1   673 126 BRAHMA-RELATED GENE 1 (BRG1) EPIGENETICALLY REGULATES CAM ACTIVATION DURING HYPOXIC PULMONARY HYPERTENSION. AIMS: ESTABLISHMENT OF AN INFLAMMATORY MILIEU FOLLOWING ELEVATED LEUKOCYTE ADHESION TO THE VASCULAR ENDOTHELIUM, WHICH IS MEDIATED BY TRANSCRIPTIONAL ACTIVATION OF CELL ADHESION MOLECULES (CAMS), CONTRIBUTES TO THE PATHOGENESIS OF CHRONIC HYPOXIA-INDUCED PULMONARY HYPERTENSION (HPH). THE EPIGENETIC SWITCH THAT DICTATES CAM TRANSACTIVATION IN RESPONSE TO HYPOXIA IN ENDOTHELIAL CELLS LEADING UP TO HPH IS NOT FULLY APPRECIATED. METHODS AND RESULTS: WE REPORT HERE THAT BRAHMA-RELATED GENE 1 (BRG1) AND BRAHMA (BRM), TWO CATALYTIC COMPONENTS OF THE MAMMALIAN CHROMATIN REMODELLING COMPLEX, WERE INDUCED IN CULTURED ENDOTHELIAL CELLS CHALLENGED WITH HYPOXIA IN VITRO AS WELL AS IN PULMONARY ARTERIES IN AN ANIMAL MODEL OF HPH. OVER-EXPRESSION OF BRG1/BRM ENHANCED, WHILE THE DEPLETION OF BRG1/BRM ATTENUATED, CAM TRANSACTIVATION AND ADHESION OF LEUKOCYTES. ENDOTHELIAL-SPECIFIC DELETION OF BRG1/BRM AMELIORATED VASCULAR INFLAMMATION AND HPH IN MICE. CHROMATIN IMMUNOPRECIPITATION (CHIP) AND RE-CHIP ASSAYS REVEALED THAT HYPOXIA UP-REGULATED THE OCCUPANCIES OF BRG1 AND BRM ON CAM PROMOTERS IN A NUCLEAR FACTOR KAPPAB (NF-KAPPAB) -DEPENDENT MANNER. FINALLY, BRG1 AND BRM ACTIVATED CAM TRANSCRIPTION BY ALTERING THE CHROMATIN STRUCTURE SURROUNDING THE CAM PROMOTERS. CONCLUSION: OUR DATA SUGGEST THAT BRG1 PROVIDES THE CRUCIAL EPIGENETIC LINK TO HYPOXIA-INDUCED CAM INDUCTION AND LEUKOCYTE ADHESION THAT ENGENDERS ENDOTHELIAL MALFUNCTION AND PATHOGENESIS OF HPH. AS SUCH, TARGETING BRG1 IN ENDOTHELIAL CELLS MAY YIELD PROMISING STRATEGIES IN THE INTERVENTION AND/OR PREVENTION OF HPH.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
2  4171  64 MEGAKARYOCYTIC LEUKEMIA 1 DIRECTS A HISTONE H3 LYSINE 4 METHYLTRANSFERASE COMPLEX TO REGULATE HYPOXIC PULMONARY HYPERTENSION. ENHANCED INTERACTION BETWEEN VASCULAR ENDOTHELIAL CELLS AND CIRCULATING LEUKOCYTES, AS A RESULT OF TRANSCRIPTIONAL ACTIVATION OF CELL ADHESION MOLECULES (CAM), HELPS ESTABLISH A PROINFLAMMATORY MILIEU CONTRIBUTING TO THE PATHOGENESIS OF CHRONIC HYPOXIA-INDUCED PULMONARY HYPERTENSION. THE MOLECULAR SWITCH THAT DICTATES CAM TRANSACTIVATION IS NOT CLEARLY DEFINED. OUR GOAL WAS TO DETERMINE THE INVOLVEMENT OF THE TRANSCRIPTIONAL MODULATOR MEGAKARYOCYTIC LEUKEMIA 1 (MKL1), ALSO KNOWN AS MYOCARDIN-RELATED TRANSCRIPTION FACTOR A (MRTF-A), IN CAM TRANSACTIVATION AND THE UNDERLYING MECHANISM. WE REPORT HERE THAT COMPARED WITH WILD-TYPE LITTERMATES, MKL1/MRTF-A KNOCKOUT MICE WERE MORE RESISTANT TO THE DEVELOPMENT OF HYPOXIA-INDUCED PULMONARY HYPERTENSION WHEN EXPOSED TO LOW OXYGEN PRESSURE. NOTABLY, CAM INDUCTION IN KNOCKOUT MICE WAS SIGNIFICANTLY ATTENUATED WITH A CONCOMITANT REDUCTION OF LEUKOCYTE ADHESION. IN CULTURED VASCULAR ENDOTHELIAL CELLS, OVEREXPRESSION OF MKL1/MRTF-A ENHANCED, WHEREAS DEPLETION OF MKL1/MRTF-A DAMPENED, HYPOXIA-INDUCED CAM TRANSACTIVATION. IN RESPONSE TO HYPOXIA, MKL1/MRTF-A FORMED A COMPLEX WITH NF-KAPPAB ON THE CAM PROMOTERS. OF INTEREST, MKL1/MRTF-A WAS RESPONSIBLE FOR RECRUITING A HISTONE H3 LYSINE 4 METHYLTRANSFERASE COMPLEX TO THE CAM PROMOTERS. FINALLY, ENDOTHELIAL-SPECIFIC SILENCING OF ASH2 AND WDR5, 2 KEY COMPONENTS OF THE HISTONE H3 LYSINE 4 METHYLTRANSFERASE COMPLEX, AMELIORATED HYPOXIA-INDUCED PULMONARY HYPERTENSION IN MICE. IN CONCLUSION, OUR DATA SUGGEST THAT MKL1/MRTF-A, BY COORDINATING KEY EPIGENETIC ALTERATIONS ON CAM PROMOTERS, PROVIDES A CRITICAL LINK TO HYPOXIA-INDUCED ENDOTHELIAL MALFUNCTION AND CONTRIBUTES TO THE PATHOGENESIS OF HYPOXIA-INDUCED PULMONARY HYPERTENSION.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
