1 1690 106 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 2 5334 21 QUADRICEPS MUSCLE WEAKNESS AND ATROPHY ARE ASSOCIATED WITH A DIFFERENTIAL EPIGENETIC PROFILE IN ADVANCED COPD. EPIGENETIC MECHANISMS REGULATE MUSCLE MASS AND FUNCTION IN MODELS OF MUSCLE DYSFUNCTION AND ATROPHY. WE ASSESSED WHETHER QUADRICEPS MUSCLE WEAKNESS AND ATROPHY ARE ASSOCIATED WITH A DIFFERENTIAL EXPRESSION PROFILE OF EPIGENETIC EVENTS IN PATIENTS WITH ADVANCED COPD (CHRONIC OBSTRUCTIVE PULMONARY DISEASE). IN VASTUS LATERALIS (VL) OF SEDENTARY SEVERE COPD PATIENTS (N=41), WHO WERE FURTHER SUBDIVIDED INTO THOSE WITH (N=25) AND WITHOUT (N=16) MUSCLE WEAKNESS AND HEALTHY CONTROLS (N=19), EXPRESSION OF MUSCLE-ENRICHED MIRNAS, HISTONE ACETYLTRANSFERASES (HATS) AND DEACETYLASES (HDACS), GROWTH AND ATROPHY SIGNALLING MARKERS, TOTAL PROTEIN AND HISTONE ACETYLATION, TRANSCRIPTION FACTORS, SMALL UBIQUITIN-RELATED MODIFIER (SUMO) LIGASES AND MUSCLE STRUCTURE WERE EXPLORED. ALL SUBJECTS WERE CLINICALLY EVALUATED. COMPARED WITH CONTROLS, IN VL OF ALL COPD TOGETHER AND IN MUSCLE-WEAKNESS PATIENTS, EXPRESSION OF MIR-1, MIR-206 AND MIR-27A, LEVELS OF LYSINE-ACETYLATED PROTEINS AND HISTONES AND ACETYLATED HISTONE 3 WERE INCREASED, WHEREAS EXPRESSION OF HDAC3, HDAC4, SIRTUIN-1 (SIRT-1), IGF-1 (INSULIN-LIKE GROWTH FACTOR-1) WERE DECREASED, AKT (V-AKT MURINE THYMOMA VIRAL ONCOGENE HOMOLOGUE 1) EXPRESSION DID NOT DIFFER, FOLLISTATIN EXPRESSION WAS GREATER, WHEREAS MYOSTATIN EXPRESSION WAS LOWER, SERUM REPONSE FACTOR (SRF) EXPRESSION WAS INCREASED AND FIBRE SIZE OF FAST-TWITCH FIBRES WAS SIGNIFICANTLY REDUCED. IN VL OF SEVERE COPD PATIENTS WITH MUSCLE WEAKNESS AND ATROPHY, EPIGENETIC EVENTS REGULATE MUSCLE DIFFERENTIATION RATHER THAN PROLIFERATION AND MUSCLE GROWTH AND ATROPHY SIGNALLING, PROBABLY AS FEEDBACK MECHANISMS TO PREVENT THOSE MUSCLES FROM UNDERGOING FURTHER ATROPHY. LYSINE-HYPERACETYLATION OF HISTONES MAY DRIVE ENHANCED PROTEIN CATABOLISM IN THOSE MUSCLES. THESE FINDINGS MAY HELP DESIGN NOVEL THERAPEUTIC STRATEGIES (ENHANCERS OF MIRNAS PROMOTING MYOGENESIS AND ACETYLATION INHIBITORS) TO SELECTIVELY TARGET MUSCLE WEAKNESS AND ATROPHY IN SEVERE COPD. 2015 3 4577 27 MYOSTATIN: BASIC BIOLOGY TO CLINICAL APPLICATION. MYOSTATIN IS A MEMBER OF THE TRANSFORMING GROWTH FACTOR (TGF)-BETA SUPERFAMILY. IT IS EXPRESSED BY ANIMAL AND HUMAN SKELETAL MUSCLE CELLS WHERE IT LIMITS MUSCLE GROWTH AND PROMOTES PROTEIN BREAKDOWN. ITS EFFECTS ARE INFLUENCED BY COMPLEX MECHANISMS INCLUDING TRANSCRIPTIONAL AND EPIGENETIC REGULATION AND MODULATION BY EXTRACELLULAR BINDING PROTEINS. DUE TO ITS ACTIONS IN PROMOTING MUSCLE ATROPHY AND CACHEXIA, MYOSTATIN HAS BEEN INVESTIGATED AS A PROMISING THERAPEUTIC TARGET TO COUNTERACT MUSCLE MASS LOSS IN EXPERIMENTAL MODELS AND PATIENTS AFFECTED BY DIFFERENT