1 3519 117 IGF-1 SIGNALING IN NEONATAL HYPOXIA-INDUCED PULMONARY HYPERTENSION: ROLE OF EPIGENETIC REGULATION. PULMONARY HYPERTENSION IS A FATAL DISEASE CHARACTERIZED BY A PROGRESSIVE INCREASE IN PULMONARY ARTERY PRESSURE ACCOMPANIED BY PULMONARY VASCULAR REMODELING AND INCREASED VASOMOTOR TONE. ALTHOUGH SOME BIOLOGICAL PATHWAYS HAVE BEEN IDENTIFIED IN NEONATAL HYPOXIA-INDUCED PULMONARY HYPERTENSION (PH), LITTLE IS KNOWN REGARDING THE ROLE OF GROWTH FACTORS IN THE PATHOGENESIS OF PH IN NEONATES. IN THIS STUDY, USING A MODEL OF HYPOXIA-INDUCED PH IN NEONATAL MICE, WE DEMONSTRATE THAT THE GROWTH FACTOR INSULIN-LIKE GROWTH FACTOR-1 (IGF-1), A POTENT ACTIVATOR OF THE AKT SIGNALING PATHWAY, IS INVOLVED IN NEONATAL PH. AFTER EXPOSURE TO HYPOXIA, IGF-1 SIGNALING IS ACTIVATED IN PULMONARY ENDOTHELIAL AND SMOOTH MUSCLE CELLS IN VITRO, AND THE IGF-1 DOWNSTREAM SIGNAL PAKT(S473) IS UPREGULATED IN LUNGS OF NEONATAL MICE. WE FOUND THAT IGF-1 REGULATES ET-1 EXPRESSION IN PULMONARY ENDOTHELIAL CELLS AND THAT IGF-1 EXPRESSION IS REGULATED BY HISTONE DEACETYLASES (HDACS). IN ADDITION, THERE IS A DIFFERENTIAL CYTOSINE METHYLATION SITE IN THE IGF-1 PROMOTER REGION IN RESPONSE TO NEONATAL HYPOXIA. MOREOVER, INHIBITION OF HDACS WITH APICIDIN DECREASES NEONATAL HYPOXIA-INDUCED GLOBAL DNA METHYLATION LEVELS IN LUNGS AND SPECIFIC CYTOSINE METHYLATION LEVELS AROUND THE PULMONARY IGF-1 PROMOTER REGION. FINALLY, HDAC INHIBITION WITH APICIDIN REDUCES CHRONIC HYPOXIA-INDUCED ACTIVATION OF IGF-1/PAKT SIGNALING IN LUNGS AND ATTENUATES RIGHT VENTRICULAR HYPERTROPHY AND PULMONARY VASCULAR REMODELING. TAKEN TOGETHER, WE CONCLUDE THAT IGF-1, WHICH IS EPIGENETICALLY REGULATED, IS INVOLVED IN THE PATHOGENESIS OF PULMONARY HYPERTENSION IN NEONATAL MICE. THIS STUDY IMPLICATES A NOVEL HDAC/IGF-1 EPIGENETIC PATHWAY IN THE REGULATION OF HYPOXIA-INDUCED PH AND WARRANTS FURTHER STUDY OF THE ROLE OF IGF-1 IN NEONATAL PULMONARY HYPERTENSIVE DISEASE.	2015	
                                                                                                                                                                                                                                                                                        
2 3351  48 HISTONE DEMETHYLASE JARID1B REGULATES PROLIFERATION AND MIGRATION OF PULMONARY ARTERIAL SMOOTH MUSCLE CELLS IN MICE WITH CHRONIC HYPOXIA-INDUCED PULMONARY HYPERTENSION VIA NUCLEAR FACTOR-KAPPA B (NFKB). CHRONIC HYPOXIA-INDUCED PULMONARY HYPERTENSION (PH) IS A DISORDER THAT IS CHARACTERIZED BY INCREASED PULMONARY ARTERIAL PRESSURE RESULTING FROM LUNG DISEASES OR SHORTAGE OF OXYGEN IN THE BODY. EXCESS PROLIFERATION OF PULMONARY VASCULAR CELLS SUCH AS PULMONARY ARTERY ENDOTHELIAL CELLS (PAECS) AND PULMONARY ARTERY SMOOTH MUSCLE CELLS (PASMCS) PLAYS A CRITICAL ROLE IN THE PATHOGENESIS OF PH. RECENT EVIDENCE INDICATES THAT, IN ADDITION TO GENETIC PREDISPOSITION AND ENVIRONMENTAL FACTORS, EPIGENETIC MECHANISMS PLAY A PIVOTAL ROLE IN ETIOLOGY OF PH. IN THIS STUDY, WE INVESTIGATED THE POSSIBLE ROLE PLAYED BY JUMONJI AT-RICH INTERACTIVE DOMAIN 1B (JARID1B), A HISTONE DEMETHYLASE, IN REGULATING THE PROLIFERATION OF VASCULAR SMOOTH MUSCLE CELLS IN CHRONIC HYPOXIA-INDUCED PH CONDITION. QUANTITATIVE POLYMERASE CHAIN REACTION ANALYSIS OF SAMPLES FROM RATS WITH PH SHOWED AN ELEVATED EXPRESSION OF JARID1B IN THEIR PASMCS, POSITIVELY CORRELATING WITH INCREASED NUCLEAR FACTOR-KAPPA B (NFKB) EXPRESSION. FURTHER FUNCTIONAL STUDIES IN VITRO INDICATED THAT OVEREXPRESSION OF JARID1B INCREASED THE PROLIFERATION AND MIGRATION OF PASMCS, WHICH WERE INHIBITED BY DEPLETION OF NFKB. GENOMEWIDE TRANSCRIPTIONAL ANALYSIS REVEALED THAT THE JARID1B REGULATED NFKB SIGNALING PATHWAY BY DIRECTLY BINDING TO ITS PROMOTER. WE HAVE ALSO SHOWN THAT JARID1B INDIRECTLY REGULATES THE EXPRESSION OF VASCULAR ENDOTHELIAL GROWTH FACTOR VIA NFKB SIGNALING AND HENCE MAY ALSO PLAY A CRUCIAL ROLE IN CONTROLLING PAECS, LEADING TO CHANGES IN VASCULAR ARCHITECTURE IN PH. OUR FINDINGS COULD LEAD TO FURTHER STUDIES ON THE ROLE OF JARID1B IN PH ETIOLOGY AND THEREFORE COULD LEAD TO A POTENTIAL THERAPEUTIC TARGET FOR CHRONIC HYPOXIA INDUCED PULMONARY HYPERTENSION.	2018	
                                                                                                                                                                                                                                                                            
