1  830 132 CHARACTERIZATION OF STRESS RESPONSE INVOLVED IN CHICKEN MYOPATHY. MYOPATHIES (WOODY BREAST (WB) AND WHITE STRIPING (WS)) OF BROILER CHICKENS HAVE BEEN CORRELATED WITH FAST GROWTH. RECENT STUDIES REPORTED THAT LOCALIZED HYPOXIA AND METABOLIC IMPAIRMENT MAY INVOLVE IN THESE MYOPATHIES OF BIRDS. IN ORDER TO BETTER UNDERSTAND THE STRESS RESPONSE MECHANISMS AFFECTING MYOPATHIES OF BROILERS, THE AIM OF THIS STUDY WAS TO EXAMINE EFFECTS OF WB AND BOTH WB/WS ON STRESS HORMONE CORTICOSTERONE (CORT) LEVELS AND EXPRESSIONAL CHANGES OF STRESS RESPONSE GENES INCLUDING GLUCOCORTICOID (GC) RECEPTOR (GR), 11BETA-HYDROXYSTEROID DEHYDROGENASE TYPE 1 (11BETA-HSD1), DNA METHYLATION REGULATORS (DNMTS), AND ARGININE VASOTOCIN RECEPTOR 1A AND 1B (V1AR, V1BR). RESULTS OF RADIOIMMUNOASSAY SHOWED THAT CORT LEVELS OF WB AND WB/WS BIRDS WERE SIGNIFICANTLY HIGHER COMPARED TO CON (P < 0.05), HOWEVER, THE COMBINATION OF WB/WS WAS NOT SIGNIFICANTLY HIGHER THAN WB BIRDS, IMPLYING THAT THE EFFECTS OF WB AND WS ON CORT ARE NOT SYNERGISTIC. HEPATIC GR EXPRESSION OF BOTH WB AND WB/WS BIRDS WERE SIGNIFICANTLY HIGHER COMPARED TO CON (P < 0.05). HOWEVER, GR EXPRESSION LEVELS IN BREAST MUSCLE OF BOTH WB AND WB/WS BIRDS WERE DECREASED COMPARED TO CON (P < 0.05). HEPATIC 11BETA-HSD1 EXPRESSION WAS INCREASED ONLY IN WB/WS BIRDS COMPARED TO CON BIRDS WITH NO SIGNIFICANT DIFFERENCE BETWEEN CON AND WB BIRDS. 11BETA-HSD1 EXPRESSION WAS DECREASED AND INCREASED IN WB AND WB/WS BIRDS COMPARED TO CON, RESPECTIVELY, IN BREAST MUSCLE (P < 0.05). DNMT1 EXPRESSION WAS SIGNIFICANTLY DECREASED IN BOTH MUSCLE AND LIVER OF WB BIRDS, AND IN MUSCLE OF WB/WS BIRDS, BUT NOT IN LIVER OF WB/WS BIRDS, INDICATING DIFFERENTIAL EFFECTS OF WS ON THE EPIGENETICAL STRESS RESPONSE OF MUSCLE AND LIVER COMPARED TO WB. V1AR EXPRESSION WAS SIGNIFICANTLY INCREASED IN MUSCLE OF WB BIRDS, AND IN LIVER OF WB/WS BIRDS COMPARED TO CON BIRDS (P < 0.05). V1BR WAS NOT CHANGED IN MUSCLE AND LIVER OF WB BIRDS COMPARED TO CON BIRDS. TAKEN TOGETHER, RESULTS SUGGEST THAT GC-INDUCED MYOPATHIES OCCUR IN FAST-GROWING BROILER CHICKENS AND CIRCULATING CORT LEVEL MIGHT BE A SIGNIFICANT BIOCHEMICAL MARKER OF MYOPATHIES (WB AND WS) OF BIRDS. IN ADDITION, CHRONIC STRESS RESPONSES IN BREAST MUSCLE AND TISSUE-SPECIFIC EPIGENETIC CHANGES OF STRESS RESPONSE GENES BY DNMTS MAY PLAY A CRITICAL ROLE IN THE OCCURRENCE OF MYOPATHIES.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