3  4000  38 LOSS OF HISTONE H3 K79 METHYLTRANSFERASE DOT1L FACILITATES KIDNEY FIBROSIS BY UPREGULATING ENDOTHELIN 1 THROUGH HISTONE DEACETYLASE 2. BACKGROUND: THE PROGRESSION RATE OF CKD VARIES SUBSTANTIALLY AMONG PATIENTS. THE GENETIC AND EPIGENETIC CONTRIBUTIONS THAT MODIFY HOW INDIVIDUAL PATIENTS RESPOND TO KIDNEY INJURY ARE LARGELY UNKNOWN. EMERGING EVIDENCE HAS SUGGESTED THAT HISTONE H3 K79 METHYLTRANSFERASE DOT1L HAS AN ANTIFIBROTIC EFFECT BY REPRESSING EDN1, WHICH ENCODES ENDOTHELIN 1 IN THE CONNECTING TUBULE/COLLECTING DUCT. METHODS: TO DETERMINE IF DELETION OF THE DOT1L GENE IS A GENETIC AND EPIGENETIC RISK FACTOR THROUGH REGULATING EDN1, WE STUDIED FOUR GROUPS OF MICE: WILD-TYPE MICE, CONNECTING TUBULE/COLLECTING DUCT-SPECIFIC DOT1L CONDITIONAL KNOCKOUT MICE (DOT1L(AC) ), DOT1L AND EDN1 DOUBLE-KNOCKOUT MICE (DE(AC) ), AND EDN1 CONNECTING TUBULE/COLLECTING DUCT-SPECIFIC CONDITIONAL KNOCKOUT MICE (EDN1(AC) ), UNDER THREE EXPERIMENTAL CONDITIONS (STREPTOZOTOCIN-INDUCED DIABETES, DURING NORMAL AGING, AND AFTER UNILATERAL URETERAL OBSTRUCTION). WE USED SEVERAL APPROACHES (COLOCALIZATION, GLUTATHIONE S-TRANSFERASE PULLDOWN, COIMMUNOPRECIPITATION, YEAST TWO-HYBRID, GEL SHIFT, AND CHROMATIN IMMUNOPRECIPITATION ASSAYS) TO IDENTIFY AND CONFIRM INTERACTION OF DOT1A (THE MAJOR DOT1L SPLICING VARIANT IN THE MOUSE KIDNEY) WITH HISTONE DEACETYLASE 2 (HDAC2), AS WELL AS THE FUNCTION OF THE DOT1A-HDAC2 COMPLEX IN REGULATING EDN1 TRANSCRIPTION. RESULTS: IN EACH CASE, DOT1L(AC) MICE DEVELOPED MORE PRONOUNCED KIDNEY FIBROSIS AND KIDNEY MALFUNCTION COMPARED WITH WILD-TYPE MICE. THESE DOT1L(AC) PHENOTYPES WERE AMELIORATED IN THE DOUBLE-KNOCKOUT DE(AC) MICE. THE INTERACTION BETWEEN DOT1A AND HDAC2 PREVENTS THE DOT1A-HDAC2 COMPLEX FROM ASSOCIATION WITH DNA, PROVIDING A COUNTERBALANCING MECHANISM GOVERNING EDN1 TRANSCRIPTION BY MODULATING H3 K79 DIMETHYLATION AND H3 ACETYLATION AT THE EDN1 PROMOTER. CONCLUSIONS: OUR STUDY CONFIRMS DOT1L TO BE A GENETIC AND EPIGENETIC MODIFIER OF KIDNEY FIBROSIS, REVEALS A NEW MECHANISM REGULATING EDN1 TRANSCRIPTION BY DOT1A AND HDAC2, AND REINFORCES ENDOTHELIN 1 AS A THERAPEUTIC TARGET OF KIDNEY FIBROSIS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                            
4  1690  35 DUAL ROLES OF CHROMATIN REMODELING PROTEIN BRG1 IN ANGIOTENSIN II-INDUCED ENDOTHELIAL-MESENCHYMAL TRANSITION. ENDOTHELIAL-MESENCHYMAL TRANSITION (ENDMT) IS CONSIDERED ONE OF THE PROCESSES UNDERLYING TISSUE FIBROSIS BY CONTRIBUTING TO THE POOL OF MYOFIBROBLASTS. IN THE PRESENT STUDY, WE INVESTIGATED THE EPIGENETIC MECHANISM WHEREBY ANGIOTENSIN II (ANG II) REGULATES ENDMT TO PROMOTE CARDIAC FIBROSIS FOCUSING ON THE ROLE OF CHROMATIN REMODELING PROTEIN BRG1. BRG1 KNOCKDOWN OR INHIBITION ATTENUATED ANG II-INDUCED ENDMT, AS EVIDENCED BY DOWN-REGULATION OF CDH5, AN ENDOTHELIAL MARKER, AND UP-REGULATION OF COL1A2, A MESENCHYMAL MARKER, IN CULTURED VASCULAR ENDOTHELIAL CELLS. ON THE ONE HAND, BRG1 INTERACTED WITH AND WAS RECRUITED BY SP1 TO THE SNAI2 (ENCODING SLUG) PROMOTER TO ACTIVATE SNAI2 TRANSCRIPTION IN RESPONSE TO ANG II STIMULATION. ONCE ACTIVATED, SLUG BOUND TO THE CDH5 PROMOTER TO REPRESS CDH5 TRANSCRIPTION. ON THE OTHER HAND, BRG1 INTERACTED WITH AND WAS RECRUITED BY SRF TO THE COL1A2 PROMOTER TO ACTIVATE COL1A2 TRANSCRIPTION. MECHANISTICALLY, BRG1 EVICTED HISTONES FROM THE TARGET PROMOTERS TO FACILITATE THE BINDINGS OF SP1 AND SRF. FINALLY, ENDOTHELIAL CONDITIONAL BRG1 KNOCKOUT MICE (CKO) EXHIBITED A REDUCTION IN CARDIAC FIBROSIS, COMPARED TO THE WILD TYPE (WT) LITTERMATES, IN RESPONSE TO CHRONIC ANG II INFUSION. IN CONCLUSION, OUR DATA DEMONSTRATE THAT BRG1 IS A KEY TRANSCRIPTIONAL COORDINATOR PROGRAMMING ANG II-INDUCED ENDMT TO CONTRIBUTE TO CARDIAC FIBROSIS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
5  4506  33 MRTF-A MEDIATES LPS-INDUCED PRO-INFLAMMATORY TRANSCRIPTION BY INTERACTING WITH THE COMPASS COMPLEX. CHRONIC INFLAMMATION UNDERSCORES THE PATHOGENESIS OF A RANGE OF HUMAN DISEASES. LIPOPOLYSACCHARIDE (LPS) ELICITS STRONG PRO-INFLAMMATORY RESPONSES IN MACROPHAGES THROUGH THE TRANSCRIPTION FACTOR NF-KAPPAB. THE EPIGENETIC MECHANISM UNDERLYING LPS-INDUCED PRO-INFLAMMATORY TRANSCRIPTION IS NOT FULLY UNDERSTOOD. HEREIN, WE DESCRIBE A ROLE FOR MYOCARDIN-RELATED TRANSCRIPTION FACTOR A (MRTF-A, ALSO KNOWN AS MKL1) IN THIS PROCESS. MRTF-A OVEREXPRESSION ENHANCED NF-KAPPAB-DEPENDENT PRO-INFLAMMATORY TRANSCRIPTION, WHEREAS MRTF-A SILENCING INHIBITED THIS PROCESS. MRTF-A DEFICIENCY ALSO REDUCED THE SYNTHESIS OF PRO-INFLAMMATORY MEDIATORS IN A MOUSE MODEL OF COLITIS. LPS PROMOTED THE RECRUITMENT OF MRTF-A TO THE PROMOTERS OF PRO-INFLAMMATORY GENES IN AN NF-KAPPAB-DEPENDENT MANNER. RECIPROCALLY, MRTF-A INFLUENCED THE NUCLEAR ENRICHMENT AND TARGET BINDING OF NF-KAPPAB. MECHANISTICALLY, MRTF-A WAS NECESSARY FOR THE ACCUMULATION OF ACTIVE HISTONE MODIFICATIONS ON NF-KAPPAB TARGET PROMOTERS BY COMMUNICATING WITH THE HISTONE H3K4 METHYLTRANSFERASE COMPLEX (COMPASS). SILENCING OF INDIVIDUAL MEMBERS OF COMPASS, INCLUDING ASH2, WDR5 AND SET1 (ALSO KNOWN AS SETD1A), DOWNREGULATED THE PRODUCTION OF PRO-INFLAMMATORY MEDIATORS AND IMPAIRED THE NF-KAPPAB KINETICS. IN SUMMARY, OUR WORK HAS UNCOVERED A PREVIOUSLY UNKNOWN FUNCTION FOR MRTF-A AND PROVIDED INSIGHTS INTO THE RATIONALIZED DEVELOPMENT OF ANTI-INFLAMMATORY THERAPEUTIC STRATEGIES.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