3 3193  35 HDAC INHIBITION REGULATES OXIDATIVE STRESS IN CD4(+)THELPER CELLS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND NON-SMALL CELL LUNG CANCER PATIENTS VIA MITOCHONDRIAL TRANSCRIPTION FACTOR A (MTTFA) MODULATING NF-KAPPAB/HIF1ALPHA AXIS. HISTONE DEACETYLASES (HDACS) PLAY A CRUCIAL ROLE IN THE EPIGENETIC REGULATION OF GENE EXPRESSION BY REMODELLING CHROMATIN. ISOENZYMES OF THE HDAC FAMILY EXHIBIT ABERRANT REGULATION IN A WIDE VARIETY OF CANCERS AS WELL AS SEVERAL INFLAMMATORY LUNG DISORDERS LIKE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). INHIBITION OF HDACS IS A POTENTIAL THERAPEUTIC STRATEGY THAT COULD BE USED TO REVERSE EPIGENETIC MODIFICATION. TRICHOSTATIN A (TSA), A POWERFUL HISTONE DEACETYLASE (HDAC) INHIBITOR, HAS ANTI-CANCER EFFECTS IN NUMEROUS CANCER TYPES. HOWEVER, IT IS NOT YET APPARENT HOW HDAC INHIBITORS AFFECT HUMAN NON-SMALL CELL LUNG CANCER CELLS (NSCLC) AND COPD. THIS STUDY AIMS TO INVESTIGATE TSA'S ROLE IN RESTORING MITOCHONDRIAL DYSFUNCTION AND ITS EFFECT ON HYPOXIA AND INFLAMMATION IN CD4(+)T CELLS OBTAINED FROM PATIENTS WITH COPD AND LUNG CANCER. AS A RESULT OF TREATMENT WITH TSA, THERE IS A REDUCTION IN THE EXPRESSION OF INFLAMMATORY CYTOKINES AND A DECREASED ENRICHMENT OF TRANSCRIPTIONAL FACTORS ASSOCIATED WITH INFLAMMATION AT VEGFA GENE LOCI. WE HAVE SEEN A SUBSTANTIAL DECREASE IN THE EXPRESSION OF NF-KAPPAB AND HIF1ALPHA, WHICH ARE THE CRITICAL MEDIATORS OF INFLAMMATION AND HYPOXIA, RESPECTIVELY. FOLLOWING TSA TREATMENT, MTTFA EXPRESSION WAS INCREASED, FACILITATING PATIENTS WITH COPD AND NSCLC IN THE RECOVERY OF THEIR DYSFUNCTIONAL MITOCHONDRIA. FURTHERMORE, WE HAVE DISCOVERED THAT TSA TREATMENT IN PATIENTS WITH COPD AND NSCLC MAY LEAD TO IMMUNOPROTECTIVE NESS BY INDUCING TH1NESS. OUR FINDING GIVES A NEW INSIGHT INTO THE EXISTING BODY OF KNOWLEDGE REGARDING TSA-BASED THERAPEUTIC METHODS AND HIGHLIGHTS THE NECESSITY OF EPIGENETIC THERAPY FOR THESE DEVASTATING LUNG DISORDERS.	2023	
                                                                                                                                                                                                                                                                                      
4 2926  32 GENERATION OF AN EPIGENETIC SIGNATURE BY CHRONIC HYPOXIA IN PROSTATE CELLS. INCREASING LEVELS OF TISSUE HYPOXIA HAVE BEEN REPORTED AS A NATURAL FEATURE OF THE AGING PROSTATE GLAND AND MAY BE A RISK FACTOR FOR THE DEVELOPMENT OF PROSTATE CANCER. IN THIS STUDY, WE HAVE USED PWR-1E BENIGN PROSTATE EPITHELIAL CELLS AND AN EQUIVALENTLY AGED HYPOXIA-ADAPTED PWR-1E SUB-LINE TO IDENTIFY PHENOTYPIC AND EPIGENETIC CONSEQUENCES OF CHRONIC HYPOXIA IN PROSTATE CELLS. WE HAVE IDENTIFIED A SIGNIFICANTLY ALTERED CELLULAR PHENOTYPE IN RESPONSE TO CHRONIC HYPOXIA AS CHARACTERIZED BY INCREASED RECEPTOR-MEDIATED APOPTOTIC RESISTANCE, THE INDUCTION OF CELLULAR SENESCENCE, INCREASED INVASION AND THE INCREASED SECRETION OF IL-1 BETA, IL6, IL8 AND TNFALPHA CYTOKINES. IN ASSOCIATION WITH THESE PHENOTYPIC CHANGES AND THE ABSENCE OF HIF-1 ALPHA PROTEIN EXPRESSION, WE HAVE DEMONSTRATED SIGNIFICANT INCREASES IN GLOBAL LEVELS OF DNA METHYLATION AND H3K9 HISTONE ACETYLATION IN THESE CELLS, CONCOMITANT WITH THE INCREASED EXPRESSION OF DNA METHYLTRANSFERASE DMNT3B AND GENE-SPECIFIC CHANGES IN DNA METHYLATION AT KEY IMPRINTING LOCI. IN CONCLUSION, WE HAVE DEMONSTRATED A GENOME-WIDE ADJUSTMENT OF DNA METHYLATION AND HISTONE ACETYLATION UNDER CHRONIC HYPOXIC CONDITIONS IN THE PROSTATE. THESE EPIGENETIC SIGNATURES MAY REPRESENT AN ADDITIONAL MECHANISM TO PROMOTE AND MAINTAIN A HYPOXIC-ADAPTED CELLULAR PHENOTYPE WITH A POTENTIAL ROLE IN TUMOUR DEVELOPMENT.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