2 5205  32 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 1846  39 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
4 4934  32 PATERNAL CHRONIC FOLATE SUPPLEMENTATION INDUCED THE TRANSGENERATIONAL INHERITANCE OF ACQUIRED DEVELOPMENTAL AND METABOLIC CHANGES IN CHICKENS. INCREASING EVIDENCE INDICATES THAT PATERNAL DIET CAN RESULT IN METABOLIC CHANGES IN OFFSPRING, BUT THE DEFINITE MECHANISM REMAINS UNCLEAR IN BIRDS. HERE, WE FED BREEDER COCKS FIVE DIFFERENT DIETS CONTAINING 0, 0.25, 1.25, 2.50 AND 5.00 MG KG(-1) FOLATE THROUGHOUT LIFE. PATERNAL FOLATE SUPPLEMENTATION (FS) WAS BENEFICIAL TO THE GROWTH AND ORGAN DEVELOPMENT OF BROILER OFFSPRING. MOST IMPORTANTLY, THE LIPID AND GLUCOSE METABOLISM OF BREEDER COCKS AND BROILER OFFSPRING WERE AFFECTED BY PATERNAL FS, ACCORDING TO BIOCHEMICAL AND METABOLOMIC ANALYSES. WE FURTHER EMPLOYED GLOBAL ANALYSES OF HEPATIC AND SPERMATOZOAL MESSENGER RNA (MRNA), LONG NON-CODING RNA (LNCRNA) AND MICRO RNA (MIRNA). SOME KEY GENES INVOLVED IN THE GLYCOLYSIS OR GLUCONEOGENESIS PATHWAY AND THE PPAR SIGNALLING PATHWAY, INCLUDING PEPCK, ANGPTL4 AND THRSP, WERE REGULATED BY DIFFERENTIALLY EXPRESSED HEPATIC AND SPERMATOZOAL MIRNAS AND LNCRNAS IN BREEDER COCKS AND BROILER OFFSPRING. MOREOVER, THE EXPRESSION OF ANGPTL4 COULD ALSO BE REGULATED BY DIFFERENTIALLY EXPRESSED MIRNAS AND LNCRNAS IN SPERMATOZOA VIA COMPETITIVE ENDOGENOUS RNA (CERNA) MECHANISMS. OVERALL, THIS MODEL SUGGESTS THAT PATERNAL FOLATE COULD TRANSGENERATIONALLY REGULATE LIPID AND GLUCOSE METABOLISM IN BROILER OFFSPRING AND THE EPIGENETIC TRANSMISSION MAY INVOLVE ALTERED SPERMATOZOAL MIRNAS AND LNCRNAS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
5 1504  32 DNA METHYLATION AND HISTONE DEACETYLATION REGULATING INSULIN SENSITIVITY DUE TO CHRONIC COLD EXPOSURE. IN THIS STUDY, WE INVESTIGATED THE CAUSAL RELATIONSHIP BETWEEN CHRONIC COLD EXPOSURE AND INSULIN RESISTANCE AND THE MECHANISMS OF HOW DNA METHYLATION AND HISTONE DEACETYLATION REGULATE COLD-REDUCED INSULIN RESISTANCE. 