MUSCLE-WASTING CONDITIONS. MOREOVER, GROWING EVIDENCE INDICATES THAT MYOSTATIN, BEYOND TO REGULATE SKELETAL MUSCLE GROWTH, MAY HAVE A ROLE IN MANY PHYSIOLOGIC AND PATHOLOGIC PROCESSES, SUCH AS OBESITY, INSULIN RESISTANCE, CARDIOVASCULAR AND CHRONIC KIDNEY DISEASE. IN THIS CHAPTER, WE REVIEW MYOSTATIN BIOLOGY, INCLUDING INTRACELLULAR AND EXTRACELLULAR REGULATORY PATHWAYS, AND THE ROLE OF MYOSTATIN IN MODULATING PHYSIOLOGIC PROCESSES, SUCH AS MUSCLE GROWTH AND AGING. MOREOVER, WE DISCUSS THE MOST RELEVANT EXPERIMENTAL AND CLINICAL EVIDENCE SUPPORTING THE EXTRA-MUSCLE EFFECTS OF MYOSTATIN. FINALLY, WE CONSIDER THE MAIN STRATEGIES DEVELOPED AND TESTED TO INHIBIT MYOSTATIN IN CLINICAL TRIALS AND DISCUSS THE LIMITS AND FUTURE PERSPECTIVES OF THE RESEARCH ON MYOSTATIN. 2022 4 4507 26 MRTF: BASIC BIOLOGY AND ROLE IN KIDNEY DISEASE. A LESSER KNOWN BUT CRUCIALLY IMPORTANT DOWNSTREAM EFFECT OF RHO FAMILY GTPASES IS THE REGULATION OF GENE EXPRESSION. THIS MAJOR ROLE IS MEDIATED VIA THE CYTOSKELETON, THE ORGANIZATION OF WHICH DICTATES THE NUCLEOCYTOPLASMIC SHUTTLING OF A SET OF TRANSCRIPTION FACTORS. CENTRAL AMONG THESE IS MYOCARDIN-RELATED TRANSCRIPTION FACTOR (MRTF), WHICH UPON ACTIN POLYMERIZATION TRANSLOCATES TO THE NUCLEUS AND BINDS TO ITS COGNATE PARTNER, SERUM RESPONSE FACTOR (SRF). THE MRTF/SRF COMPLEX THEN DRIVES A LARGE COHORT OF GENES INVOLVED IN CYTOSKELETON REMODELING, CONTRACTILITY, EXTRACELLULAR MATRIX ORGANIZATION AND MANY OTHER PROCESSES. ACCORDINGLY, MRTF, ACTIVATED BY A VARIETY OF MECHANICAL AND CHEMICAL STIMULI, AFFECTS A PLETHORA OF FUNCTIONS WITH PHYSIOLOGICAL AND PATHOLOGICAL RELEVANCE. THESE INCLUDE CELL MOTILITY, DEVELOPMENT, METABOLISM AND THUS METASTASIS FORMATION, INFLAMMATORY RESPONSES AND-PREDOMINANTLY-ORGAN FIBROSIS. THE AIM OF THIS REVIEW IS TWOFOLD: TO PROVIDE AN UP-TO-DATE SUMMARY ABOUT THE BASIC BIOLOGY AND REGULATION OF THIS VERSATILE TRANSCRIPTIONAL COACTIVATOR; AND TO HIGHLIGHT ITS PRINCIPAL INVOLVEMENT IN THE PATHOBIOLOGY OF KIDNEY DISEASE. ACTING THROUGH BOTH DIRECT TRANSCRIPTIONAL AND EPIGENETIC MECHANISMS, MRTF PLAYS A KEY (YET NOT FULLY APPRECIATED) ROLE IN THE INDUCTION OF A PROFIBROTIC EPITHELIAL PHENOTYPE (PEP) AS WELL AS IN FIBROBLAST-MYOFIBROBLAST TRANSITION, PRIME PATHOMECHANISMS IN CHRONIC KIDNEY DISEASE AND RENAL FIBROSIS. 2021 5 2314 29 EPIGENETIC REGULATION OF ENDOTHELIAL-TO-MESENCHYMAL TRANSITION IN CHRONIC HEART DISEASE. ENDOTHELIAL-TO-MESENCHYMAL TRANSITION (ENDMT) IS A PROCESS IN WHICH ENDOTHELIAL CELLS LOSE THEIR PROPERTIES AND TRANSFORM INTO FIBROBLAST-LIKE CELLS. THIS TRANSITION PROCESS CONTRIBUTES TO CARDIAC FIBROSIS, A COMMON FEATURE OF PATIENTS WITH CHRONIC HEART FAILURE. TO DATE, NO SPECIFIC THERAPIES TO HALT OR REVERSE CARDIAC FIBROSIS ARE AVAILABLE, SO KNOWLEDGE OF THE UNDERLYING MECHANISMS OF CARDIAC