5  164  34 ABNORMAL HISTONE METHYLATION IS RESPONSIBLE FOR INCREASED VASCULAR ENDOTHELIAL GROWTH FACTOR 165A SECRETION FROM AIRWAY SMOOTH MUSCLE CELLS IN ASTHMA. VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF), A KEY ANGIOGENIC MOLECULE, IS ABERRANTLY EXPRESSED IN SEVERAL DISEASES INCLUDING ASTHMA WHERE IT CONTRIBUTES TO BRONCHIAL VASCULAR REMODELING AND CHRONIC INFLAMMATION. ASTHMATIC HUMAN AIRWAY SMOOTH MUSCLE CELLS HYPERSECRETE VEGF, BUT THE MECHANISM IS UNCLEAR. IN THIS STUDY, WE DEFINED THE MECHANISM IN HUMAN AIRWAY SMOOTH MUSCLE CELLS FROM NONASTHMATIC AND ASTHMATIC PATIENTS. WE FOUND THAT ASTHMATIC CELLS LACKED A REPRESSION COMPLEX AT THE VEGF PROMOTER, WHICH WAS PRESENT IN NONASTHMATIC CELLS. RECRUITMENT OF G9A, TRIMETHYLATION OF HISTONE H3 AT LYSINE 9 (H3K9ME3), AND A RESULTANT DECREASE IN RNA POLYMERASE II AT THE VEGF PROMOTER WAS CRITICAL TO REPRESSION OF VEGF SECRETION IN NONASTHMATIC CELLS. AT THE ASTHMATIC PROMOTER, H3K9ME3 WAS ABSENT BECAUSE OF FAILED RECRUITMENT OF G9A; RNA POLYMERASE II BINDING, IN ASSOCIATION WITH TATA-BINDING PROTEIN-ASSOCIATED FACTOR 1, WAS INCREASED; H3K4ME3 WAS PRESENT; AND SP1 BINDING WAS EXAGGERATED AND SUSTAINED. IN CONTRAST, DNA METHYLATION AND HISTONE ACETYLATION WERE SIMILAR IN ASTHMATIC AND NONASTHMATIC CELLS. THIS IS THE FIRST STUDY, TO OUR KNOWLEDGE, TO SHOW THAT AIRWAY CELLS IN ASTHMA HAVE ALTERED EPIGENETIC REGULATION OF REMODELING GENE(S). HISTONE METHYLATION AT GENES SUCH AS VEGF MAY BE AN IMPORTANT NEW THERAPEUTIC TARGET.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
6 4111  33 MECHANISMS CONTRIBUTING TO PERSISTENTLY ACTIVATED CELL PHENOTYPES IN PULMONARY HYPERTENSION. CHRONIC PULMONARY HYPERTENSION (PH) IS CHARACTERIZED BY THE ACCUMULATION OF PERSISTENTLY ACTIVATED CELL TYPES IN THE PULMONARY VESSEL EXHIBITING ABERRANT EXPRESSION OF GENES INVOLVED IN APOPTOSIS RESISTANCE, PROLIFERATION, INFLAMMATION AND EXTRACELLULAR MATRIX (ECM) REMODELLING. CURRENT THERAPIES FOR PH, FOCUSING ON VASODILATATION, DO NOT NORMALIZE THESE ACTIVATED PHENOTYPES. FURTHERMORE, CURRENT APPROACHES TO DEFINE ADDITIONAL THERAPEUTIC TARGETS HAVE FOCUSED ON DETERMINING THE INITIATING SIGNALS AND THEIR DOWNSTREAM EFFECTORS THAT ARE IMPORTANT IN PH ONSET AND DEVELOPMENT. ALTHOUGH THESE APPROACHES HAVE PRODUCED A LARGE NUMBER OF COMPELLING PH TREATMENT TARGETS, MANY PROMISING HUMAN DRUGS HAVE FAILED IN PH CLINICAL TRIALS. HEREIN, WE PROPOSE THAT ONE CONTRIBUTING FACTOR TO THESE FAILURES IS THAT PROCESSES IMPORTANT IN PH DEVELOPMENT MAY NOT BE GOOD TREATMENT TARGETS IN THE ESTABLISHED PHASE OF CHRONIC PH. WE HYPOTHESIZE THAT THIS IS DUE TO ALTERATIONS OF CHROMATIN STRUCTURE IN PH CELLS, RESULTING IN FUNCTIONAL DIFFERENCES BETWEEN THE SAME FACTOR OR PATHWAY IN NORMAL OR EARLY PH CELLS VERSUS CELLS IN CHRONIC PH. WE PROPOSE THAT THE HIGH EXPRESSION OF GENES INVOLVED IN THE PERSISTENTLY ACTIVATED PHENOTYPE OF PH VASCULAR CELLS IS PERPETUATED BY AN OPEN CHROMATIN STRUCTURE AND MULTIPLE TRANSCRIPTION FACTORS (TFS) VIA THE RECRUITMENT OF HIGH LEVELS OF EPIGENETIC REGULATORS INCLUDING THE HISTONE ACETYLASES P300/CBP, HISTONE ACETYLATION READERS INCLUDING BRDS, THE MEDIATOR COMPLEX AND THE POSITIVE TRANSCRIPTION ELONGATION FACTOR (ABSTRACT FIGURE). THUS, DETERMINING HOW GENE EXPRESSION IS CONTROLLED BY EXAMINING CHROMATIN STRUCTURE, TFS AND EPIGENETIC REGULATORS ASSOCIATED WITH ABERRANTLY EXPRESSED GENES IN PULMONARY VASCULAR CELLS IN CHRONIC PH, MAY UNCOVER NEW PH THERAPEUTIC TARGETS.	2019	
                                                                                                                                                                                                                                                                                                              