6    63  22 A HIGH METHYLATION LEVEL OF A NOVEL -284 BP CPG ISLAND IN THE RAMP1 GENE PROMOTER IS POTENTIALLY ASSOCIATED WITH MIGRAINE IN WOMEN. MIGRAINE IS A COMPLEX NEUROVASCULAR DISORDER AFFECTING ONE BILLION PEOPLE WORLDWIDE, MAINLY FEMALES. IT IS CHARACTERIZED BY ATTACKS OF MODERATE TO SEVERE HEADACHE PAIN, WITH ASSOCIATED SYMPTOMS. RECEPTOR ACTIVITY MODIFYING PROTEIN (RAMP1) IS PART OF THE CALCITONIN GENE-RELATED PEPTIDE (CGRP) RECEPTOR, A PHARMACOLOGICAL TARGET FOR MIGRAINE. EPIGENETIC PROCESSES, SUCH AS DNA METHYLATION, PLAY A ROLE IN CLINICAL PRESENTATION OF VARIOUS DISEASES. DNA METHYLATION OCCURS MOSTLY IN THE GENE PROMOTER AND CAN CONTROL GENE EXPRESSION. WE INVESTIGATED THE METHYLATION STATE OF THE RAMP1 PROMOTER IN 104 FEMALE BLOOD DNA SAMPLES: 54 MIGRAINEURS AND 50 CONTROLS. WE TREATED DNA WITH SODIUM BISULFITE AND PERFORMED PCR, SANGER SEQUENCING, AND EPIGENETIC SEQUENCING METHYLATION (ESME) SOFTWARE ANALYSIS. WE IDENTIFIED 51 CPG DINUCLEOTIDES, AND 5 SHOWED METHYLATION VARIABILITY. MIGRAINEURS HAD A HIGHER NUMBER OF INDIVIDUALS WITH ALL FIVE CPG METHYLATED WHEN COMPARED TO CONTROLS (26% VS. 16%), ALTHOUGH NON-SIGNIFICANT (P = 0.216). WE ALSO FOUND THAT CPG -284 BP, RELATED TO THE TRANSCRIPTION START SITE (TSS), SHOWED HIGHER METHYLATION LEVELS IN CASES (P = 0.011). THIS CPG MAY POTENTIALLY PLAY A ROLE IN MIGRAINE, AFFECTING RAMP1 TRANSCRIPTION OR RECEPTOR MALFUNCTIONING AND/OR ALTERED CGRP BINDING. WE HOPE TO CONFIRM THIS FINDING IN A LARGER COHORT AND ESTABLISH AN EPIGENETIC BIOMARKER TO PREDICT FEMALE MIGRAINE RISK.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
7  2071  28 EPIGENETIC CONTROL OF THE E-CADHERIN GENE (CDH1) BY CPG METHYLATION IN COLECTOMY SAMPLES OF PATIENTS WITH ULCERATIVE COLITIS. E-CADHERIN BELONGS TO THE CADHERIN FAMILY OF CALCIUM-DEPENDENT CELL-ADHESION MOLECULES. THE CADHERINS PLAY AN ESSENTIAL ROLE IN BIOLOGICAL PROCESSES SUCH AS ORDERING OF CELL SORTING, MIGRATION, AND DIFFERENTIATION, AND THEIR MALFUNCTIONING IS CONNECTED WITH NEOPLASIA. NEOPLASTIC PROGRESSION IN PATIENTS WITH CHRONIC ULCERATIVE COLITIS IS CHARACTERIZED BY THE DEVELOPMENT OF EPITHELIAL DYSPLASIA. TRANSCRIPTIONAL SILENCING OF TUMOR-SUPPRESSOR GENES BY PROMOTER METHYLATION HAS BEEN OBSERVED IN DIFFERENT TYPES OF HUMAN CANCERS AND DYSPLASIA. TO EXPLORE THE MODE OF E-CADHERIN REGULATION, 156 BIOPSY SAMPLES FROM 26 PATIENTS WITH LONG-STANDING ULCERATIVE COLITIS WERE SCREENED. TO DETECT THE METHYLATION STATUS OF OUR SAMPLES, A METHYLATION-SPECIFIC PCR WAS APPLIED. METHYLATION OF THE E-CADHERIN (CDH1) PROMOTER WAS DETECTED IN 93% OF THE PATIENTS WITH DYSPLASTIC BIOPSY SAMPLES, IN CONTRAST TO ONLY 6% OF THE PATIENTS WITHOUT DYSPLASIA (P < 0.001). WE ALSO EXAMINED THE LEVEL OF SYNTHESIS OF E-CADHERIN PROTEIN BY IMMUNOHISTOCHEMICAL STAINING IN DIFFERENT PARAFFIN-EMBEDDED SAMPLES OF DYSPLASTIC AND NON-DYSPLASTIC ORIGIN IN A SUBSET OF OUR PATIENTS. SAMPLES WITH DYSPLASIA DISPLAYED REDUCED LEVELS, WHEREAS SAMPLES WITHOUT DYSPLASIA REVEALED NORMAL E-CADHERIN PROTEIN SYNTHESIS. THESE RESULTS SHOW THAT THE E-CADHERIN PROMOTER IS SUBJECTED TO EPIGENETIC CONTROL IN COLORECTAL ULCERATION. OBVIOUSLY, THIS EVENT MAY PLAY AN IMPORTANT ROLE IN THE PROGRESSION FROM CHRONIC INFLAMMATION TO COLORECTAL CANCER. FOR THIS REASON, METHYLATION OF THE CDH1 PROMOTER IS AN ATTRACTIVE NEW BIOMARKER FOR DETECTING ULCERATIVE COLITIS PATIENTS WITH A HIGH RISK FOR DEVELOPING COLORECTAL CANCERS.	2002	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