FIBROSIS IS URGENTLY NEEDED. IN ADDITION, ENDMT CONTRIBUTES TO OTHER CARDIOVASCULAR PATHOLOGIES SUCH AS ATHEROSCLEROSIS AND PULMONARY HYPERTENSION, BUT ALSO TO CANCER AND ORGAN FIBROSIS. REMARKABLY, THE MOLECULAR MECHANISMS DRIVING ENDMT ARE LARGELY UNKNOWN. EPIGENETICS PLAY AN IMPORTANT ROLE IN REGULATING GENE TRANSCRIPTION AND TRANSLATION AND HAVE BEEN IMPLICATED IN THE ENDMT PROCESS. THEREFORE, EPIGENETICS MIGHT BE THE MISSING LINK IN UNRAVELING THE UNDERLYING MECHANISMS OF ENDMT. HERE, WE REVIEW THE INVOLVEMENT OF EPIGENETIC REGULATORS DURING ENDMT IN THE CONTEXT OF CARDIAC FIBROSIS. THE ROLE OF DNA METHYLATION, HISTONE MODIFICATIONS (ACETYLATION AND METHYLATION), AND NONCODING RNAS (MICRORNAS, LONG NONCODING RNAS, AND CIRCULAR RNAS) IN THE FACILITATION AND INHIBITION OF ENDMT ARE DISCUSSED, AND POTENTIAL THERAPEUTIC EPIGENETIC TARGETS WILL BE HIGHLIGHTED. 2018 6 1633 24 DO EPIGENETIC EVENTS TAKE PLACE IN THE VASTUS LATERALIS OF PATIENTS WITH MILD CHRONIC OBSTRUCTIVE PULMONARY DISEASE? MUSCLE DYSFUNCTION IS A MAJOR COMORBIDITY IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). SEVERAL BIOLOGICAL MECHANISMS INCLUDING EPIGENETIC EVENTS REGULATE MUSCLE MASS AND FUNCTION IN MODELS OF MUSCLE ATROPHY. INVESTIGATIONS CONDUCTED SO FAR HAVE FOCUSED ON THE ELUCIDATION OF BIOLOGICAL MECHANISMS INVOLVED IN MUSCLE DYSFUNCTION IN ADVANCED COPD. WE ASSESSED WHETHER THE EPIGENETIC PROFILE MAY BE ALTERED IN THE VASTUS LATERALIS OF PATIENTS WITH MILD COPD, NORMAL BODY COMPOSITION, AND MILDLY IMPAIRED MUSCLE FUNCTION AND EXERCISE CAPACITY. IN VASTUS LATERALIS (VL) OF MILD COPD PATIENTS WITH WELL-PRESERVED BODY COMPOSITION AND IN HEALTHY AGE-MATCHED CONTROLS, EXPRESSION OF DNA METHYLATION, MUSCLE-ENRICHED MICRORNAS, HISTONE ACETYLTRANSFERASES (HTAS) AND DEACETYLASES (HDACS), PROTEIN ACETYLATION, SMALL UBIQUITIN-RELATED MODIFIER (SUMO) LIGASES, AND MUSCLE STRUCTURE WERE EXPLORED. ALL SUBJECTS WERE CLINICALLY EVALUATED. COMPARED TO HEALTHY CONTROLS, IN THE VL OF MILD COPD PATIENTS, MUSCLE FUNCTION AND EXERCISE CAPACITY WERE MODERATELY REDUCED, DNA METHYLATION LEVELS DID NOT DIFFER, MIR-1 EXPRESSION LEVELS WERE INCREASED AND POSITIVELY CORRELATED WITH BOTH FORCED EXPIRATORY VOLUME IN ONE SECOND (FEV1) AND QUADRICEPS FORCE, HDAC4 PROTEIN LEVELS WERE INCREASED, AND MUSCLE FIBER TYPES AND SIZES WERE NOT DIFFERENT. MODERATE SKELETAL MUSCLE DYSFUNCTION IS A RELEVANT FEATURE IN PATIENTS WITH MILD COPD AND PRESERVED BODY COMPOSITION. SEVERAL EPIGENETIC EVENTS ARE DIFFERENTIALLY EXPRESSED IN THE LIMB MUSCLES OF THESE PATIENTS, PROBABLY AS AN ATTEMPT TO COUNTERBALANCE THE UNDERLYING MECHANISMS THAT ALTER MUSCLE FUNCTION AND MASS. THE STUDY OF PATIENTS AT EARLY STAGES OF THEIR DISEASE IS OF INTEREST AS THEY ARE A TARGET FOR TIMELY THERAPEUTIC INTERVENTIONS THAT MAY SLOW DOWN THE COURSE OF THE DISEASE AND PREVENT THE DELETERIOUS EFFECTS OF MAJOR COMORBIDITIES. 