7  172  38 ABSENCE OF HDAC3 BY MATRIX STIFFNESS PROMOTES CHROMATIN REMODELING AND FIBROBLAST ACTIVATION IN IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC AND FATAL DISEASE CHARACTERIZED BY PROGRESSIVE AND IRREVERSIBLE LUNG SCARRING ASSOCIATED WITH PERSISTENT ACTIVATION OF FIBROBLASTS. EPIGENETICS COULD INTEGRATE DIVERSE MICROENVIRONMENTAL SIGNALS, SUCH AS STIFFNESS, TO DIRECT PERSISTENT FIBROBLAST ACTIVATION. HISTONE MODIFICATIONS BY DEACETYLASES (HDAC) MAY PLAY AN ESSENTIAL ROLE IN THE GENE EXPRESSION CHANGES INVOLVED IN THE PATHOLOGICAL REMODELING OF THE LUNG. PARTICULARLY, HDAC3 IS CRUCIAL FOR MAINTAINING CHROMATIN AND REGULATING GENE EXPRESSION, BUT LITTLE IS KNOWN ABOUT ITS ROLE IN IPF. IN THE STUDY, CONTROL AND IPF-DERIVED FIBROBLASTS WERE USED TO DETERMINE THE INFLUENCE OF HDAC3 ON CHROMATIN REMODELING AND GENE EXPRESSION ASSOCIATED WITH IPF SIGNATURE. ADDITIONALLY, THE CELLS WERE GROWN ON HYDROGELS TO MIMIC THE STIFFNESS OF A FIBROTIC LUNG. OUR RESULTS SHOWED A DECREASED HDAC3 IN THE NUCLEUS OF IPF FIBROBLASTS, WHICH CORRELATES WITH CHANGES IN NUCLEUS SIZE AND HETEROCHROMATIN LOSS. THE INHIBITION OF HDAC3 WITH A PHARMACOLOGICAL INHIBITOR CAUSES HYPERACETYLATION OF H3K9 AND PROVOKES AN INCREASED EXPRESSION OF COL1A1, ACTA2, AND P21. COMPARABLE RESULTS WERE FOUND IN HYDROGELS, WHERE MATRIX STIFFNESS PROMOTES THE LOSS OF NUCLEAR HDAC3 AND INCREASES THE PROFIBROTIC SIGNATURE. FINALLY, LATRUNCULIN B WAS USED TO CONFIRM THAT CHANGES BY STIFFNESS DEPEND ON THE MECHANOTRANSDUCTION SIGNALS. TOGETHER, THESE RESULTS SUGGEST THAT HDAC3 COULD BE A LINK BETWEEN EPIGENETIC MECHANISMS AND THE FIBROTIC MICROENVIRONMENT.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
8 2002  26 EPIGENETIC AND POST-TRANSCRIPTIONAL REPRESSION SUPPORT METABOLIC SUPPRESSION IN CHRONICALLY HYPOXIC GOLDFISH. GOLDFISH ENTER A HYPOMETABOLIC STATE TO SURVIVE CHRONIC HYPOXIA. WE RECENTLY DESCRIBED TISSUE-SPECIFIC CONTRIBUTIONS OF MEMBRANE LIPID COMPOSITION REMODELING AND MITOCHONDRIAL FUNCTION TO METABOLIC SUPPRESSION ACROSS DIFFERENT GOLDFISH TISSUES. HOWEVER, THE MOLECULAR AND ESPECIALLY EPIGENETIC FOUNDATIONS OF HYPOXIA TOLERANCE IN GOLDFISH UNDER METABOLIC SUPPRESSION ARE NOT WELL UNDERSTOOD. HERE WE SHOW THAT COMPONENTS OF THE MOLECULAR OXYGEN-SENSING MACHINERY ARE ROBUSTLY ACTIVATED ACROSS TISSUES IRRESPECTIVE OF HYPOXIA DURATION. INDUCTION OF GENE EXPRESSION OF ENZYMES INVOLVED IN DNA METHYLATION TURNOVER AND MICRORNA BIOGENESIS SUGGEST A ROLE FOR EPIGENETIC TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL SUPPRESSION OF GENE EXPRESSION IN THE HYPOXIA-ACCLIMATED BRAIN. CONVERSELY, MECHANISTIC TARGET OF RAPAMYCIN-DEPENDENT TRANSLATIONAL MACHINERY ACTIVITY IS NOT REDUCED IN LIVER AND WHITE MUSCLE, SUGGESTING THIS PATHWAY DOES NOT CONTRIBUTE TO LOWERING CELLULAR ENERGY EXPENDITURE. FINALLY, MOLECULAR EVIDENCE SUPPORTS PREVIOUSLY REPORTED CHRONIC HYPOXIA-DEPENDENT CHANGES IN MEMBRANE CHOLESTEROL, LIPID METABOLISM AND MITOCHONDRIAL FUNCTION VIA CHANGES IN TRANSCRIPTS INVOLVED IN CHOLESTEROL BIOSYNTHESIS, BETA-OXIDATION, AND MITOCHONDRIAL FUSION IN MULTIPLE TISSUES. OVERALL, THIS STUDY SHOWS THAT CHRONIC HYPOXIA ROBUSTLY INDUCES EXPRESSION OF OXYGEN-SENSING MACHINERY ACROSS TISSUES, INDUCES REPRESSIVE TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL EPIGENETIC MARKS ESPECIALLY IN THE CHRONIC HYPOXIA-ACCLIMATED BRAIN AND SUPPORTS A ROLE FOR MEMBRANE REMODELING AND MITOCHONDRIAL FUNCTION AND DYNAMICS IN PROMOTING METABOLIC SUPPRESSION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
9 1117  30 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
10 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
11 3604  31 IMPROVEMENT OF PHYSICAL DECLINE THROUGH COMBINED EFFECTS OF MUSCLE ENHANCEMENT AND MITOCHONDRIAL ACTIVATION BY A GASTRIC HORMONE GHRELIN IN MALE 5/6NX CKD MODEL MICE. BECAUSE A PHYSICAL DECLINE CORRELATES WITH AN INCREASED RISK OF A WIDE RANGE OF DISEASE AND MORBIDITY, AN IMPROVEMENT OF PHYSICAL PERFORMANCE IS EXPECTED TO BRING SIGNIFICANT CLINICAL BENEFITS. THE PRIMARY CAUSE OF PHYSICAL DECLINE IN 5/6 NEPHRECTOMIZED (5/6NX) CHRONIC KIDNEY DISEASE MODEL MICE HAS BEEN REGARDED AS A DECREASE IN MUSCLE MASS; HOWEVER, OUR RECENT STUDY SHOWED THAT A DECREASE IN MUSCLE MITOCHONDRIA PLAYS A CRITICAL ROLE. IN THE PRESENT STUDY, WE EXAMINED THE EFFECTS OF A GASTRIC HORMONE GHRELIN, WHICH HAS BEEN REPORTED TO PROMOTE MUSCLE MITOCHONDRIAL OXIDATION, ON THE PHYSICAL DECLINE IN THE CHRONIC KIDNEY DISEASE MODEL MICE, FOCUSING ON THE EPIGENETIC MODULATIONS OF A MITOCHONDRIAL