8  5860  31 SULFORAPHANE PREVENTS ANGIOTENSIN II-INDUCED CARDIOMYOPATHY BY ACTIVATION OF NRF2 THROUGH EPIGENETIC MODIFICATION. NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR (NRF2) IS AN IMPORTANT REGULATOR OF CELLULAR ANTIOXIDANT DEFENCE. WE PREVIOUSLY SHOWED THAT SFN PREVENTED ANG II-INDUCED CARDIAC DAMAGE VIA ACTIVATION OF NRF2. HOWEVER, THE UNDERLYING MECHANISM OF SFN'S PERSISTENT CARDIAC PROTECTION REMAINS UNCLEAR. THIS STUDY AIMED TO EXPLORE THE POTENTIAL OF SFN IN ACTIVATING CARDIAC NRF2 THROUGH EPIGENETIC MECHANISMS. WILD-TYPE MICE WERE INJECTED SUBCUTANEOUSLY WITH ANG II, WITH OR WITHOUT SFN. ADMINISTRATION OF CHRONIC ANG II-INDUCED CARDIAC INFLAMMATORY FACTOR EXPRESSION, OXIDATIVE DAMAGE, FIBROSIS AND CARDIAC REMODELLING AND DYSFUNCTION, ALL OF WHICH WERE EFFECTIVELY IMPROVED BY SFN TREATMENT, COUPLED WITH AN UP-REGULATION OF NRF2 AND DOWNSTREAM GENES. BISULFITE GENOME SEQUENCING AND CHROMATIN IMMUNOPRECIPITATION (CHIP) WERE PERFORMED TO DETECT THE METHYLATION LEVEL OF THE FIRST 15 CPGS AND HISTONE H3 ACETYLATION (AC-H3) STATUS IN THE NRF2 PROMOTER REGION, RESPECTIVELY. THE RESULTS SHOWED THAT SFN REDUCED ANG II-INDUCED CPG HYPERMETHYLATION AND PROMOTED AC-H3 ACCUMULATION IN THE NRF2 PROMOTER REGION, ACCOMPANIED BY THE INHIBITION OF GLOBAL DNMT AND HDAC ACTIVITY, AND A DECREASED PROTEIN EXPRESSION OF KEY DNMT AND HDAC ENZYMES. TAKEN TOGETHER, SFN EXERTS ITS CARDIOPROTECTIVE EFFECT THROUGH EPIGENETIC MODIFICATION OF NRF2, WHICH MAY PARTIALLY CONTRIBUTE TO LONG-TERM ACTIVATION OF CARDIAC NRF2.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
9  6572  26 TRAUMATIC STRESS-INDUCED PERSISTENT CHANGES IN DNA METHYLATION REGULATE NEUROPEPTIDE Y EXPRESSION IN RAT JEJUNUM. BACKGROUND: STRESS-INDUCED CHRONIC NEUROPSYCHIATRIC CONDITIONS SUCH AS ANXIETY ARE OFTEN CO-MORBID WITH GASTROINTESTINAL MALFUNCTIONS. WHILE WE FIND ENDURING ANXIETY-LIKE SYMPTOMS FOLLOWING MINIMAL TRAUMATIC BRAIN INJURY (MTBI) IN RATS, GASTROINTESTINAL CONSEQUENCES OF MTBI REMAIN ELUSIVE. METHODS: IN THIS STUDY, WE EXAMINED THE EFFECTS OF MTBI ON A MAJOR GUT PEPTIDE, NEUROPEPTIDE Y (NPY) AND GUT MOTILITY. DNA METHYLATION WAS STUDIED AS A POSSIBLE EPIGENETIC MECHANISM OPERATIVE IN THE REGULATION OF NPY EXPRESSION IN THE GUT. KEY RESULTS: MINIMAL TRAUMATIC BRAIN INJURY REDUCED THE GUT MOTILITY 48 HOURS AND 30 DAYS AFTER TRAUMA. THE EXPRESSION OF DNA METHYLTRANSFERASE ISOFORMS (DNMT1, DNMT3A, AND DNMT3B) WAS ALTERED IN THE JEJUNUM 48 HOURS AND 30 DAYS AFTER MTBI. HOWEVER, THE MRNA LEVELS OF GROWTH ARREST AND DNA DAMAGE 45 (GADD45) ISOFORMS, GADD45A, AND GADD45B, WHICH ARE BELIEVED TO BE INVOLVED IN ACTIVE DNA DEMETHYLATION, INITIALLY DECREASED AT 48 HOURS BUT SUBSEQUENTLY INCREASED AFTER 30 DAYS OF TRAUMA. SIMILARLY, DNA HYPOMETHYLATION AT THE NPY PROMOTER REGION IN THE JEJUNUM WAS CORRELATED WITH THE INCREASE IN NPY MRNA AND PROTEIN LEVELS 30 DAYS POST-TRAUMA. ON THE OTHER HAND, DNA HYPOMETHYLATION AT 48 HOURS WAS ASSOCIATED WITH A DECLINE IN NPY EXPRESSION. TREATMENT WITH 5-AZACYTIDINE (5-AZAC), A DNMT INHIBITOR, RETARDED DNA METHYLATION AND RESTORED THE NPY MRNA LEVELS IN THE JEJUNUM OF MTBI-INDUCED RATS. CONCLUSIONS & INFERENCES: THESE RESULTS SUGGEST THAT DNA DEMETHYLATION COULD BE OPERATIVE AS AN EPIGENETIC MECHANISM IN THE LONG-TERM REGULATION OF NPY GENE EXPRESSION TO ALTER THE GUT MOTILITY DURING TRAUMATIC STRESS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
10  4574  36 MYOCARDIN-RELATED TRANSCRIPTION FACTOR A EPIGENETICALLY REGULATES RENAL FIBROSIS IN DIABETIC NEPHROPATHY. DIABETIC NEPHROPATHY (DN) IS ONE OF THE MOST COMMON COMPLICATIONS ASSOCIATED WITH DIABETES AND CHARACTERIZED BY RENAL MICROVASCULAR INJURY ALONG WITH ACCELERATED SYNTHESIS OF EXTRACELLULAR MATRIX PROTEINS CAUSING TUBULOINTERSTITIAL FIBROSIS. PRODUCTION OF TYPE I COLLAGEN, THE MAJOR COMPONENT OF EXTRACELLULAR MATRIX, IS AUGMENTED DURING RENAL FIBROSIS AFTER CHRONIC EXPOSURE TO HYPERGLYCEMIA. HOWEVER, THE TRANSCRIPTIONAL MODULATOR RESPONSIBLE FOR THE EPIGENETIC MANIPULATION LEADING TO INDUCTION OF TYPE I COLLAGEN GENES IS NOT CLEARLY DEFINED. WE SHOW HERE THAT TUBULOINTERSTITIAL FIBROSIS AS A RESULT OF DN WAS DIMINISHED IN MYOCARDIN-RELATED TRANSCRIPTION FACTOR A (MRTF-A) -DEFICIENT MICE. IN CULTURED RENAL TUBULAR EPITHELIAL CELLS AND THE KIDNEYS OF MICE WITH DN, MRTF-A WAS INDUCED BY GLUCOSE AND SYNERGIZED WITH