1 4506 112 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 2 4574 37 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 3 4171 43 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 4 5592 32 ROLE OF TUMOR NECROSIS FACTOR-ALPHA IN THE HUMAN SYSTEMIC ENDOTOXIN-INDUCED TRANSCRIPTOME. TNFALPHA HAS BEEN IMPLICATED IN THE PATHOGENESIS OF VARIOUS INFLAMMATORY DISEASES. DIFFERENT STRATEGIES TO INHIBIT TNFALPHA IN PATIENTS WITH SEPSIS AND CHRONIC INFLAMMATORY CONDITIONS HAVE SHOWN CONTRASTING OUTCOMES. ALTHOUGH TNFALPHA INHIBITORS ARE WIDELY USED IN CLINICAL PRACTICE, THE IMPACT OF TNFALPHA ANTAGONISM ON WHITE BLOOD CELL GENE EXPRESSION PROFILES DURING ACUTE INFLAMMATION IN HUMANS IN VIVO HAS NOT BEEN ASSESSED. WE HERE LEVERAGED THE ESTABLISHED MODEL OF HUMAN ENDOTOXEMIA TO EXAMINE THE EFFECT OF THE TNFALPHA ANTAGONIST, ETANERCEPT, ON THE GENOME-WIDE TRANSCRIPTIONAL RESPONSES IN CIRCULATING LEUKOCYTES INDUCED BY INTRAVENOUS LPS ADMINISTRATION IN MALE SUBJECTS. ETANERCEPT PRE-TREATMENT RESULTED IN A MARKEDLY DAMPENED TRANSCRIPTIONAL RESPONSE TO LPS. GENE CO-EXPRESSION NETWORK ANALYSIS REVEALED THIS LPS-INDUCED TRANSCRIPTOME CAN BE CATEGORIZED AS TNFALPHA RESPONSIVE AND NON-RESPONSIVE MODULES. HIGHLY SIGNIFICANT TNFALPHA RESPONSIVE MODULES INCLUDE NF-KB SIGNALING, ANTIVIRAL RESPONSES AND T-CELL MEDIATED RESPONSES. WITHIN THESE TNFALPHA RESPONSIVE MODULES WE DELINEATE FUNDAMENTAL GENES INVOLVED IN EPIGENETIC MODIFICATIONS, TRANSCRIPTIONAL INITIATION AND ELONGATION. THUS, WE PROVIDE COMPREHENSIVE INFORMATION ABOUT MOLECULAR PATHWAYS THAT MIGHT BE TARGETED BY THERAPEUTIC INTERVENTIONS THAT SEEK TO INHIBIT TNFALPHA ACTIVITY DURING HUMAN INFLAMMATORY DISEASES. 2013 5 2228 34 EPIGENETIC MODIFICATIONS OF HISTONES IN PERIODONTAL DISEASE. PERIODONTITIS IS A CHRONIC INFECTIOUS DISEASE DRIVEN BY DYSBIOSIS, AN IMBALANCE BETWEEN COMMENSAL BACTERIA AND THE HOST ORGANISM. PERIODONTITIS IS A LEADING CAUSE OF TOOTH LOSS IN ADULTS AND OCCURS IN ABOUT 50% OF THE US POPULATION. IN ADDITION TO THE CLINICAL CHALLENGES ASSOCIATED WITH TREATING PERIODONTITIS, THE PROGRESSION AND CHRONIC NATURE OF THIS DISEASE SERIOUSLY AFFECT HUMAN HEALTH. EMERGING EVIDENCE SUGGESTS THAT PERIODONTITIS IS ASSOCIATED WITH MECHANISMS BEYOND BACTERIA-INDUCED PROTEIN AND TISSUE DEGRADATION. HERE, WE HYPOTHESIZE