ACTIVATOR GENE, PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA COACTIVATOR-1ALPHA (PGC-1ALPHA). GHRELIN TREATMENT IMPROVED A DECLINE IN EXERCISE ENDURANCE OF 5/6NX MICE, ASSOCIATED WITH AN INCREASE IN BOTH OF THE MUSCLE MASS AND MITOCHONDRIAL AMOUNT. THE EXPRESSION LEVEL OF PGC-1ALPHA WAS DECREASED IN THE SKELETAL MUSCLE OF 5/6NX MICE, WHICH WAS ASSOCIATED WITH AN INCREASE IN THE METHYLATION RATIO OF THE CYTOSINE RESIDUE AT 260 BASE PAIRS UPSTREAM OF THE INITIATION POINT. CONVERSELY, GHRELIN TREATMENT DE-METHYLATED THE CYTOSINE RESIDUE AND INCREASED THE EXPRESSION OF PGC-1ALPHA. A REPRESENTATIVE MUSCLE ANABOLIC FACTOR, IGF-1, DID NOT AFFECT THE EXPRESSION OF PGC-1ALPHA AND MUSCLE MITOCHONDRIAL AMOUNT, ALTHOUGH IT INCREASED MUSCLE MASS. AS A RESULT, IGF-1 TREATMENT IN 5/6NX MICE DID NOT INCREASE THE DECREASED EXERCISE ENDURANCE AS EFFECTIVELY AS GHRELIN TREATMENT DID. THESE FINDINGS INDICATE AN ADVANTAGE OF GHRELIN TREATMENT FOR A RECOVERY OF PHYSICAL DECLINE.	2015	
                                                                                                                                                                                                                                                                                                                                                                    
12 4302  42 MICRORNA-223 CONTROLS THE EXPRESSION OF HISTONE DEACETYLASE 2: A NOVEL AXIS IN COPD. REDUCED ACTIVITY OF HISTONE DEACETYLASE 2 (HDAC2) HAS BEEN DESCRIBED IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), BUT THE MECHANISMS RESULTING IN DECREASED EXPRESSION OF THIS IMPORTANT EPIGENETIC MODIFIER REMAIN UNKNOWN. HERE, WE EMPLOYED SEVERAL IN VITRO EXPERIMENTS TO ADDRESS THE ROLE OF MICRORNAS (MIRNAS) ON THE REGULATION OF HDAC2 IN ENDOTHELIAL CELLS. MANIPULATION OF MIRNA LEVELS IN HUMAN PULMONARY ARTERY ENDOTHELIAL CELLS (HPAEC) WAS ACHIEVED BY USING ELECTROPORATION WITH ANTI-MIRNAS AND MIRNA MIMICS. TARGET PREDICTION SOFTWARE IDENTIFIED MIR-223 AS A POTENTIAL REPRESSOR OF HDAC2. IN SUBSEQUENT STIMULATION EXPERIMENTS USING INFLAMMATORY CYTOKINES KNOWN TO BE INCREASED IN PATIENTS WITH COPD, MIR-223 WAS FOUND TO BE SIGNIFICANTLY INDUCED. FUNCTIONAL ANALYSIS DEMONSTRATED THAT OVEREXPRESSION OF MIR-223 DECREASED HDAC2 EXPRESSION AND ACTIVITY IN HPAEC. CONVERSELY, HDAC2 EXPRESSION AND ACTIVITY WAS PRESERVED IN ANTI-MIR-223-TREATED CELLS. DIRECT MIRNA-TARGET INTERACTION WAS CONFIRMED BY REPORTER GENE ASSAY. IN A NEXT STEP, REDUCED EXPRESSION OF HDAC2 WAS FOUND TO INCREASE THE LEVELS OF THE CHEMOKINE FRACTALKINE (CX3CL1). IN VIVO STUDIES CONFIRMED ELEVATED EXPRESSION LEVELS OF MIR-223 IN MICE EXPOSED TO CIGARETTE SMOKE AND IN EMPHYSEMATOUS LUNG TISSUE FROM LPS-TREATED MICE. MOREOVER, A SIGNIFICANT INVERSE CORRELATION OF MIR-223 AND HDAC2 EXPRESSION WAS FOUND IN TWO INDEPENDENT COHORTS OF COPD PATIENTS. THESE DATA EMPHASIZE THAT MIR-223, THE MOST PREVALENT MIRNA IN COPD, CONTROLS EXPRESSION AND ACTIVITY OF HDAC2 IN PULMONARY CELLS, WHICH, IN TURN, MIGHT ALTER THE EXPRESSION PROFILE OF CHEMOKINES. THIS PATHWAY PROVIDES A NOVEL PATHOGENIC LINK BETWEEN DYSREGULATED MIRNA EXPRESSION AND EPIGENETIC ACTIVITY IN COPD. KEY MESSAGES: HISTONE DEACETYLASE 2 IS DIRECTLY TARGETED BY MIR-223. LEVELS OF MIR-223 ARE INDUCED BY INTERLEUKIN-1BETA AND TUMOR NECROSIS FACTOR-ALPHA. MIR-223 CONTROLS THE EXPRESSION OF FRACTALKINE BY TARGETING HISTONE DEACETYLASE 2. MIR-223 LEVELS ARE INCREASED IN COPD MOUSE MODELS. MIR-223 LEVELS INVERSELY CORRELATE WITH HDAC2 EXPRESSION IN COPD PATIENTS.	2016	