2014 7 673 35 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 8 5860 33 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 6417 25 THE SWI/SNF CHROMATIN REMODELING COMPLEXES BAF AND PBAF DIFFERENTIALLY REGULATE EPIGENETIC TRANSITIONS IN EXHAUSTED CD8(+) T CELLS. CD8(+) T CELL EXHAUSTION (TEX) LIMITS DISEASE CONTROL DURING CHRONIC VIRAL INFECTIONS AND CANCER. HERE, WE INVESTIGATED THE EPIGENETIC FACTORS MEDIATING MAJOR CHROMATIN-REMODELING EVENTS IN TEX-CELL DEVELOPMENT. A PROTEIN-DOMAIN-FOCUSED IN VIVO CRISPR SCREEN IDENTIFIED DISTINCT FUNCTIONS FOR TWO VERSIONS OF THE SWI/SNF CHROMATIN-REMODELING COMPLEX IN TEX-CELL DIFFERENTIATION. DEPLETION OF THE CANONICAL SWI/SNF FORM, BAF, IMPAIRED INITIAL CD8(+) T CELL RESPONSES IN ACUTE AND CHRONIC INFECTION. IN CONTRAST, DISRUPTION OF PBAF ENHANCED TEX-CELL PROLIFERATION AND SURVIVAL. MECHANISTICALLY, PBAF REGULATED THE EPIGENETIC AND TRANSCRIPTIONAL TRANSITION FROM TCF-1(+) PROGENITOR TEX CELLS TO MORE DIFFERENTIATED TCF-1(-) TEX SUBSETS. WHEREAS PBAF ACTED TO PRESERVE TEX PROGENITOR BIOLOGY, BAF WAS REQUIRED TO GENERATE EFFECTOR-LIKE TEX CELLS, SUGGESTING THAT THE BALANCE OF THESE FACTORS COORDINATES TEX-CELL SUBSET DIFFERENTIATION. TARGETING PBAF IMPROVED TUMOR CONTROL BOTH ALONE AND IN COMBINATION WITH ANTI-PD-L1 IMMUNOTHERAPY. THUS, PBAF MAY PRESENT A THERAPEUTIC TARGET IN CANCER IMMUNOTHERAPY. 2023 10 3519 28 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 11 5679 16 SHORT- AND LONG-TERM HINDLIMB IMMOBILIZATION AND RELOADING: PROFILE OF EPIGENETIC EVENTS IN GASTROCNEMIUS. SKELETAL MUSCLE DYSFUNCTION AND ATROPHY ARE CHARACTERISTIC FEATURES ACCOMPANYING CHRONIC CONDITIONS. EPIGENETIC EVENTS REGULATE MUSCLE MASS AND FUNCTION MAINTENANCE. WE HYPOTHESIZED THAT THE PATTERN OF EPIGENETIC EVENTS (MUSCLE-ENRICHED MICRORNAS AND HISTONE ACETYLATION) AND ACETYLATION OF TRANSCRIPTION FACTORS KNOWN TO SIGNAL MUSCLE WASTING MAY DIFFER BETWEEN EARLY- AND LATE-TIME POINTS IN SKELETAL MUSCLES OF MICE EXPOSED TO HINDLIMB IMMOBILIZATION (I) AND RECOVERY FOLLOWING I. BODY AND MUSCLE WEIGHTS, GRIP STRENGTH, MUSCLE-ENRICHED MICRORNAS, HISTONE DEACETYLASES (HDACS), ACETYLATION OF PROTEINS, HISTONES, AND TRANSCRIPTION FACTORS (TF), MYOGENIC TF FACTORS, AND MUSCLE PHENOTYPE WERE ASSESSED IN GASTROCNEMIUS OF MICE EXPOSED TO PERIODS (1, 2, 3, 7, 15, AND 30 DAYS, I GROUPS) OF HINDLIMB IMMOBILIZATION, AND IN THOSE EXPOSED TO RELOADING FOR DIFFERENT PERIODS OF TIME (1, 3, 7, 15, AND 30 DAYS, R GROUPS) FOLLOWING 7-DAY IMMOBILIZATION. COMPARED TO NON-IMMOBILIZED CONTROLS, MUSCLE WEIGHT, LIMB STRENGTH, MICRORNAS, ESPECIALLY MIR-486, SIRT1 LEVELS, AND SLOW- AND FAST-TWITCH CROSS-SECTIONAL AREAS WERE DECREASED IN MICE OF I