GLUCOSE TO ACTIVATE COLLAGEN TRANSCRIPTION. NOTABLY, MRTF-A SILENCING LED TO THE DISAPPEARANCE OF PROMINENT HISTONE MODIFICATIONS INDICATIVE OF TRANSCRIPTIONAL ACTIVATION, INCLUDING ACETYLATED HISTONE H3K18/K27 AND TRIMETHYLATED HISTONE H3K4. DETAILED ANALYSIS REVEALED THAT MRTF-A RECRUITED P300, A HISTONE ACETYLTRANSFERASE, AND WD REPEAT-CONTAINING PROTEIN 5 (WDR5), A KEY COMPONENT OF THE HISTONE H3K4 METHYLTRANSFERASE COMPLEX, TO THE COLLAGEN PROMOTERS AND ENGAGED THESE PROTEINS IN TRANSCRIPTIONAL ACTIVATION. ESTRADIOL SUPPRESSED COLLAGEN PRODUCTION BY DAMPENING THE EXPRESSION AND BINDING ACTIVITY OF MRTF-A AND INTERFERING WITH THE INTERACTION BETWEEN P300 AND WDR5 IN RENAL EPITHELIAL CELLS. THEREFORE, TARGETING THE MRTF-A-ASSOCIATED EPIGENETIC MACHINERY MIGHT YIELD INTERVENTIONAL STRATEGIES AGAINST DN-ASSOCIATED RENAL FIBROSIS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
11   674  51 BRAHMA-RELATED GENE 1 BRIDGES EPIGENETIC REGULATION OF PROINFLAMMATORY CYTOKINE PRODUCTION TO STEATOHEPATITIS IN MICE. CHRONIC INFLAMMATION, INFLICTED BY THE SPILLOVER OF PROINFLAMMATORY MEDIATORS, LINKS METABOLIC DYSFUNCTION TO NONALCOHOLIC STEATOHEPATITIS (NASH). THE EPIGENETIC MANEUVERINGS THAT UNDERSCORE ACCELERATED SYNTHESIS OF PROINFLAMMATORY MEDIATORS IN RESPONSE TO NUTRITIONAL INPUTS ARE NOT CLEARLY DEFINED. HERE WE REPORT THAT THE ATP-DEPENDENT CHROMATIN REMODELING PROTEINS BRAHMA-RELATED GENE 1 (BRG1) AND BRAHMA (BRM) WERE UP-REGULATED IN VITRO IN CULTURED HEPATOCYTES TREATED WITH FREE FATTY ACID OR GLUCOSE AND IN VIVO IN ANIMAL MODELS OF NASH. OCCUPANCY OF BRG1 AND BRM ON THE PROMOTER REGIONS OF PROINFLAMMATORY GENES WAS INCREASED IN VITRO IN CELLS AND EX VIVO IN LIVER TISSUES. ESTRADIOL SUPPRESSED THE INDUCTION AND RECRUITMENT OF BRG1/BRM BY PALMITATE. RECRUITMENT OF BRG1 AND BRM RELIED ON NUCLEAR FACTOR KAPPA B/P65; RECIPROCALLY, BRG1 AND BRM CONTRIBUTED TO THE STABILIZATION OF P65 BINDING. IMPORTANTLY, OVEREXPRESSION OF BRG1/BRM ENHANCED, WHEREAS KNOCKDOWN OF BRG1/BRM ATTENUATED, THE INDUCTION OF PROINFLAMMATORY MEDIATORS IN HEPATOCYTES CHALLENGED WITH EXCESSIVE NUTRIENT. MECHANISTICALLY, BRG1 AND BRM WERE INVOLVED IN THE MAINTENANCE OF A CHROMATIN MICROENVIRONMENT MARKED BY ACTIVE HISTONE MODIFICATIONS AND FRIENDLY TO THE ACCESS OF THE GENERAL TRANSCRIPTIONAL MACHINERY. FINALLY, DEPLETION OF BRG1/BRM BY SHORT HAIRPIN RNA ATTENUATED THE RELEASE OF PROINFLAMMATORY MEDIATORS IN THE LIVER AND SIGNIFICANTLY AMELIORATED HEPATIC PATHOLOGY IN NASH MICE. CONCLUSION: OUR DATA ILLUSTRATE A BRG1-DEPENDENT PATHWAY THAT CONNECTS THE EPIGENETIC REGULATION OF PROINFLAMMATORY GENES TO THE PATHOGENESIS OF NASH AND POINT TO A POTENTIAL DRUGGABLE TARGET IN THE THERAPEUTIC INTERVENTION OF NASH.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
12  6318  21 THE RENIN-ANGIOTENSIN SYSTEM AND REACTIVE OXYGEN SPECIES: IMPLICATIONS IN PANCREATITIS. SIGNIFICANCE: THE RENIN-ANGIOTENSIN SYSTEM (RAS) IS A CIRCULATING HORMONAL SYSTEM INVOLVED IN THE REGULATION OF BLOOD PRESSURE AND CIRCULATING FLUID ELECTROLYTES. RECENT FINDINGS HAVE REVEALED THAT LOCALLY GENERATED ANGIOTENSIN (ANG) II PLAYS A PIVOTAL ROLE IN NORMAL PHYSIOLOGY AS WELL AS PATHOPHYSIOLOGY IN VARIOUS TISSUES AND ORGANS, INCLUDING THE PANCREAS. THIS REVIEW ARTICLE SUMMARIZES CURRENT PROGRESS THAT HAS BEEN MADE IN ELUCIDATING THE PUTATIVE ROLES OF ANG II IN BOTH ACUTE AND CHRONIC PANCREATITIS. RECENT ADVANCES: A CONVERGENCE OF EVIDENCE SUGGESTS THAT THE UNDERLYING MECHANISM MAY INVOLVE REACTIVE OXYGEN SPECIES (ROS)-GENERATING SYSTEMS, SUCH AS NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE, AND SUBSEQUENT ELEVATION OF PROINFLAMMATORY AND PROFIBROGENIC GENE EXPRESSION AS WELL AS PROTEIN ACTIVITY. MORE IMPORTANTLY, ANG II-INDUCED ROS INTERACTS WITH OTHER ROS-GENERATING SYSTEMS TO POSITIVELY FEED-FORWARD THE ROS-INDUCED SIGNALING. CRITICAL ISSUES AND FUTURE DIRECTIONS: ADVANCES IN BASIC RESEARCH INDICATE THAT RAS BLOCKERS MAY PROVIDE POTENTIAL THERAPEUTIC ROLE FOR THE MANAGEMENT OF PANCREATIC INFLAMMATION AND, MORE IMPORTANTLY, PANCREATITIS-ASSOCIATED COMPLICATIONS. GENETIC ALTERATIONS RESULTING FROM A MALFUNCTION IN THE EPIGENETIC CONTROL OF PANCREATIC RAS COULD BE A CAUSATIVE FACTOR IN THE DEVELOPMENT OF PANCREATITIS.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