13 4544  30 MUSCLE HYPERTROPHY IN HYPOXIA WITH INFLAMMATION IS CONTROLLED BY BROMODOMAIN AND EXTRA-TERMINAL DOMAIN PROTEINS. SOME OF THE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) PATIENTS ENGAGED IN EXERCISE-BASED MUSCLE REHABILITATION PROGRAMS ARE UNRESPONSIVE. TO UNRAVEL THE RESPECTIVE ROLE OF CHRONIC HYPOXIA AND PULMONARY INFLAMMATION ON SOLEUS MUSCLE HYPERTROPHIC CAPACITIES, WE CHALLENGED MALE WISTAR RATS TO REPEATED LIPOPOLYSACCHARIDE INSTILLATIONS, ASSOCIATED OR NOT WITH A CHRONIC HYPOXIA EXPOSURE. MUSCLE HYPERTROPHY WAS INITIATED BY BILATERAL ABLATION OF SOLEUS AGONISTS 1 WEEK BEFORE SACRIFICE. TO UNDERSTAND THE ROLE PLAYED BY THE HISTONE ACETYLATION, WE ALSO TREATED OUR ANIMALS WITH AN INHIBITOR OF BROMODOMAINS AND EXTRA TERMINAL PROTEINS (I-BET) DURING THE WEEK AFTER SURGERY. PULMONARY INFLAMMATION TOTALLY INHIBITED THIS HYPERTROPHY RESPONSE UNDER BOTH NORMOXIC AND HYPOXIC CONDITIONS (26% LOWER THAN CONTROL SURGERY, P < 0.05), CONSISTENT WITH THE S6K1 AND MYOGENIN MEASUREMENTS. CHANGES IN HISTONE ACETYLATION AND CLASS IIA HISTONE DEACETYLASES EXPRESSION, FOLLOWING PULMONARY INFLAMMATION, SUGGESTED A PUTATIVE ROLE FOR HISTONE ACETYLATION SIGNALING IN THE ALTERED HYPERTROPHY RESPONSE. THE I-BET DRUG RESTORED THE HYPERTROPHY RESPONSE SUGGESTING THAT THE NON-RESPONSE OF MUSCLE TO A HYPERTROPHIC STIMULUS COULD BE MODULATED BY EPIGENETIC MECHANISMS, INCLUDING HISTONE-ACETYLATION DEPENDANT PATHWAYS. DRUGS TARGETING SUCH EPIGENETIC MECHANISMS MAY OPEN THERAPEUTIC PERSPECTIVES FOR COPD PATIENTS WITH SYSTEMIC INFLAMMATION WHO ARE UNRESPONSIVE TO REHABILITATION.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
14 1708  35 DYSFUNCTION OF ENDOTHELIAL PROGENITOR CELLS FROM SMOKERS AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE PATIENTS DUE TO INCREASED DNA DAMAGE AND SENESCENCE. CARDIOVASCULAR DISEASE (CVD) IS A MAJOR CAUSE OF DEATH IN SMOKERS, PARTICULARLY IN THOSE WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). CIRCULATING ENDOTHELIAL PROGENITOR CELLS (EPC) ARE REQUIRED FOR ENDOTHELIAL HOMEOSTASIS, AND THEIR DYSFUNCTION CONTRIBUTES TO CVD. TO INVESTIGATE EPC DYSFUNCTION IN SMOKERS, WE ISOLATED AND EXPANDED BLOOD OUTGROWTH ENDOTHELIAL CELLS (BOEC) FROM PERIPHERAL BLOOD SAMPLES FROM HEALTHY NONSMOKERS, HEALTHY SMOKERS, AND COPD PATIENTS. BOEC FROM SMOKERS AND COPD PATIENTS SHOWED INCREASED DNA DOUBLE-STRAND BREAKS AND SENESCENCE COMPARED TO NONSMOKERS. SENESCENCE NEGATIVELY CORRELATED WITH THE EXPRESSION AND ACTIVITY OF SIRTUIN-1 (SIRT1), A PROTEIN DEACETYLASE THAT PROTECTS AGAINST DNA DAMAGE AND CELLULAR SENESCENCE. INHIBITION OF DNA DAMAGE RESPONSE BY SILENCING OF ATAXIA TELANGIECTASIA MUTATED (ATM) KINASE RESULTED IN UPREGULATION OF SIRT1 EXPRESSION AND DECREASED SENESCENCE. TREATMENT OF BOEC FROM COPD PATIENTS WITH THE SIRT1 ACTIVATOR RESVERATROL OR AN ATM INHIBITOR (KU-55933) ALSO RESCUED THE SENESCENT PHENOTYPE. USING AN IN VIVO MOUSE MODEL OF ANGIOGENESIS, WE DEMONSTRATED THAT SENESCENT BOEC FROM COPD PATIENTS ARE DYSFUNCTIONAL, DISPLAYING IMPAIRED ANGIOGENIC ABILITY AND INCREASED APOPTOSIS COMPARED TO CELLS FROM HEALTHY NONSMOKERS. THEREFORE, THIS STUDY IDENTIFIES EPIGENETIC REGULATION OF DNA DAMAGE AND SENESCENCE AS PATHOGENETIC MECHANISMS LINKED TO ENDOTHELIAL PROGENITORS' DYSFUNCTION IN SMOKERS AND COPD PATIENTS. THESE DEFECTS MAY CONTRIBUTE TO VASCULAR DISEASE AND CARDIOVASCULAR EVENTS IN SMOKERS AND COULD THEREFORE CONSTITUTE THERAPEUTIC TARGETS FOR INTERVENTION.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                     
15 1251  24 CURRENT PERSPECTIVES ON ROLE OF CHROMATIN MODIFICATIONS AND DEACETYLASES IN LUNG INFLAMMATION IN COPD. CHROMATIN MODIFICATIONS AND EPIGENETIC REGULATION ARE CRITICAL FOR SUSTAINED AND ABNORMAL INFLAMMATORY RESPONSE SEEN IN LUNGS OF PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) BECAUSE THE ACTIVITIES OF ENZYMES THAT REGULATE THESE EPIGENETIC MODIFICATIONS ARE ALTERED IN RESPONSE TO CIGARETTE SMOKE. CIGARETTE SMOKE INDUCES CHROMATIN MODIFICATIONS AND EPIGENETIC CHANGES BY CAUSING POST-TRANSLATIONAL MODIFICATIONS OF HISTONE ACETYLTRANSFERASES, AND HISTONE/NON-HISTONE DEACETYLASES (HDACS), SUCH AS HDAC2 AND SIRTUIN 1 (SIRT1), WHICH LEADS TO CHROMATIN REMODELING. IN THIS REVIEW, WE DISCUSSED THE CURRENT KNOWLEDGE ON CIGARETTE SMOKE/OXIDANTS-INDUCED POST-TRANSLATIONAL MODIFICATIONS OF DEACETYLASES (HDAC2 AND SIRT1), DISRUPTION OF HDAC2/SIRT1-RELA/P65 COREPRESSOR COMPLEX ASSOCIATED WITH ACETYLATION OF RELA/P65, AND CHROMATIN MODIFICATIONS (HISTONE H3 PHOSPHO-ACETYLATION) LEADING TO SUSTAINED PRO-INFLAMMATORY GENE TRANSCRIPTION. KNOWLEDGE ON MOLECULAR MECHANISMS OF EPIGENETIC CHANGES IN ABNORMAL LUNG INFLAMMATION WILL HELP IN UNDERSTANDING THE PATHOPHYSIOLOGY OF COPD WHICH MAY LEAD TO THE DEVELOPMENT OF NOVEL EPIGENETIC THERAPIES IN THE NEAR FUTURE.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