GROUPS, WHEREAS PAX7 AND ACETYLATED FOXO1 AND FOXO3 LEVELS WERE INCREASED. MUSCLE RELOADING FOLLOWING SPLINT REMOVAL IMPROVED MUSCLE MASS LOSS, STRENGTH, AND FIBER ATROPHY, BY INCREASING MICRORNAS, PARTICULARLY MIR-486, AND SIRT1 CONTENT, WHILE DECREASING ACETYLATED FOXO1 AND FOXO3 LEVELS. IN THIS MOUSE MODEL OF DISUSE MUSCLE ATROPHY, MUSCLE-ENRICHED MICRORNAS, ESPECIALLY MIR-486, THROUGH PAX7 REGULATION DELAYED MUSCLE CELL DIFFERENTIATION FOLLOWING UNLOADING OF GASTROCNEMIUS MUSCLE. ACETYLATION OF FOXO1 AND 3 SEEMED TO DRIVE MUSCLE MASS LOSS AND ATROPHY, WHILE DEACETYLATION OF THESE FACTORS THROUGH SIRT1 WOULD ENABLE THE MUSCLE FIBERS TO REGENERATE. J. CELL. PHYSIOL. 232: 1415-1427, 2017. (C) 2016 WILEY PERIODICALS, INC. 2017 12 3730 25 INHIBITION OF THE COREST REPRESSOR COMPLEX PROMOTES WOUND RE-EPITHELIALIZATION VIA REGULATION OF KERATINOCYTE MIGRATION. WOUND HEALING IS A COMPLEX PROCESS INVOLVING PHASES OF HEMOSTASIS, INFLAMMATION, PROLIFERATION, AND REMODELING. THE REGENERATIVE PROCESS IN THE SKIN REQUIRES COORDINATION BETWEEN MANY REGULATORS INCLUDING SIGNALING MOLECULES, TRANSCRIPTION FACTORS AND THE EPIGENETIC MACHINERY. HERE WE SHOW THAT CHROMATIN REGULATORS HISTONE DEACETYLASE 1 (HDAC1) AND LYSINE-SPECIFIC HISTONE DEMETHYLASE 1 (LSD1), KEY COMPONENTS OF THE COREST REPRESSOR COMPLEX, ARE UPREGULATED IN THE REGENERATING EPIDERMIS DURING WOUND REPAIR. WE ALSO SHOW THAT CORIN, A SYNTHETIC DUAL INHIBITOR OF THE COREST COMPLEX AND HDAC1/LSD1 ACTIVITIES, SIGNIFICANTLY ACCELERATES WOUND CLOSURE THROUGH ENHANCED RE-EPITHELIALIZATION IN A MOUSE TAIL WOUND MODEL. ACETYLATED H3K9 EXPRESSION, A HISTONE MODIFICATION TARGETED BY HDAC1, IS INCREASED IN KERATINOCYTES AFTER TOPICAL TREATMENT WITH 100 NM AND 1 MUM OF CORIN. IN VITRO EXPERIMENTS DEMONSTRATE THAT CORIN PROMOTES MIGRATION AND INHIBITS PROLIFERATION OF HUMAN KERATINOCYTES. FURTHERMORE, EXPRESSION LEVELS OF GENES PROMOTING KERATINOCYTE MIGRATION, SUCH AS AREG, CD24, EPHB2, ITGAX, PTGS, SCT1, SERPINB2, SERPINE1, SLPI, SNAI2 AND TWIST INCREASED IN KERATINOCYTES TREATED WITH CORIN. THESE DATA DEMONSTRATE THAT DUAL INHIBITION OF CLASS I HDACS AND LSD1 BY CORIN, MAY SERVE AS A NEW APPROACH FOR PROMOTING WOUND RE-EPITHELIALIZATION AND PROVIDE A PLATFORM FOR FURTHER APPLICATIONS OF CORIN FOR THE TREATMENT OF CHRONIC WOUNDS. 2023 13 5995 32 TGFBETA-INDUCED FIBROBLAST ACTIVATION REQUIRES PERSISTENT AND TARGETED HDAC-MEDIATED GENE REPRESSION. TISSUE FIBROSIS IS A CHRONIC DISEASE DRIVEN BY PERSISTENT FIBROBLAST ACTIVATION THAT HAS RECENTLY BEEN LINKED TO EPIGENETIC MODIFICATIONS. HERE, WE SCREENED A SMALL LIBRARY OF EPIGENETIC SMALL-MOLECULE MODULATORS TO IDENTIFY COMPOUNDS CAPABLE OF INHIBITING OR REVERSING TGFBETA-MEDIATED FIBROBLAST ACTIVATION. WE IDENTIFIED PRACINOSTAT, AN HDAC INHIBITOR, AS A POTENT