13  2774  32 EXTRACELLULAR SUPEROXIDE DISMUTASE (EC-SOD) REGULATES GENE METHYLATION AND CARDIAC FIBROSIS DURING CHRONIC HYPOXIC STRESS. CHRONIC HYPOXIC STRESS INDUCES EPIGENETIC MODIFICATIONS MAINLY DNA METHYLATION IN CARDIAC FIBROBLASTS, INACTIVATING TUMOR SUPPRESSOR GENES (RASSF1A) AND ACTIVATING KINASES (ERK1/2) LEADING TO FIBROBLAST PROLIFERATION AND CARDIAC FIBROSIS. THE RAS/ERK SIGNALING PATHWAY IS AN INTRACELLULAR SIGNAL TRANSDUCTION CRITICALLY INVOLVED IN FIBROBLAST PROLIFERATION. RASSF1A FUNCTIONS THROUGH ITS EFFECT ON DOWNSTREAM ERK1/2. THE ANTIOXIDANT ENZYME, EXTRACELLULAR SUPEROXIDE DISMUTASE (EC-SOD), DECREASES OXIDATIVE STRESS FROM CHRONIC HYPOXIA, BUT ITS EFFECTS ON THESE EPIGENETIC CHANGES HAVE NOT BEEN FULLY EXPLORED. TO TEST OUR HYPOTHESIS, WE USED AN IN-VITRO MODEL: WILD-TYPE C57B6 MALE MICE (WT) AND TRANSGENIC MALES WITH AN EXTRA COPY OF HUMAN HEC-SOD (TG). THE STUDIED ANIMALS WERE HOUSED IN HYPOXIA (10% O(2)) FOR 21 DAYS. THE RIGHT VENTRICULAR TISSUE WAS STUDIED FOR CARDIAC FIBROSIS MARKERS USING RT-PCR AND WESTERN BLOT ANALYSES. PRIMARY C57BL6 MOUSE CARDIAC FIBROBLAST TISSUE CULTURE WAS USED TO STUDY THE IN-VITRO MODEL, THE DOWNSTREAM EFFECTS OF RASSF-1 EXPRESSION AND METHYLATION, AND ITS RELATION TO ERK1/2. OUR FINDINGS SHOWED A SIGNIFICANT INCREASE IN CARDIAC FIBROSIS MARKERS: COLLAGEN 1, ALPHA SMOOTH MUSCLE ACTIN (ASMA), AND SNAIL, IN THE WT HYPOXIC ANIMALS AS COMPARED TO THE TG HYPOXIC GROUP (P < 0.05). THE EXPRESSION OF DNA METHYLATION ENZYMES (DNMT 1&3B) WAS SIGNIFICANTLY INCREASED IN THE WT HYPOXIC MICE AS COMPARED TO THE HYPOXIC TG MICE (P < 0.001). RASSF1A EXPRESSION WAS SIGNIFICANTLY LOWER AND ERK1/2 WAS SIGNIFICANTLY HIGHER IN HYPOXIA WT COMPARED TO THE HYPOXIC TG GROUP (P < 0.05). USE OF SIRNA TO BLOCK RASSF1A GENE EXPRESSION IN MURINE CARDIAC FIBROBLAST TISSUE CULTURE LED TO INCREASED FIBROBLAST PROLIFERATION (P < 0.05). METHYLATION OF THE RASSF1A PROMOTER REGION WAS SIGNIFICANTLY REDUCED IN THE TG HYPOXIC GROUP COMPARED TO THE WT HYPOXIC GROUP (0.59 VS. 0.75, RESPECTIVELY). BASED ON OUR FINDINGS, WE CAN SPECULATE THAT EC-SOD SIGNIFICANTLY ATTENUATES RASSF1A GENE METHYLATION AND CAN ALLEVIATE CARDIAC FIBROSIS INDUCED BY HYPOXIA.	2021	
                                                                                                                                                                                                                                                                                                                                                                    
14  3865  27 JAK2 REGULATES MISMATCH REPAIR PROTEIN-MEDIATED EPIGENETIC ALTERATIONS IN RESPONSE TO OXIDATIVE DAMAGE. AT SITES OF CHRONIC INFLAMMATION EPITHELIAL CELLS UNDERGO ABERRANT DNA METHYLATION THAT CONTRIBUTES TO TUMORIGENESIS. INFLAMMATION IS ASSOCIATED WITH AN INCREASE IN REACTIVE OXYGEN SPECIES (ROS) THAT CAUSE OXIDATIVE DNA DAMAGE, WHICH HAS ALSO BEEN LINKED TO EPIGENETIC ALTERATIONS. WE PREVIOUSLY DEMONSTRATED THAT IN RESPONSE TO ROS, MISMATCH REPAIR PROTEINS MSH2 AND MSH6 RECRUIT EPIGENETIC SILENCING PROTEINS DNA METHYLTRANSFERASE 1 (DNMT1) AND POLYCOMB REPRESSIVE COMPLEX 2 (PRC2) MEMBERS TO SITES OF DNA DAMAGE, RESULTING IN TRANSCRIPTIONAL REPRESSION OF TUMOR SUPPRESSOR GENES (TSGS). HOWEVER, IT WAS UNCLEAR WHAT SIGNAL IS UNIQUE TO ROS THAT RESULTS IN THE CHROMATIN BINDING OF MSH2 AND MSH6. HEREIN, WE DEMONSTRATE THAT IN RESPONSE TO HYDROGEN PEROXIDE (H(2) O(2) ), JAK2 LOCALIZES TO THE NUCLEUS AND INTERACTS WITH MSH2 AND MSH6. INHIBITION OR KNOCKDOWN OF JAK2 REDUCES THE H(2) O(2) -INDUCED CHROMATIN INTERACTION OF MSH2, MSH6, DNMT1, AND PRC2 MEMBERS, REDUCES H(2) O(2) -INDUCED GLOBAL INCREASE IN TRIMETHYLATION OF LYSINE 27 OF HISTONE H3 (H3K27ME3), AND ABROGATES OXIDATIVE DAMAGE-INDUCED TRANSCRIPTIONAL REPRESSION OF CANDIDATE TSGS. MOREOVER, JAK2 MRNA EXPRESSION IS ASSOCIATED WITH CPG ISLAND METHYLATOR PHENOTYPE (CIMP) STATUS IN HUMAN COLORECTAL CANCER. OUR FINDINGS PROVIDE NOVEL INSIGHT INTO THE CONNECTION BETWEEN KINASE ACTIVATION AND EPIGENETIC ALTERATIONS DURING OXIDATIVE DAMAGE AND INFLAMMATION. ENVIRON. MOL. MUTAGEN. 60:308-319, 2019. (C) 2018 WILEY PERIODICALS, INC.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
