR 2 KINASE (EEF2K) BLOCKS PEPTIDE ELONGATION BY PHOSPHORYLATING EUKARYOTIC ELONGATION FACTOR 2. PREVIOUS STUDIES EXAMINING PLACENTAS FROM INTRAUTERINE GROWTH RESTRICTED (IUGR) NEWBORN INFANTS SHOW DECREASED EEF2K EXPRESSION AND ACTIVITY DESPITE CHRONIC NUTRIENT DEPRIVATION. HOWEVER, THE EFFECT OF IUGR ON HEPATIC EEF2K EXPRESSION IN THE FETUS IS UNKNOWN. WE, THEREFORE, EXAMINED THE TRANSCRIPTIONAL REGULATION OF HEPATIC EEF2K GENE EXPRESSION IN A SPRAGUE-DAWLEY RAT MODEL OF IUGR. WE FOUND DECREASED HEPATIC EEF2K MRNA AND PROTEIN LEVELS IN IUGR OFFSPRING AT BIRTH COMPARED WITH CONTROL, CONSISTENT WITH PREVIOUS PLACENTAL OBSERVATIONS. FURTHERMORE, THE CPG ISLAND WITHIN THE EEF2K PROMOTER DEMONSTRATED INCREASED METHYLATION AT A CRITICAL USF 1/2 TRANSCRIPTION FACTOR BINDING SITE. IN VITRO METHYLATION OF THIS BINDING SITE CAUSED NEAR COMPLETE LOSS OF EEF2K PROMOTER ACTIVITY, DESIGNATING THIS PROMOTER AS METHYLATION SENSITIVE. THE EEF2K PROMOTOR IN IUGR OFFSPRING ALSO LOST THE PROTECTIVE HISTONE COVALENT MODIFICATIONS ASSOCIATED WITH UNMETHYLATED CGIS. IN ADDITION, THE +1 NUCLEOSOME WAS DISPLACED 3' AND RNA POLYMERASE LOADING WAS REDUCED AT THE IUGR EEF2K PROMOTER. OUR FINDINGS PROVIDE EVIDENCE TO EXPLAIN WHY IUGR-INDUCED CHRONIC NUTRIENT DEPRIVATION DOES NOT RESULT IN THE UPREGULATION OF EEF2K GENE TRANSCRIPTION.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
18 3991  28 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
19  905  29 CHRONIC EXPOSURE TO CANNABINOIDS DURING ADOLESCENCE CAUSES LONG-LASTING BEHAVIORAL DEFICITS IN ADULT MICE. REGULAR USE OF MARIJUANA DURING ADOLESCENCE ENHANCES THE RISK OF LONG-LASTING NEUROBIOLOGICAL CHANGES IN ADULTHOOD. THE PRESENT STUDY WAS AIMED AT ASSESSING THE EFFECT OF LONG-TERM ADMINISTRATION OF THE SYNTHETIC CANNABINOID WIN55212.2 DURING ADOLESCENCE IN YOUNG ADULT MICE. ADOLESCENT MICE AGED 5 WEEKS WERE SUBJECTED DAILY TO THE PHARMACOLOGICAL ACTION OF WIN55212.2 FOR 3 WEEKS AND WERE THEN LEFT UNDISTURBED IN THEIR HOME CAGE FOR A 5-WEEK PERIOD AND FINALLY EVALUATED BY BEHAVIORAL TESTING. MICE THAT RECEIVED THE DRUG DURING ADOLESCENCE SHOWED MEMORY IMPAIRMENT IN THE MORRIS WATER MAZE, AS WELL AS A DOSE-DEPENDENT MEMORY IMPAIRMENT IN FEAR CONDITIONING. IN ADDITION, THE ADMINISTRATION OF 3 MG/KG WIN55212.2 IN ADOLESCENCE INCREASED ADULT HIPPOCAMPAL AEA LEVELS AND PROMOTED DNA HYPERMETHYLATION AT THE INTRAGENIC REGION OF THE INTRACELLULAR SIGNALING MODULATOR RGS7, WHICH WAS ACCOMPANIED BY A LOWER RATE OF MRNA TRANSCRIPTION OF THIS GENE, SUGGESTING A POTENTIAL CAUSAL RELATION. ALTHOUGH THE CONCRETE MECHANISMS UNDERLYING THE BEHAVIORAL OBSERVATIONS REMAIN TO BE ELUCIDATED, WE DEMONSTRATE THAT LONG-TERM ADMINISTRATION OF 3 MG/KG OF WIN DURING ADOLESCENCE LEADS TO INCREASED ENDOCANNABINOID LEVELS AND ALTERED RGS7 EXPRESSION IN ADULTHOOD AND ESTABLISH A POTENTIAL LINK TO EPIGENETIC CHANGES.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
20  217  28 ACUTE EXERCISE INCREASES THE EXPRESSION OF KIR2DS4 BY PROMOTER DEMETHYLATION IN NK CELLS. POSITIVE EFFECTS OF EXERCISE ON CANCER PREVENTION AND PROGRESSION HAVE BEEN PROPOSED TO BE MEDIATED BY STIMULATING NATURAL KILLER (NK) CELLS. BECAUSE NK CELL RECEPTORS ARE REGULATED BY EPIGENETIC MODIFICATIONS, WE INVESTIGATED WHETHER ACUTE AEROBIC EXERCISE AND TRAINING CHANGE PROMOTER DNA METHYLATION AND GENE EXPRESSION OF THE ACTIVATING KIR2DS4 AND THE INHIBITING KIR3DL1 GENE. SIXTEEN HEALTHY WOMEN (50-60 YEARS) PERFORMED A GRADED EXERCISE TEST (GXT) AND WERE RANDOMIZED INTO EITHER A PASSIVE CONTROL GROUP OR AN INTERVENTION GROUP PERFORMING A FOUR-WEEK ENDURANCE EXERCISE INTERVENTION. BLOOD SAMPLES (PRE-, POST-GXT AND POST-TRAINING) WERE USED FOR ISOLATION OF DNA/RNA OF NK CELLS TO ASSESS DNA PROMOTER METHYLATION BY TARGETED DEEP-AMPLICON SEQUENCING AND GENE EXPRESSION BY QRT-PCR. POTENTIAL CHANGES IN NK CELL SUBSETS WERE DETERMINED BY FLOW CYTOMETRY. ACUTE AND CHRONIC EXERCISE DID NOT PROVOKE SIGNIFICANT ALTERATIONS OF NK CELL PROPORTIONS. PROMOTER METHYLATION DECREASED AND GENE EXPRESSION INCREASED FOR KIR2DS4 AFTER ACUTE EXERCISE. A HIGH GENE EXPRESSION CORRELATED WITH A LOW METHYLATION OF CPGS THAT WERE ALTERED BY ACUTE EXERCISE. CHRONIC EXERCISE RESULTED IN A MINOR DECREASE OF DNA METHYLATION AND DID NOT ALTER GENE EXPRESSION. ACUTE EXERCISE PROVOKES EPIGENETIC MODIFICATIONS, AFFECTING THE BALANCE BETWEEN THE ACTIVATING KIR2DS4 AND THE INHIBITING KIR3DL1, WITH POTENTIAL BENEFITS ON NK CELL FUNCTION.	2019