ATTENUATOR OF LUNG FIBROBLAST ACTIVATION AND CONFIRMED ITS EFFICACY IN PATIENT-DERIVED FIBROBLASTS ISOLATED FROM FIBROTIC LUNG TISSUE. MECHANISTICALLY, WE FOUND THAT HDAC-DEPENDENT TRANSCRIPTIONAL REPRESSION WAS AN EARLY AND ESSENTIAL EVENT IN TGFBETA-MEDIATED FIBROBLAST ACTIVATION. TREATMENT OF LUNG FIBROBLASTS WITH PRACINOSTAT BROADLY ATTENUATED TGFBETA-MEDIATED EPIGENETIC REPRESSION AND PROMOTED FIBROBLAST QUIESCENCE. WE CONFIRMED A SPECIFIC ROLE FOR HDAC-DEPENDENT HISTONE DEACETYLATION IN THE PROMOTER REGION OF THE ANTI-FIBROTIC GENE PPARGC1A (PGC1ALPHA) IN RESPONSE TO TGFBETA STIMULATION. FINALLY, WE IDENTIFIED HDAC7 AS A KEY FACTOR WHOSE SIRNA-MEDIATED KNOCKDOWN ATTENUATES FIBROBLAST ACTIVATION WITHOUT ALTERING GLOBAL HISTONE ACETYLATION. TOGETHER, THESE RESULTS PROVIDE NOVEL MECHANISTIC INSIGHT INTO THE ESSENTIAL ROLE HDACS PLAY IN TGFBETA-MEDIATED FIBROBLAST ACTIVATION VIA TARGETED GENE REPRESSION. 2019 14 6232 29 THE LONG NONCODING RNA MEG3 REGULATES MYOBLAST PLASTICITY AND MUSCLE REGENERATION THROUGH EPITHELIAL-MESENCHYMAL TRANSITION. FORMATION OF SKELETAL MUSCLE IS AMONG THE MOST STRIKING EXAMPLES OF CELLULAR PLASTICITY IN ANIMAL TISSUE DEVELOPMENT, AND WHILE MUSCLE PROGENITOR CELLS ARE REPROGRAMMED BY EPITHELIAL-MESENCHYMAL TRANSITION (EMT) TO MIGRATE DURING EMBRYONIC DEVELOPMENT, THE REGULATION OF EMT IN POST-NATAL MYOGENESIS REMAINS POORLY UNDERSTOOD. HERE, WE DEMONSTRATE THAT THE LONG NONCODING RNA (LNCRNA) MEG3 REGULATES EMT IN MYOBLAST DIFFERENTIATION AND SKELETAL MUSCLE REGENERATION. CHRONIC INHIBITION OF MEG3 IN C2C12 MYOBLASTS INDUCED EMT, AND SUPPRESSED CELL STATE TRANSITIONS REQUIRED FOR DIFFERENTIATION. FURTHERMORE, ADENOVIRAL MEG3 KNOCKDOWN COMPROMISED MUSCLE REGENERATION, WHICH WAS ACCOMPANIED BY ABNORMAL MESENCHYMAL GENE EXPRESSION AND INTERSTITIAL CELL PROLIFERATION. TRANSCRIPTOMIC AND PATHWAY ANALYSES OF MEG3-DEPLETED C2C12 MYOBLASTS AND INJURED SKELETAL MUSCLE REVEALED A SIGNIFICANT DYSREGULATION OF EMT-RELATED GENES, AND IDENTIFIED TGFBETA AS A KEY UPSTREAM REGULATOR. IMPORTANTLY, INHIBITION OF TGFBETAR1 AND ITS DOWNSTREAM EFFECTORS, AND THE EMT TRANSCRIPTION FACTOR SNAI2, RESTORED MANY ASPECTS OF MYOGENIC DIFFERENTIATION IN MEG3-DEPLETED MYOBLASTS IN VITRO WE FURTHER DEMONSTRATE THAT REDUCTION OF MEG3-DEPENDENT EZH2 ACTIVITY RESULTS IN EPIGENETIC ALTERATIONS ASSOCIATED WITH TGFBETA ACTIVATION. THUS, MEG3 REGULATES MYOBLAST IDENTITY TO FACILITATE PROGRESSION INTO DIFFERENTIATION. 