15  4810  21 OBESITY--A CHRONIC HEALTH PROBLEM IN CLONED MICE? THE MAJORITY OF CLONED ANIMALS DERIVED BY NUCLEAR TRANSFER DIE DURING GESTATION AND DISPLAY NEONATAL ABNORMALITIES. HOWEVER, BECAUSE OF THE LONG GENERATION INTERVAL OF CLONED ANIMAL SPECIES, THE LONG-TERM CONSEQUENCES OF CLONING ON HEALTH HAVE BEEN DIFFICULT TO ACCESS. RECENT STUDIES IN MICE HAVE PROVIDED EVIDENCE THAT CLONED ANIMALS MIGHT HAVE CHRONIC HEALTH PROBLEMS SUCH AS OBESITY. OBESITY IN CLONED MICE IS LIKELY TO REFLECT EPIGENETIC ABNORMALITIES THAT ARISE PARTLY FROM INADEQUATE NUCLEAR PROGRAMMING; THESE OBESE MICE DISPLAY A UNIQUE PHENOTYPE THAT IS SUGGESTIVE OF A DEFECT OTHER THAN MALFUNCTION OF THE LEPTIN-MELANOCORTIN SYSTEM, WHICH OCCURS IN MOST RODENT MODELS OF OBESITY AND IN HUMAN OBESITY.	2003	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
16    52  28 A DNA METHYLATION BASED MEASURE OUTPERFORMS CIRCULATING CRP AS A MARKER OF CHRONIC INFLAMMATION AND PARTLY REFLECTS THE MONOCYTIC RESPONSE TO LONG-TERM INFLAMMATORY EXPOSURE: A CANADIAN LONGITUDINAL STUDY ON AGING ANALYSIS. A KEY HALLMARK IN THE AGE-RELATED DYSFUNCTION OF PHYSIOLOGICAL SYSTEMS IS DISRUPTION RELATED TO THE REGULATION OF INFLAMMATION, OFTEN RESULTING IN A CHRONIC, LOW-GRADE INFLAMMATORY STATE (I.E., INFLAMMAGING). IN ORDER TO UNDERSTAND THE CAUSES OF OVERALL SYSTEM DECLINE, METHODS TO QUANTIFY THE LIFE-LONG EXPOSURE OR DAMAGE RELATED TO CHRONIC INFLAMMATION ARE CRITICAL. HERE, WE CHARACTERIZE A COMPREHENSIVE EPIGENETIC INFLAMMATION SCORE (EIS) BASED ON DNA METHYLATION LOCI (CPGS) THAT ARE ASSOCIATED WITH CIRCULATING LEVELS OF C-REACTIVE PROTEIN (CRP). IN A COHORT OF 1446 OLDER ADULTS, WE SHOW THAT ASSOCIATIONS TO AGE AND HEALTH-RELATED TRAITS SUCH AS SMOKING HISTORY, CHRONIC CONDITIONS, AND ESTABLISHED MEASURES OF ACCELERATED AGING WERE STRONGER FOR EIS THAN CRP, WHILE THE RISK OF LONGITUDINAL OUTCOMES SUCH AS OUTPATIENT OR INPATIENT VISITS AND INCREASED FRAILTY WERE RELATIVELY SIMILAR. TO DETERMINE WHETHER VARIATION IN EIS ACTUALLY REFLECTS THE CELLULAR RESPONSE TO CHRONIC INFLAMMATION WE EXPOSED THP1 MYELO-MONOCYTIC CELLS TO LOW LEVELS OF INFLAMMATORY MEDIATORS FOR 14 DAYS, FINDING THAT EIS INCREASED IN RESPONSE TO BOTH CRP (P = 0.011) AND TNF (P = 0.068). INTERESTINGLY, A REFINED VERSION OF EIS BASED ONLY ON THOSE CPGS THAT CHANGED IN VITRO WAS MORE STRONGLY ASSOCIATED WITH MANY OF THE AFOREMENTIONED TRAITS AS COMPARED TO EIS. IN CONCLUSION, OUR STUDY DEMONSTRATES THAT EIS OUTPERFORMS CIRCULATING CRP WITH REGARD TO ITS ASSOCIATION TO HEALTH-TRAITS THAT ARE SYNONYMOUS WITH CHRONIC INFLAMMATION AND ACCELERATED AGING, AND SUBSTANTIATES ITS POTENTIAL ROLE AS A CLINICALLY RELEVANT TOOL FOR STRATIFYING PATIENT RISK OF ADVERSE OUTCOMES PRIOR TO TREATMENT OR FOLLOWING ILLNESS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
17  5942  27 TARGETING OF CELLULAR REDOX METABOLISM FOR MITIGATION OF RADIATION INJURY. ACCIDENTAL EXPOSURE TO IONIZING RADIATION IS A SERIOUS CONCERN TO HUMAN LIFE. STUDIES ON THE MITIGATION OF SIDE EFFECTS FOLLOWING EXPOSURE TO ACCIDENTAL RADIATION EVENTS ARE ONGOING. RECENT STUDIES HAVE SHOWN THAT RADIATION CAN ACTIVATE SEVERAL SIGNALING PATHWAYS, LEADING TO CHANGES IN THE METABOLISM OF FREE RADICALS INCLUDING REACTIVE OXYGEN SPECIES (ROS) AND NITRIC OXIDE (NO). CELLULAR AND MOLECULAR MECHANISMS SHOW THAT RADIATION CAN CAUSE DISRUPTION OF NORMAL REDUCTION/OXIDATION (REDOX) SYSTEM. MITOCHONDRIA MALFUNCTION FOLLOWING EXPOSURE TO RADIATION AND MUTATIONS IN MITOCHONDRIA DNA (MTDNA) HAVE A KEY ROLE IN CHRONIC OXIDATIVE STRESS. FURTHERMORE, EXPOSURE TO RADIATION LEADS TO INFILTRATION OF INFLAMMATORY CELLS SUCH AS MACROPHAGES, LYMPHOCYTES AND MAST CELLS, WHICH ARE IMPORTANT SOURCES OF ROS AND NO. THESE CELLS GENERATE FREE RADICALS VIA UPREGULATION OF SOME PRO-OXIDANT ENZYMES SUCH AS NADPH OXIDASES, INDUCIBLE NITRIC OXIDE SYNTHASE (INOS) AND CYCLOOXYGENASE-2 (COX-2). EPIGENETIC CHANGES ALSO HAVE A KEY ROLE IN A SIMILAR WAY. OTHER MEDIATORS SUCH AS MAMMALIAN TARGET OF RAPAMYCIN (MTOR) AND PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR), WHICH ARE INVOLVED IN THE NORMAL METABOLISM OF CELLS HAVE ALSO BEEN SHOWN TO REGULATE CELL DEATH FOLLOWING EXPOSURE TO RADIATION. THESE MECHANISMS ARE TISSUE SPECIFIC. INHIBITION OR ACTIVATION OF EACH OF THESE TARGETS CAN BE SUGGESTED FOR MITIGATION OF RADIATION INJURY IN A SPECIFIC TISSUE. IN THE CURRENT PAPER, WE REVIEW THE CELLULAR AND MOLECULAR CHANGES IN THE METABOLISM OF CELLS AND ROS/NO FOLLOWING EXPOSURE TO RADIATION. FURTHERMORE, THE POSSIBLE STRATEGIES FOR MITIGATION OF RADIATION INJURY THROUGH MODULATION OF CELLULAR METABOLISM IN IRRADIATED ORGANS WILL BE DISCUSSED.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