46 ADULT MALE MICE FROM POSTNATAL DAY 90-180 WERE RANDOMLY ASSIGNED TO CONTROL GROUP AND COLD-EXPOSURE GROUP. MICE IN COLD-EXPOSURE GROUP WERE PLACED AT TEMPERATURE FROM -1 TO 4 DEGREES C FOR 30 DAYS TO MIMIC CHRONIC COLD ENVIRONMENT. THEN, FASTING BLOOD GLUCOSE, BLOOD INSULIN LEVEL AND INSULIN RESISTANCE INDEX WERE MEASURED WITH ENZYMATIC METHODS. IMMUNOFLUORESCENT LABELING WAS CARRIED OUT TO VISUALIZE THE INSULIN RECEPTOR SUBSTRATE 2 (IRS2), OBESE RECEPTOR (OB-R, A LEPTIN RECEPTOR), VOLTAGE-DEPENDENT ANION CHANNEL PROTEIN 1 (VDAC1), CYTOCHROME C (CYTC), 5-METHYLCYTOSINE (5-MC) POSITIVE CELLS IN HIPPOCAMPAL CA1 AREA. FURTHERMORE, THE EXPRESSIONS OF SOME PROTEINS MENTIONED ABOVE WERE DETECTED WITH WESTERN BLOT. THE RESULTS SHOWED: 1 IN CIRCLE CHRONIC COLD EXPOSURE COULD REDUCE THE INSULIN RESISTANCE INDEX (P < 0.01) AND INCREASE THE NUMBER OF IRS2 POSITIVE CELLS AND OB-R POSITIVE CELLS IN HIPPOCAMPUS (P < 0.01). 2 IN CIRCLE THE EXPRESSIONS OF MITOCHONDRIAL ENERGY-RELATIVE PROTEINS, VDAC1 AND CYTC, WERE HIGHER IN COLD-EXPOSURE GROUP THAN IN CONTROL GROUP WITH BOTH IMMUNOHISTOCHEMICAL STAINING AND WESTERN BLOT (P < 0.01). 3 IN CIRCLE CHRONIC COLD EXPOSURE INCREASED DNA METHYLATION AND HISTONE DEACETYLATION IN THE PYRAMIDAL CELLS OF CA1 AREA AND LED TO AN INCREASE IN THE EXPRESSION OF HISTONE DEACETYLASE 1 (HDAC1) AND DNA METHYLATION RELATIVE ENZYMES (P < 0.01). IN CONCLUSION, CHRONIC COLD EXPOSURE CAN IMPROVE INSULIN SENSITIVITY, WITH THE INVOLVEMENT OF DNA METHYLATION, HISTONE DEACETYLATION AND THE REGULATION OF MITOCHONDRIAL ENERGY METABOLISM. THESE EPIGENETIC MODIFICATIONS PROBABLY FORM THE BASIC MECHANISM OF COLD-REDUCED INSULIN RESISTANCE.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
6 2714  36 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
7 1368  39 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	

8  316  35 ALCOHOL-ASSOCIATED FOLATE DISTURBANCES RESULT IN ALTERED METHYLATION OF FOLATE-REGULATING GENES. FOLATE PLAYS A CRITICAL ROLE IN MAINTAINING NORMAL METABOLIC, ENERGY, DIFFERENTIATION AND GROWTH STATUS OF ALL MAMMALIAN CELLS. THE STEADY-STATE ACCUMULATION OF FOLATE SEEMS TO DEPEND ON THE ACTIVITY OF TWO ENZYMES: FOLYLPOLYGLUTAMATE SYNTHETASE (FPGS), WHICH ADDS GLUTAMATE RESIDUES, AND GAMMA-GLUTAMYL HYDROLASE (GGH), WHICH REMOVES THEM, ENABLING IT TO BE TRANSPORTED ACROSS THE BIOLOGICAL MEMBRANES. OVEREXPRESSION OF GGH AND DOWNREGULATION OF FPGS WOULD BE EXPECTED TO DECREASE INTRACELLULAR FOLATE IN ITS POLYGLUTAMYLATED FORM, THEREBY INCREASING EFFLUX OF FOLATE AND ITS RELATED MOLECULES, WHICH MIGHT LEAD TO RESISTANCE TO DRUGS OR FOLATE DEFICIENCY. THE STUDY WAS SOUGHT TO DELINEATE THE ACTIVITY OF GGH AND EXPRESSION FPGS IN TISSUES INVOLVED IN FOLATE HOMEOSTASIS DURING ALCOHOLISM