2021 15 674 35 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 16 592 28 BET BROMODOMAIN PROTEINS REGULATE TRANSCRIPTIONAL REPROGRAMMING IN GENETIC DILATED CARDIOMYOPATHY. THE BROMODOMAIN AND EXTRATERMINAL (BET) FAMILY COMPRISES EPIGENETIC READER PROTEINS THAT ARE IMPORTANT REGULATORS OF INFLAMMATORY AND HYPERTROPHIC GENE EXPRESSION IN THE HEART. WE PREVIOUSLY IDENTIFIED THE ACTIVATION OF PROINFLAMMATORY GENE NETWORKS AS A KEY EARLY DRIVER OF DILATED CARDIOMYOPATHY (DCM) IN TRANSGENIC MICE EXPRESSING A MUTANT FORM OF PHOSPHOLAMBAN (PLNR9C) - A GENETIC CAUSE OF DCM IN HUMANS. WE HYPOTHESIZED THAT BETS COACTIVATE THIS INFLAMMATORY PROCESS, REPRESENTING A CRITICAL NODE IN THE PROGRESSION OF DCM. TO TEST THIS HYPOTHESIS, WE TREATED PLNR9C OR AGE-MATCHED WT MICE LONGITUDINALLY WITH THE SMALL MOLECULE BET BROMODOMAIN INHIBITOR JQ1 OR VEHICLE. BET INHIBITION ABROGATED ADVERSE CARDIAC REMODELING, REDUCED CARDIAC FIBROSIS, AND PROLONGED SURVIVAL IN PLNR9C MICE BY INHIBITING EXPRESSION OF PROINFLAMMATORY GENE NETWORKS AT ALL STAGES OF DISEASE. SPECIFICALLY, JQ1 HAD PROFOUND EFFECTS ON PROINFLAMMATORY GENE NETWORK EXPRESSION IN CARDIAC FIBROBLASTS, WHILE HAVING LITTLE EFFECT ON GENE EXPRESSION IN CARDIOMYOCYTES. CARDIAC FIBROBLAST PROLIFERATION WAS ALSO SUBSTANTIALLY REDUCED BY JQ1. MECHANISTICALLY, WE DEMONSTRATED THAT BRD4 SERVES AS A DIRECT AND ESSENTIAL REGULATOR OF NF-KAPPAB-MEDIATED PROINFLAMMATORY GENE EXPRESSION IN CARDIAC FIBROBLASTS. SUPPRESSING PROINFLAMMATORY GENE EXPRESSION VIA BET BROMODOMAIN INHIBITION COULD BE A NOVEL THERAPEUTIC STRATEGY FOR CHRONIC DCM IN HUMANS. 2020 17 4574 30 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 18 598 27 BETA-ADRENERGIC SIGNALING PROMOTES TUMOR ANGIOGENESIS AND PROSTATE CANCER PROGRESSION THROUGH HDAC2-MEDIATED SUPPRESSION OF THROMBOSPONDIN-1. CHRONIC BEHAVIORAL STRESS AND BETA-ADRENERGIC SIGNALING HAVE BEEN SHOWN TO PROMOTE CANCER PROGRESSION, WHOSE UNDERLYING MECHANISMS ARE LARGELY UNCLEAR, ESPECIALLY THE INVOLVEMENT OF EPIGENETIC REGULATION. HISTONE DEACETYLASE-2 (HDAC2), AN EPIGENETIC REGULATOR, IS CRITICAL FOR STRESS-INDUCED CARDIAC HYPERTROPHY. IT IS UNKNOWN WHETHER IT IS NECESSARY FOR BETA-ADRENERGIC SIGNALING-PROMOTED CANCER PROGRESSION. USING XENOGRAFT MODELS, WE SHOWED THAT CHRONIC BEHAVIORAL STRESS AND BETA-ADRENERGIC SIGNALING PROMOTE ANGIOGENESIS AND PROSTATE CANCER PROGRESSION. HDAC2 WAS INDUCED BY BETA-ADRENERGIC SIGNALING IN VITRO AND IN MOUSE XENOGRAFTS. WE NEXT UNCOVERED THAT HDAC2 IS A DIRECT TARGET OF CAMP RESPONSE ELEMENT-BINDING PROTEIN (CREB) THAT IS ACTIVATED BY BETA-ADRENERGIC SIGNALING. NOTABLY, HDAC2 IS NECESSARY FOR BETA-ADRENERGIC SIGNALING TO INDUCE ANGIOGENESIS. WE FURTHER DEMONSTRATED THAT, UPON CREB ACTIVATION, HDAC2 REPRESSES THROMBOSPONDIN-1 (TSP1), A POTENT ANGIOGENESIS INHIBITOR, THROUGH EPIGENETIC REGULATION. TOGETHER, THESE DATA ESTABLISH A NOVEL PATHWAY THAT HDAC2 AND TSP1 ACT DOWNSTREAM OF CREB ACTIVATION IN BETA-ADRENERGIC SIGNALING TO PROMOTE CANCER PROGRESSION. 