16 5972  25 TET REPRESSION AND INCREASED DNMT ACTIVITY SYNERGISTICALLY INDUCE ABERRANT DNA METHYLATION. CHRONIC INFLAMMATION IS DEEPLY INVOLVED IN VARIOUS HUMAN DISORDERS, SUCH AS CANCER, NEURODEGENERATIVE DISORDERS, AND METABOLIC DISORDERS. INDUCTION OF EPIGENETIC ALTERATIONS, ESPECIALLY ABERRANT DNA METHYLATION, IS ONE OF THE MAJOR MECHANISMS, BUT HOW IT IS INDUCED IS STILL UNCLEAR. HERE, WE FOUND THAT EXPRESSION OF TET GENES, METHYLATION ERASERS, WAS DOWNREGULATED IN INFLAMED MOUSE AND HUMAN TISSUES, AND THAT THIS WAS CAUSED BY UPREGULATION OF TET-TARGETING MIRNAS SUCH AS MIR20A, MIR26B, AND MIR29C, LIKELY DUE TO ACTIVATION OF NF-KAPPAB SIGNALING DOWNSTREAM OF IL-1BETA AND TNF-ALPHA. HOWEVER, TET KNOCKDOWN INDUCED ONLY MILD ABERRANT METHYLATION. NITRIC OXIDE (NO), PRODUCED BY NOS2, ENHANCED ENZYMATIC ACTIVITY OF DNA METHYLTRANSFERASES (DNMTS), METHYLATION WRITERS, AND NO EXPOSURE INDUCED MINIMAL ABERRANT METHYLATION. IN CONTRAST, A COMBINATION OF TET KNOCKDOWN AND NO EXPOSURE SYNERGISTICALLY INDUCED ABERRANT METHYLATION, INVOLVING GENOMIC REGIONS NOT METHYLATED BY EITHER ALONE. THE RESULTS SHOWED THAT A VICIOUS COMBINATION OF TET REPRESSION, DUE TO NF-KAPPAB ACTIVATION, AND DNMT ACTIVATION, DUE TO NO PRODUCTION, IS RESPONSIBLE FOR ABERRANT METHYLATION INDUCTION IN HUMAN TISSUES.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
17 1326  23 DEPLETION OF NUCLEAR HISTONE H2A VARIANTS IS ASSOCIATED WITH CHRONIC DNA DAMAGE SIGNALING UPON DRUG-EVOKED SENESCENCE OF HUMAN SOMATIC CELLS. CELLULAR SENESCENCE IS ASSOCIATED WITH GLOBAL CHROMATIN CHANGES, ALTERED GENE EXPRESSION, AND ACTIVATION OF CHRONIC DNA DAMAGE SIGNALING. THESE EVENTS ULTIMATELY LEAD TO MORPHOLOGICAL AND PHYSIOLOGICAL TRANSFORMATIONS IN PRIMARY CELLS. IN THIS STUDY, WE SHOW THAT CHRONIC DNA DAMAGE SIGNALS CAUSED BY GENOTOXIC STRESS IMPACT THE EXPRESSION OF HISTONES H2A FAMILY MEMBERS AND LEAD TO THEIR DEPLETION IN THE NUCLEI OF SENESCENT HUMAN FIBROBLASTS. OUR DATA REINFORCE THE HYPOTHESIS THAT PROGRESSIVE CHROMATIN DESTABILIZATION MAY LEAD TO THE LOSS OF EPIGENETIC INFORMATION AND IMPAIRED CELLULAR FUNCTION ASSOCIATED WITH CHRONIC DNA DAMAGE UPON DRUG-EVOKED SENESCENCE. WE PROPOSE THAT CHANGES IN THE HISTONE BIOSYNTHESIS AND CHROMATIN ASSEMBLY MAY DIRECTLY CONTRIBUTE TO CELLULAR AGING. IN ADDITION, WE ALSO OUTLINE THE METHOD THAT ALLOWS FOR QUANTITATIVE AND UNBIASED MEASUREMENT OF THESE CHANGES.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
18 6431  31 THE USE OF TARGETED NEXT GENERATION SEQUENCING TO EXPLORE CANDIDATE REGULATORS OF TGF-BETA1'S IMPACT ON KIDNEY CELLS. AIMS/HYPOTHESIS: TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA1) PLAYS AN IMPORTANT REGULATORY ROLE IN THE PROGRESSION OF CHRONIC KIDNEY FAILURE. FURTHER, DAMAGE TO KIDNEY GLOMERULAR MESANGIAL CELLS IS CENTRAL TO THE PROGRESSION OF DIABETIC NEPHROPATHY. THE AIM OF THIS STUDY WAS TO EXPLORE THE GENETIC ASSOCIATIONS BETWEEN MRNA, MICRORNA, AND EPIGENETICS IN MESANGIAL CELLS IN RESPONSE TO TGF-BETA1. METHODS: THE REGULATORY EFFECTS OF TGF-BETA1 ON MESANGIAL CELLS WERE INVESTIGATED AT DIFFERENT MOLECULAR LEVELS BY TREATING MESANGIAL CELLS WITH TGF-BETA1 FOR 3 DAYS FOLLOWED BY GENOME-WIDE MIRNA, RNA, DNA METHYLATION, AND H3K27ME3 EXPRESSION PROFILING USING NEXT GENERATION SEQUENCING (NGS). RESULTS: OUR RESULTS PROVIDE THE FIRST COMPREHENSIVE, COMPUTATIONALLY INTEGRATED REPORT OF RNA-SEQ, MIRNA-SEQ, AND EPIGENOMIC ANALYSES ACROSS ALL GENETIC VARIATIONS, CONFIRMING THE OCCURRENCE OF DNA METHYLATION AND H3K27ME3 IN RESPONSE TO TGF-BETA1. OUR FINDINGS SHOW THAT THE EXPRESSION OF KLF7 AND GJA4 ARE INVOLVED IN TGF-BETA1 REGULATED DNA METHYLATION. OUR DATA ALSO PROVIDE EVIDENCE OF THE ASSOCIATION BETWEEN EPIGENETIC CHANGES AND THE EXPRESSION OF GENES CLOSELY RELATED TO TGF-BETA1 REGULATION. CONCLUSION: THIS STUDY HAS ADVANCED OUR CURRENT KNOWLEDGE OF MECHANISMS THAT CONTRIBUTE TO THE EXPRESSION OF TGF-BETA1-REGULATED GENES INVOLVED IN THE PATHOGENESIS OF KIDNEY DISEASE. THE MOLECULAR UNDERPINNINGS OF TGF-BETA1 STIMULATION OF KIDNEY CELLS WAS DETERMINED, THEREBY PROVIDING A ROBUST PLATFORM FOR FURTHER TARGET EXPLORATION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