AND THE EPIGENETIC REGULATION OF THESE ENZYMES AND TRANSPORTERS REGULATING INTRACELLULAR FOLATE LEVELS. WE DETERMINED THE ACTIVITY OF GGH AND EXPRESSION OF FPGS IN TISSUES AFTER 3 MONTHS OF ETHANOL FEEDING TO RATS AT 1 G/KG BODY WEIGHT/DAY. THE RESULTS SHOWED THAT THERE WAS NOT ANY SIGNIFICANT CHANGE IN THE ACTIVITY OF FOLATE HYDROLYZING ENZYME GGH IN ETHANOL-FED RATS WHILE THERE WAS SIGNIFICANT DOWN REGULATION IN THE EXPRESSION OF FPGS. ETHANOL FEEDING DECREASED THE TOTAL AS WELL AS POLYGLUTAMATED FOLATE LEVELS. THERE WAS TISSUE-SPECIFIC HYPER/HYPO METHYLATION OF FOLATE TRANSPORTER GENES VIZ. PCFT AND RFC BY CHRONIC ETHANOL FEEDING. MOREOVER, HYPERMETHYLATION OF FPGS GENE WAS OBSERVED IN INTESTINE AND KIDNEY WITHOUT ANY CHANGE IN METHYLATION LEVELS OF GGH IN THE ETHANOL-FED RATS. IN CONCLUSION, THE INITIAL DECONJUGATION OF POLYGLUTAMYLATED FOLATE BY GGH WAS NOT IMPAIRED IN ETHANOL-FED RATS WHILE THE CONVERSION OF MONOGLUTAMYLATED FOLATE TO POLYGLUTAMYLATED FORM MIGHT BE IMPAIRED. THERE WAS TISSUE-SPECIFIC ALTERED METHYLATION OF FOLATE TRANSPORTER GENES BY CHRONIC ETHANOL FEEDING.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
9 5652  33 SEX DIMORPHIC CHANGES IN TRH GENE METHYLATION AND THYROID-AXIS RESPONSE TO ENERGY DEMANDS IN MATERNALLY SEPARATED RATS. THE HYPOTHALAMUS-PITUITARY-THYROID (HPT) AXIS REGULATES ENERGY BALANCE THROUGH THE PLEIOTROPIC ACTION OF THYROID HORMONES. HPT BASAL ACTIVITY AND STIMULATION BY COLD OR VOLUNTARY EXERCISE ARE REPRESSED BY PREVIOUS CHRONIC STRESS IN ADULTS. MATERNAL SEPARATION (MS) MODIFIES HPT BASAL ACTIVITY; WE THUS STUDIED THE RESPONSE OF THE AXIS TO ENERGY DEMANDS AND ANALYZED POSSIBLE EPIGENETIC CHANGES ON TRH PROMOTER. NONHANDLED (NH) OR MS MALE WISTAR RATS WERE COLD EXPOSED 1 H AT ADULTHOOD; TRH EXPRESSION IN THE HYPOTHALAMIC PARAVENTRICULAR NUCLEUS (PVN) AND SERUM THYROTROPIN (TSH) CONCENTRATION WERE INCREASED ONLY IN NH RATS. TWO WEEKS OF VOLUNTARY EXERCISE DECREASED FAT MASS AND INCREASED TRH EXPRESSION, AND THYROID HORMONES CONCENTRATION CHANGED PROPORTIONALLY TO RUNNING DISTANCE IN NH MALE RATS AND MS MALE RATS. ALTHOUGH NH FEMALES RAN MORE THAN MS AND MUCH MORE THAN MALES, EXERCISE DECREASED BODY WEIGHT AND FAT MASS ONLY IN NH RATS WITH NO CHANGE ON ANY PARAMETER OF THE HPT AXIS BUT INCREASED POMC EXPRESSION IN ARCUATE-NUCLEUS OF NH AND NPY IN MS FEMALES. OVERALL, THE METHYLATION PATTERN OF PVN TRH GENE