THAT BACTERIA ARE ABLE TO INDUCE EPIGENETIC MODIFICATIONS IN ORAL EPITHELIAL CELLS MEDIATED BY HISTONE MODIFICATIONS. IN THIS STUDY, WE FOUND THAT DYSBIOSIS IN VIVO LED TO EPIGENETIC MODIFICATIONS, INCLUDING ACETYLATION OF HISTONES AND DOWNREGULATION OF DNA METHYLTRANSFERASE 1. IN ADDITION, IN VITRO EXPOSURE OF ORAL EPITHELIAL CELLS TO LIPOPOLYSACCHARIDES RESULTED IN HISTONE MODIFICATIONS, ACTIVATION OF TRANSCRIPTIONAL COACTIVATORS, SUCH AS P300/CBP, AND ACCUMULATION OF NUCLEAR FACTOR-KAPPAB (NF-KAPPAB). GIVEN THAT ORAL EPITHELIAL CELLS ARE THE FIRST LINE OF DEFENSE FOR THE PERIODONTIUM AGAINST BACTERIA, WE ALSO EVALUATED WHETHER ACTIVATION OF PATHOGEN RECOGNITION RECEPTORS INDUCED HISTONE MODIFICATIONS. WE FOUND THAT ACTIVATION OF THE TOLL-LIKE RECEPTORS 1, 2, AND 4 AND THE NUCLEOTIDE-BINDING OLIGOMERIZATION DOMAIN PROTEIN 1 INDUCED HISTONE ACETYLATION IN ORAL EPITHELIAL CELLS. OUR FINDINGS CORROBORATE THE EMERGING CONCEPT THAT EPIGENETIC MODIFICATIONS PLAY A ROLE IN THE DEVELOPMENT OF PERIODONTITIS. 2016 6 2067 28 EPIGENETIC CONTROL OF MACROPHAGE SHAPE TRANSITION TOWARDS AN ATYPICAL ELONGATED PHENOTYPE BY HISTONE DEACETYLASE ACTIVITY. INFLAMMATORY CHRONIC PATHOLOGIES ARE COMPLEX PROCESSES CHARACTERIZED BY AN IMBALANCE BETWEEN THE RESOLUTION OF THE INFLAMMATORY PHASE AND THE ESTABLISHMENT OF TISSUE REPAIR. THE MAIN PLAYERS IN THESE INFLAMMATORY PATHOLOGIES ARE BONE MARROW DERIVED MONOCYTES (BMDMS). HOWEVER, HOW MONOCYTE DIFFERENTIATION IS MODULATED TO GIVE RISE TO SPECIFIC MACROPHAGE SUBPOPULATIONS (M1 OR M2) THAT MAY EITHER MAINTAIN THE CHRONIC INFLAMMATORY PROCESS OR LEAD TO WOUND HEALING IS STILL UNCLEAR. CONSIDERING THAT INHIBITORS OF HISTONE DEACETYLASE (HDAC) HAVE AN ANTI-INFLAMMATORY ACTIVITY, WE ASKED WHETHER THIS ENZYME WOULD PLAY A ROLE ON MONOCYTE DIFFERENTIATION INTO M1 OR M2 PHENOTYPE AND IN THE CELL SHAPE TRANSITION THAT FOLLOWS. WE THEN INDUCED MURINE BONE MARROW PROGENITORS INTO MONOCYTE/MACROPHAGE DIFFERENTIATION PATHWAY USING MEDIA CONTAINING GM-CSF AND THE HDAC BLOCKER, TRICHOSTATIN A (TSA). WE FOUND THAT THE PHARMACOLOGICAL INHIBITION OF HDAC ACTIVITY LED TO A SHAPE TRANSITION FROM THE TYPICAL MACROPHAGE PANCAKE-LIKE SHAPE INTO AN ELONGATED MORPHOLOGY, WHICH WAS CORRELATED TO A MIXED M1/M2 PROFILE OF CYTOKINE AND CHEMOKINE SECRETION. OUR RESULTS PRESENT, FOR THE FIRST TIME, THAT HDAC ACTIVITY ACTS AS A REGULATOR OF MACROPHAGE DIFFERENTIATION IN THE ABSENCE OF LYMPHOCYTE STIMULI. WE PROPOSE THAT HDAC ACTIVITY DOWN REGULATES MACROPHAGE PLASTICITY FAVORING THE PRO-INFLAMMATORY PHENOTYPE. 