18  1117  33 COMPARATIVE AND EXPERIMENTAL STUDIES ON THE GENES ALTERED BY CHRONIC HYPOXIA IN HUMAN BRAIN MICROENDOTHELIAL CELLS. BACKGROUND : HYPOXIA INDUCIBLE FACTOR 1 ALPHA (HIF1A) IS A MASTER REGULATOR OF ACUTE HYPOXIA; HOWEVER, WITH CHRONIC HYPOXIA, HIF1A LEVELS RETURN TO THE NORMOXIC LEVELS. IMPORTANTLY, THE GENES THAT ARE INVOLVED IN THE CELL SURVIVAL AND VIABILITY UNDER CHRONIC HYPOXIA ARE NOT KNOWN. THEREFORE, WE TESTED THE HYPOTHESIS THAT CHRONIC HYPOXIA LEADS TO THE UPREGULATION OF A CORE GROUP OF GENES WITH ASSOCIATED CHANGES IN THE PROMOTER DNA METHYLATION THAT MEDIATES THE CELL SURVIVAL UNDER HYPOXIA. RESULTS : WE EXAMINED THE EFFECT OF CHRONIC HYPOXIA (3 DAYS; 0.5% OXYGEN) ON HUMAN BRAIN MICRO ENDOTHELIAL CELLS (HBMEC) VIABILITY AND APOPTOSIS. HYPOXIA CAUSED A SIGNIFICANT REDUCTION IN CELL VIABILITY AND AN INCREASE IN APOPTOSIS. NEXT, WE EXAMINED CHRONIC HYPOXIA ASSOCIATED CHANGES IN TRANSCRIPTOME AND GENOME-WIDE PROMOTER METHYLATION. THE DATA OBTAINED WAS COMPARED WITH 16 OTHER MICROARRAY STUDIES ON CHRONIC HYPOXIA. NINE GENES WERE ALTERED IN RESPONSE TO CHRONIC HYPOXIA IN ALL 17 STUDIES. INTERESTINGLY, HIF1A WAS NOT ALTERED WITH CHRONIC HYPOXIA IN ANY OF THE STUDIES. FURTHERMORE, WE COMPARED OUR DATA TO THREE OTHER STUDIES THAT IDENTIFIED HIF-RESPONSIVE GENES BY VARIOUS APPROACHES. ONLY TWO GENES WERE FOUND TO BE HIF DEPENDENT. WE SILENCED EACH OF THESE 9 GENES USING CRISPR/CAS9 SYSTEM. DOWNREGULATION OF EGLN3 SIGNIFICANTLY INCREASED THE CELL DEATH UNDER CHRONIC HYPOXIA, WHEREAS DOWNREGULATION OF ERO1L, ENO2, ADRENOMEDULLIN, AND SPAG4 REDUCED THE CELL DEATH UNDER HYPOXIA. CONCLUSIONS : WE PROVIDE A CORE GROUP OF GENES THAT REGULATES CELLULAR ACCLIMATIZATION UNDER CHRONIC HYPOXIC STRESS, AND MOST OF THEM ARE HIF INDEPENDENT.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
19  3527  29 IL-6 ENHANCES THE NUCLEAR TRANSLOCATION OF DNA CYTOSINE-5-METHYLTRANSFERASE 1 (DNMT1) VIA PHOSPHORYLATION OF THE NUCLEAR LOCALIZATION SEQUENCE BY THE AKT KINASE. THE EPIGENETIC PROGRAMMING OF GENOMIC DNA IS ACCOMPLISHED, IN PART, BY SEVERAL DNA CYTOSINE-5-METHYLTRANSFERASES THAT ACT BY COVALENTLY MODIFYING CYTOSINES WITH THE ADDITION OF A METHYL GROUP. THIS COVALENT MODIFICATION IS MAINTAINED BY THE DNA CYTOSINE-5-METHYLTRANSFERASE-1 ENZYME (DNMT1), WHICH IS CAPABLE OF ACTING IN CONCERT WITH OTHER SIMILAR ENZYMES TO SILENCE IMPORTANT TUMOR SUPPRESSOR GENES. IL-6 IS A MULTIFUNCTIONAL MEDIATOR OF INFLAMMATION, ACTING THROUGH SEVERAL MAJOR SIGNALING CASCADES, INCLUDING THE PHOSPHATIDYLINOSITOL-3-KINASE PATHWAY (PI-3-K), WHICH ACTIVATES PROTEIN KINASE B (AKT/PKB) DOWNSTREAM. HERE, WE SHOW THAT THE SUBCELLULAR LOCALIZATION OF DNMT1 CAN BE ALTERED BY THE ADDITION OF IL-6, INCREASING THE RATE OF NUCLEAR TRANSLOCATION OF THE ENZYME FROM THE CYTOSOLIC COMPARTMENT. THE MECHANISM OF NUCLEAR TRANSLOCATION OF DNMT1 IS GREATLY ENHANCED BY PHOSPHORYLATION OF THE DNMT1 NUCLEAR LOCALIZATION SIGNAL (NLS) BY PKB/AKT KINASE. MUTAGENIC ALTERATION OF THE TWO AKT TARGET AMINO ACIDS WITHIN THE NLS RESULTS IN A MAJOR LOSS OF DNMT1 NUCLEAR TRANSLOCATION, WHILE THE CREATION OF A "PHOSPHO-MIMIC" AMINO ACID (MUTATION TO ACIDIC RESIDUES) RESTORES THIS COMPARTMENTATION ABILITY. THESE OBSERVATIONS SUGGEST AN INTERESTING HYPOTHESIS REGARDING HOW MEDIATORS OF CHRONIC INFLAMMATION MAY DISTURB THE DELICATE BALANCE OF CELLULAR COMPARTMENTALIZATION OF IMPORTANT PROTEINS, AND REVEALS A POTENTIAL MECHANISM FOR THE INDUCTION OR ENHANCEMENT OF TUMOR GROWTH VIA ALTERATION OF THE COMPONENTS INVOLVED IN THE EPIGENETIC PROGRAMMING OF A CELL.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
20   982  29 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