PROMOTER WAS SIMILAR IN NH MALES AND FEMALES; MS MODIFIED METHYLATION OF SPECIFIC CPG SITES, A THYROID HORMONE RECEPTOR (THR)-BINDING SITE PRESENT AFTER THE INITIATION SITE WAS HYPOMETHYLATED IN MS MALES; IN MS FEMALES, THE THR BINDING SITE OF THE PROXIMAL PROMOTER (SITE 4) AND 2 SITES IN THE FIRST INTRON WERE HYPERMETHYLATED. OUR STUDIES SHOWED THAT, IN A SEX-DIMORPHIC MANNER, MS BLUNTED THE RESPONSES OF HPT AXIS TO ENERGY DEMANDS IN ADULT ANIMALS AND CAUSED METHYLATION CHANGES ON TRH PROMOTER THAT COULD ALTER T3 FEEDBACK.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
10 3813  27 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
11 1429  36 DIFFERENTIAL EXPRESSION OF MICRORNAS IN THE HIPPOCAMPI OF MALE AND FEMALE RODENTS AFTER CHRONIC ALCOHOL ADMINISTRATION. BACKGROUND: WOMEN ARE MORE VULNERABLE THAN MEN TO THE NEUROTOXICITY AND SEVERE BRAIN DAMAGE CAUSED BY CHRONIC HEAVY ALCOHOL USE. IN ADDITION, BRAIN DAMAGE DUE TO CHRONIC HEAVY ALCOHOL USE MAY BE ASSOCIATED WITH SEX-DEPENDENT EPIGENETIC MODIFICATIONS. THIS STUDY AIMED TO IDENTIFY MICRORNAS (MIRNAS) AND THEIR TARGET GENES THAT ARE DIFFERENTIALLY EXPRESSED IN THE HIPPOCAMPI OF MALE AND FEMALE ANIMAL MODELS IN RESPONSE TO ALCOHOL. METHODS: AFTER CHRONIC ALCOHOL ADMINISTRATION (3~3.5 G/KG/DAY) IN MALE (CONTROL, N = 10; ALCOHOL, N = 12) OR FEMALE (CONTROL, N = 10; ALCOHOL, N = 12) SPRAGUE-DAWLEY RATS FOR 6 WEEKS, WE MEASURED BODY WEIGHTS AND DOUBLECORTIN (DCX; A NEUROGENESIS MARKER) CONCENTRATIONS AND ANALYZED UP- OR DOWNREGULATED MIRNAS USING GENECHIP MIRNA 4.0 ARRAYS. THE DIFFERENTIALLY EXPRESSED MIRNAS AND THEIR PUTATIVE TARGET GENES WERE VALIDATED BY RT-QPCR. RESULTS: ALCOHOL ATTENUATED BODY WEIGHT GAIN ONLY IN THE MALE GROUP. ON THE OTHER HAND, ALCOHOL LED TO INCREASED SERUM AST IN FEMALE RATS AND DECREASED SERUM TOTAL CHOLESTEROL CONCENTRATIONS IN MALE RATS. THE EXPRESSION OF DCX WAS SIGNIFICANTLY REDUCED IN THE HIPPOCAMPI OF MALE ALCOHOL-TREATED RATS. NINE MIRNAS WERE SIGNIFICANTLY UP- OR DOWNREGULATED IN MALE ALCOHOL-TREATED RATS, INCLUDING UPREGULATION OF MIR-125A-3P, LET-7A-5P, AND MIR-3541, AND DOWNREGULATION OF THEIR TARGET GENES (PRDM5, SUV39H1, PTPRZ1, MAPK9, ING4, WT1, NKX3-1, DAB2IP, RNF152, RIPK1, LIN28A, APBB3, NRAS, AND ACVR1C). ON THE OTHER HAND, 7 MIRNAS WERE SIGNIFICANTLY UP- OR DOWNREGULATED IN ALCOHOL-TREATED FEMALE RATS, INCLUDING DOWNREGULATION OF MIR-881-3P AND MIR-504 AND