2017 19 4345 24 MIR-103 PROMOTES ENDOTHELIAL MALADAPTATION BY TARGETING LNCWDR59. BLOOD FLOW AT ARTERIAL BIFURCATIONS AND CURVATURES IS NATURALLY DISTURBED. ENDOTHELIAL CELLS (ECS) FAIL TO ADAPT TO DISTURBED FLOW, WHICH TRANSCRIPTIONALLY DIRECT ECS TOWARD A MALADAPTED PHENOTYPE, CHARACTERIZED BY CHRONIC REGENERATION OF INJURED ECS. MICRORNAS (MIRNAS) CAN REGULATE EC MALADAPTATION THROUGH TARGETING OF PROTEIN-CODING RNAS. HOWEVER, LONG NONCODING RNAS (LNCRNAS), KNOWN EPIGENETIC REGULATORS OF BIOLOGICAL PROCESSES, CAN ALSO BE MIRNA TARGETS, BUT THEIR CONTRIBUTION ON EC MALADAPTATION IS UNCLEAR. HERE WE SHOW THAT HYPERLIPIDEMIA- AND OXLDL-INDUCED UPREGULATION OF MIR-103 INHIBITS EC PROLIFERATION AND PROMOTES ENDOTHELIAL DNA DAMAGE THROUGH TARGETING OF NOVEL LNCWDR59. MIR-103 IMPEDES LNCWDR59 INTERACTION WITH NOTCH1-INHIBITOR NUMB, THEREFORE AFFECTING NOTCH1-INDUCED EC PROLIFERATION. MOREOVER, MIR-103 INCREASES THE SUSCEPTIBILITY OF PROLIFERATING ECS TO OXLDL-INDUCED MITOTIC ABERRATIONS, CHARACTERIZED BY AN INCREASED MICRONUCLEIC FORMATION AND DNA DAMAGE ACCUMULATION, BY AFFECTING NOTCH1-RELATED BETA-CATENIN CO-ACTIVATION. COLLECTIVELY, THESE DATA INDICATE THAT MIR-103 PROGRAMS ECS TOWARD A MALADAPTED PHENOTYPE THROUGH TARGETING OF LNCWDR59, WHICH MAY PROMOTE ATHEROSCLEROSIS. 2018 20 6453 27 THIOREDOXIN INTERACTING PROTEIN (TXNIP) INDUCES INFLAMMATION THROUGH CHROMATIN MODIFICATION IN RETINAL CAPILLARY ENDOTHELIAL CELLS UNDER DIABETIC CONDITIONS. CHRONIC HYPERGLYCEMIA AND ACTIVATION OF RECEPTOR FOR ADVANCED GLYCATION END PRODUCTS (RAGE) ARE KNOWN RISK FACTORS FOR MICROVASCULAR DISEASE DEVELOPMENT IN DIABETIC RETINOPATHY. THIOREDOXIN-INTERACTING PROTEIN (TXNIP), AN ENDOGENOUS INHIBITOR OF ANTIOXIDANT THIOREDOXIN (TRX), PLAYS A CAUSATIVE ROLE IN DIABETES AND ITS VASCULAR COMPLICATIONS. HEREIN WE INVESTIGATE WHETHER HG AND RAGE INDUCE INFLAMMATION IN RAT RETINAL ENDOTHELIAL CELLS (EC) UNDER DIABETIC CONDITIONS IN CULTURE THROUGH TXNIP ACTIVATION AND WHETHER EPIGENETIC MECHANISMS PLAY A ROLE IN INFLAMMATORY GENE EXPRESSION. WE SHOW THAT RAGE ACTIVATION BY ITS LIGAND S100B OR HG TREATMENT OF RETINAL EC INDUCES THE EXPRESSION OF TXNIP AND INFLAMMATORY GENES SUCH AS COX2, VEGF-A, AND ICAM1. TXNIP SILENCING BY SIRNA IMPEDES RAGE AND HG EFFECTS WHILE STABLE OVER-EXPRESSION OF A CDNA FOR HUMAN TXNIP IN EC ELEVATES INFLAMMATION. P38 MAPK-NF-KAPPAB SIGNALING PATHWAY AND HISTONE H3 LYSINE (K) NINE MODIFICATIONS ARE INVOLVED IN TXNIP-INDUCED INFLAMMATION. CHROMATIN IMMUNOPRECIPITATION (CHIP) ASSAYS REVEAL THAT TXNIP OVER-EXPRESSION IN EC ABOLISHES H3K9 TRI-METHYLATION, A MARKER FOR GENE INACTIVATION, AND INCREASES H3K9 ACETYLATION, AN INDICATOR OF GENE INDUCTION, AT PROXIMAL COX2 PROMOTER BEARING THE NF-KAPPAB-BINDING SITE. THESE FINDINGS HAVE IMPORTANT IMPLICATIONS TOWARD UNDERSTANDING THE MOLECULAR MECHANISMS OF OCULAR INFLAMMATION AND ENDOTHELIAL DYSFUNCTION IN DIABETIC RETINOPATHY. 2009