19 2022  39 EPIGENETIC CHANGES ASSOCIATED WITH DISEASE PROGRESSION IN A MOUSE MODEL OF CHILDHOOD ALLERGIC ASTHMA. DEVELOPMENT OF ASTHMA IN CHILDHOOD IS LINKED TO VIRAL INFECTIONS OF THE LOWER RESPIRATORY TRACT IN EARLY LIFE, WITH SUBSEQUENT CHRONIC EXPOSURE TO ALLERGENS. PROGRESSION TO PERSISTENT ASTHMA IS ASSOCIATED WITH A TH2-BIASED IMMUNOLOGICAL RESPONSE AND STRUCTURAL REMODELLING OF THE AIRWAYS. THE UNDERLYING MECHANISMS ARE UNCLEAR, BUT COULD INVOLVE EPIGENETIC CHANGES. TO INVESTIGATE THIS, WE EMPLOYED A RECENTLY DEVELOPED MOUSE MODEL IN WHICH SELF-LIMITED NEONATAL INFECTION WITH A PNEUMOVIRUS, FOLLOWED BY SENSITISATION TO OVALBUMIN VIA THE RESPIRATORY TRACT AND LOW-LEVEL CHRONIC CHALLENGE WITH AEROSOLISED ANTIGEN, LEADS TO DEVELOPMENT OF AN ASTHMATIC PHENOTYPE. WE ASSESSED EXPRESSION OF MICRORNA BY CELLS IN THE PROXIMAL AIRWAYS, COMPARING CHANGES OVER THE PERIOD OF DISEASE PROGRESSION, AND USED TARGET PREDICTION DATABASES TO IDENTIFY GENES LIKELY TO BE UP- OR DOWNREGULATED AS A CONSEQUENCE OF ALTERED REGULATION OF MICRORNA. IN PARALLEL, WE ASSESSED DNA METHYLATION IN PULMONARY CD4(+) T CELLS. WE FOUND THAT A LIMITED NUMBER OF MICRORNAS EXHIBITED MARKED UP- OR DOWNREGULATION FOLLOWING EARLY-LIFE INFECTION AND SENSITISATION, FOR MANY OF WHICH THE LEVELS OF EXPRESSION WERE FURTHER CHANGED FOLLOWING CHRONIC CHALLENGE WITH THE SENSITIZING ANTIGEN. TARGETS OF THESE MICRORNAS INCLUDED GENES INVOLVED IN IMMUNE OR INFLAMMATORY RESPONSES (E.G. GATA3, KITL) AND IN TISSUE REMODELLING (E.G. IGF1, TGFBR1), AS WELL AS GENES FOR VARIOUS TRANSCRIPTION FACTORS AND SIGNALLING PROTEINS. IN PULMONARY CD4(+) T CELLS, THERE WAS SIGNIFICANT DEMETHYLATION AT PROMOTER SITES FOR INTERLEUKIN-4 AND INTERFERON-GAMMA, THE LATTER INCREASING FOLLOWING CHRONIC CHALLENGE. WE CONCLUDE THAT, IN THIS MODEL, PROGRESSION TO AN ASTHMATIC PHENOTYPE IS LINKED TO EPIGENETIC REGULATION OF GENES ASSOCIATED WITH INFLAMMATION AND STRUCTURAL REMODELLING, AND WITH T-CELL COMMITMENT TO A TH2 IMMUNOLOGICAL RESPONSE. EPIGENETIC CHANGES ASSOCIATED WITH THIS PATTERN OF GENE ACTIVATION MIGHT PLAY A ROLE IN THE DEVELOPMENT OF CHILDHOOD ASTHMA.	2013	
                                                                                      
20 5571  36 ROLE OF MICRORNA 1207-5P AND ITS HOST GENE, THE LONG NON-CODING RNA PVT1, AS MEDIATORS OF EXTRACELLULAR MATRIX ACCUMULATION IN THE KIDNEY: IMPLICATIONS FOR DIABETIC NEPHROPATHY. DIABETIC NEPHROPATHY IS THE MOST COMMON CAUSE OF CHRONIC KIDNEY FAILURE AND END-STAGE RENAL DISEASE IN THE WESTERN WORLD. ONE OF THE MAJOR CHARACTERISTICS OF THIS DISEASE IS THE EXCESSIVE ACCUMULATION OF EXTRACELLULAR MATRIX (ECM) IN THE KIDNEY GLOMERULI. WHILE BOTH ENVIRONMENTAL AND GENETIC DETERMINANTS ARE RECOGNIZED FOR THEIR ROLE IN THE DEVELOPMENT OF DIABETIC NEPHROPATHY, EPIGENETIC FACTORS, SUCH AS DNA METHYLATION, LONG NON-CODING RNAS, AND MICRORNAS, HAVE ALSO RECENTLY BEEN FOUND TO UNDERLIE SOME OF THE BIOLOGICAL MECHANISMS, INCLUDING ECM ACCUMULATION, LEADING TO THE DISEASE. WE PREVIOUSLY FOUND THAT A LONG NON-CODING RNA, THE PLASMACYTOMA VARIANT TRANSLOCATION 1 (PVT1), INCREASES PLASMINOGEN ACTIVATOR INHIBITOR 1 (PAI-1) AND TRANSFORMING GROWTH FACTOR BETA 1 (TGF-BETA1) IN MESANGIAL CELLS, THE TWO MAIN CONTRIBUTORS TO ECM ACCUMULATION IN THE GLOMERULI UNDER HYPERGLYCEMIC CONDITIONS, AS WELL AS FIBRONECTIN 1 (FN1), A MAJOR ECM COMPONENT. HERE, WE REPORT THAT MIR-1207-5P, A PVT1-DERIVED MICRORNA, IS ABUNDANTLY EXPRESSED IN KIDNEY CELLS, AND IS UPREGULATED BY GLUCOSE AND TGF-BETA1. WE ALSO FOUND THAT LIKE PVT1, MIR-1207-5P INCREASES EXPRESSION OF TGF-BETA1, PAI-1, AND FN1 BUT IN A MANNER THAT IS INDEPENDENT OF ITS HOST GENE. IN ADDITION, REGULATION OF MIR-1207-5P EXPRESSION BY GLUCOSE AND TGFBETA1 IS INDEPENDENT OF PVT1. THESE RESULTS PROVIDE EVIDENCE SUPPORTING IMPORTANT ROLES FOR MIR-1207-5P AND ITS HOST GENE IN THE COMPLEX PATHOGENESIS OF DIABETIC NEPHROPATHY.	2013