UPREGULATION OF THEIR TARGET GENES (NAA50, CLOCK, CBFB, ARIH1, UBE2G1, AND GNG7). CONCLUSIONS: THESE RESULTS SUGGEST THAT CHRONIC HEAVY ALCOHOL USE PRODUCES SEX-DEPENDENT EFFECTS ON NEUROGENESIS AND MIRNA EXPRESSION IN THE HIPPOCAMPUS AND THAT SEX DIFFERENCES SHOULD BE CONSIDERED WHEN DEVELOPING MIRNA BIOMARKERS TO DIAGNOSE OR TREAT ALCOHOLICS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
12 3432  34 HYDROGEN SULFIDE BIOSYNTHESIS IS IMPAIRED IN THE OSTEOARTHRITIC JOINT. OSTEOARTHRITIS (OA) IS THE MOST COMMON FORM OF ARTHRITIS AND IT IS A LEADING CAUSE OF DISABILITY IN THE ELDERLY. ITS COMPLETE ETIOLOGY IS NOT KNOWN ALTHOUGH THERE ARE SEVERAL METABOLIC, GENETIC, EPIGENETIC, AND LOCAL CONTRIBUTING FACTORS INVOLVED. AT THE MOMENT, THERE IS NO CURE FOR THIS PATHOLOGY AND TREATMENT ALTERNATIVES TO RETARD OR STOP ITS PROGRESSION ARE INTENSIVELY BEING SOUGHT. HYDROGEN SULFIDE (H(2)S) IS A SMALL GASEOUS MOLECULE AND IS PRESENT IN SULFUROUS MINERAL WATERS AS ITS ACTIVE COMPONENT. DATA FROM RECENT CLINICAL TRIALS SHOWS THAT BALNEOTHERAPY (IMMERSION IN MINERAL AND/OR THERMAL WATERS FROM NATURAL SPRINGS) IN SULFUROUS WATERS CAN IMPROVE OA SYMPTOMS, IN PARTICULAR, PAIN AND FUNCTION. YET, THE UNDERLYING MECHANISMS ARE POORLY KNOWN. HYDROGEN SULFIDE IS ALSO CONSIDERED, WITH NO AND CO, AN ENDOGENOUS SIGNALING GASOTRANSMITTER. IT IS SYNTHESIZED ENDOGENOUSLY WITH THE HELP OF THREE ENZYMES, CYSTATHIONINE GAMMA-LYASE (CTH), CYSTATHIONINE BETA-SYNTHASE (CBS), AND 3-MERCAPTOPYRUVATE SULFURTRANSFERASE (3-MPST). HERE, THE EXPRESSION OF THESE THREE ENZYMES WAS DEMONSTRATED BY QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION (QRT-PCR) AND THEIR PROTEIN ABUNDANCE [BY IMMUNOHISTOCHEMISTRY AND WESTERN BLOT (WB)] IN HUMAN ARTICULAR CARTILAGE. NO SIGNIFICANT DIFFERENCES WERE FOUND IN CBS OR CTH EXPRESSION OR ABUNDANCE, BUT MRNA AND PROTEIN LEVELS OF 3-MPST WERE SIGNIFICANTLY REDUCED IN CARTILAGE FORM OA DONORS. ALSO, THE BIOSYNTHESIS OF H(2)S FROM OA CARTILAGE, MEASURED WITH A SPECIFIC MICROELECTRODE, WAS SIGNIFICANTLY LOWER THAN IN OA-FREE TISSUE. YET, NO DIFFERENCES WERE FOUND IN H(2)S CONCENTRATION IN SERUM FROM OA PATIENTS AND OA-FREE DONORS. THE CURRENT RESULTS SUGGEST THAT REDUCED LEVELS OF THE MITOCHONDRIAL ENZYME 3-MPST IN OA CARTILAGE MIGHT BE, AT LEAST IN PART, RESPONSIBLE FOR A REDUCTION IN H(2)S BIOSYNTHESIS IN THIS TISSUE AND THAT IMPAIRED H(2)S BIOSYNTHESIS IN THE JOINT MIGHT BE A CONTRIBUTING FACTOR TO OA. THIS COULD CONTRIBUTE TO EXPLAIN WHY EXOGENOUS SUPPLEMENTATION OF H(2)S, FOR INSTANCE WITH SULFUROUS THERMAL WATER, HAS POSITIVE EFFECTS IN OA PATIENTS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
13 2032  33 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
14  217  31 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
15  433  35 ANTIDEPRESSANT TREATMENT IS ASSOCIATED WITH EPIGENETIC ALTERATIONS OF HOMER1 PROMOTER IN A MOUSE MODEL OF CHRONIC DEPRESSION. BACKGROUND: UNDERSTANDING THE NEUROBIOLOGY OF DEPRESSION AND THE MECHANISM OF ACTION OF THERAPEUTIC MEASURES IS CURRENTLY A RESEARCH PRIORITY. WE HAVE SHOWN THAT THE EXPRESSION OF THE SYNAPTIC PROTEIN HOMER1A CORRELATES WITH DEPRESSION-LIKE BEHAVIOR AND ITS INDUCTION IS A COMMON MECHANISM OF ACTION OF DIFFERENT ANTIDEPRESSANT TREATMENTS. HOWEVER, THE MECHANISM OF HOMER1A REGULATION IS STILL UNKNOWN. METHODS: WE COMBINED THE CHRONIC DESPAIR MOUSE MODEL (CDM) OF CHRONIC DEPRESSION WITH DIFFERENT ANTIDEPRESSANT TREATMENTS. DEPRESSION-LIKE BEHAVIOR WAS CHARACTERIZED BY FORCED SWIM AND TAIL SUSPENSION TESTS, AND VIA AUTOMATIC MEASUREMENT OF SUCROSE PREFERENCE IN INTELLICAGE. THE HOMER1 MRNA EXPRESSION AND PROMOTER DNA METHYLATION WERE ANALYZED IN CORTEX AND PERIPHERAL BLOOD BY QRT-PCR AND PYROSEQUENCING. RESULTS: CDM MICE SHOW DECREASED HOMER1A AND HOMER1B/C MRNA EXPRESSION IN CORTEX AND BLOOD SAMPLES, WHILE CHRONIC TREATMENT WITH IMIPRAMINE AND FLUOXETINE OR ACUTE KETAMINE APPLICATION INCREASES THEIR LEVEL ONLY IN THE CORTEX. THE QUANTITATIVE ANALYSES OF THE METHYLATION OF 7 CPG SITES, LOCATED ON THE HOMER1 PROMOTER REGION CONTAINING SEVERAL CRE BINDING SITES, SHOW A SIGNIFICANT INCREASE IN DNA METHYLATION IN THE CORTEX OF CDM MICE. IN CONTRAST, ANTIDEPRESSANT TREATMENTS REDUCE THE METHYLATION LEVEL. LIMITATIONS: HOMER1 EXPRESSION AND PROMOTOR METHYLATION WERE NOT ANALYZED IN DIFFERENT BLOOD CELL TYPES. OTHER CPG SITES OF HOMER1 PROMOTER SHOULD BE INVESTIGATED IN FUTURE STUDIES. OUR EXPERIMENTAL APPROACH DOES NOT DISTINGUISH BETWEEN METHYLATION AND HYDROXYMETHYLATION. CONCLUSIONS: WE DEMONSTRATE THAT STRESS-INDUCED DEPRESSION-LIKE BEHAVIOR AND ANTIDEPRESSANT TREATMENTS ARE ASSOCIATED WITH EPIGENETIC ALTERATIONS OF HOMER1 PROMOTER, PROVIDING NEW INSIGHTS INTO THE MECHANISM OF ANTIDEPRESSANT TREATMENT.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
16 3206  37 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
17 1328  43 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
18 1182  36 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
19 2967  34 GENETIC AND EPIGENETIC REGULATION OF CATECHOL-O-METHYLTRANSFERASE IN RELATION TO INFLAMMATION IN CHRONIC FATIGUE SYNDROME AND FIBROMYALGIA. BACKGROUND: CATECHOL-O-METHYLTRANSFERASE (COMT) HAS BEEN SHOWN TO INFLUENCE CLINICAL PAIN, DESCENDING MODULATION, AND EXERCISE-INDUCED SYMPTOM WORSENING. COMT REGULATES NOCICEPTIVE PROCESSING AND INFLAMMATION, KEY PATHOPHYSIOLOGICAL FEATURES OF CHRONIC FATIGUE SYNDROME AND FIBROMYALGIA (CFS/FM). WE AIMED TO DETERMINE THE INTERACTIONS BETWEEN GENETIC AND EPIGENETIC MECHANISMS REGULATING COMT AND ITS INFLUENCE ON INFLAMMATORY MARKERS AND SYMPTOMS IN PATIENTS WITH CFS/FM. METHODS: A CASE-CONTROL STUDY WITH REPEATED-MEASURES DESIGN WAS USED TO REDUCE THE CHANCE OF FALSE POSITIVE AND INCREASE THE POWER OF OUR FINDINGS. FIFTY-FOUR PARTICIPANTS (28 PATIENTS WITH CFS/FM AND 26 CONTROLS) WERE ASSESSED TWICE WITHIN 4 DAYS. THE ASSESSMENT INCLUDED CLINICAL QUESTIONNAIRES, NEUROPHYSIOLOGICAL ASSESSMENT (PAIN THRESHOLDS, TEMPORAL SUMMATION, AND CONDITIONED PAIN MODULATION), AND BLOOD WITHDRAWAL IN ORDER TO ASSESS RS4818, RS4633, AND RS4680 COMT POLYMORPHISMS AND PERFORM HAPLOTYPE ESTIMATION, DNA METHYLATION IN THE COMT GENE (BOTH MB-COMT AND S-COMT PROMOTERS), AND CYTOKINE EXPRESSION (TNF-ALPHA, IFN-GAMMA, IL-6, AND TGF-BETA). RESULTS: COMT HAPLOTYPES WERE ASSOCIATED WITH DNA METHYLATION IN THE S-COMT PROMOTER, TGF-BETA EXPRESSION, AND SYMPTOMS. HOWEVER, THIS WAS NOT SPECIFIC FOR ONE CONDITION. SIGNIFICANT BETWEEN-GROUP DIFFERENCES WERE FOUND FOR INCREASED DNA METHYLATION IN THE MB-COMT PROMOTER AND DECREASED IFN-GAMMA EXPRESSION IN PATIENTS. DISCUSSION: OUR RESULTS ARE CONSISTENT WITH BASIC AND CLINICAL RESEARCH, PROVIDING INTERESTING INSIGHTS INTO GENETIC-EPIGENETIC REGULATORY MECHANISMS. MB-COMT DNA METHYLATION MIGHT BE AN INDEPENDENT FACTOR CONTRIBUTING TO THE PATHOPHYSIOLOGY OF CFS/FM. FURTHER RESEARCH ON DNA METHYLATION IN COMPLEX CONDITIONS SUCH AS CFS/FM IS WARRANTED. WE RECOMMEND FUTURE RESEARCH TO EMPLOY A REPEATED-MEASURE DESIGN TO CONTROL FOR BIOMARKERS VARIABILITY AND WITHIN-SUBJECT CHANGES.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
20 3991  32 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