2015 7 1479 26 DIVERSE TARGETS OF THE TRANSCRIPTION FACTOR STAT3 CONTRIBUTE TO T CELL PATHOGENICITY AND HOMEOSTASIS. STAT3, AN ESSENTIAL TRANSCRIPTION FACTOR WITH PLEIOTROPIC FUNCTIONS, PLAYS CRITICAL ROLES IN THE PATHOGENESIS OF AUTOIMMUNITY. DESPITE RECENT DATA LINKING STAT3 WITH INFLAMMATORY BOWEL DISEASE, EXACTLY HOW IT CONTRIBUTES TO CHRONIC INTESTINAL INFLAMMATION IS NOT KNOWN. USING A T CELL TRANSFER MODEL OF COLITIS, WE FOUND THAT STAT3 EXPRESSION IN T CELLS WAS ESSENTIAL FOR THE INDUCTION OF BOTH COLITIS AND SYSTEMIC INFLAMMATION. STAT3 WAS CRITICAL IN MODULATING THE BALANCE OF T HELPER 17 (TH17) AND REGULATORY T (TREG) CELLS, AS WELL AS IN PROMOTING CD4(+) T CELL PROLIFERATION. WE USED CHROMATIN IMMUNOPRECIPITATION AND MASSIVE PARALLEL SEQUENCING (CHIP-SEQ) TO DEFINE THE GENOME-WIDE TARGETS OF STAT3 IN CD4(+) T CELLS. WE FOUND THAT STAT3 BOUND TO MULTIPLE GENES INVOLVED IN TH17 CELL DIFFERENTIATION, CELL ACTIVATION, PROLIFERATION, AND SURVIVAL, REGULATING BOTH EXPRESSION AND EPIGENETIC MODIFICATIONS. THUS, STAT3 ORCHESTRATES MULTIPLE CRITICAL ASPECTS OF T CELL FUNCTION IN INFLAMMATION AND HOMEOSTASIS. 2010 8 926 33 CHRONIC INFLAMMATION PATHWAY NF-KAPPAB COOPERATES WITH EPIGENETIC REPROGRAMMING TO DRIVE THE MALIGNANT PROGRESSION OF GLIOBLASTOMA. WITHOUT AN EFFECTIVE STRATEGY FOR TARGETED THERAPY, GLIOBLASTOMA IS STILL INCURABLE WITH A MEDIAN SURVIVAL OF ONLY 15 MONTHS. BOTH CHRONIC INFLAMMATION AND EPIGENETIC REPROGRAMMING ARE HALLMARKS OF CANCER. HOWEVER, THE MECHANISMS AND CONSEQUENCES OF THEIR COOPERATION IN GLIOBLASTOMA REMAIN UNKNOWN. HERE, WE DISCOVER THAT CHRONIC INFLAMMATION GOVERNS H3K27ME3 REPROGRAMMING IN GLIOBLASTOMA THROUGH THE CANONICAL NF-KAPPAB PATHWAY TO TARGET EZH2. BEING A CRUCIAL MEDIATOR OF CHRONIC INFLAMMATION, THE CANONICAL NF-KAPPAB SIGNALLING SPECIFICALLY DIRECTS THE EXPRESSION AND REDISTRIBUTION OF H3K27ME3 BUT NOT H3K4ME3, H3K9ME3 AND H3K36ME3. USING RNA-SEQ SCREENING TO FOCUS ON GENES ENCODING METHYLTRANSFERASES AND DEMETHYLASES OF HISTONE, WE IDENTIFY EZH2 AS A KEY METHYLTRANSFERASE TO CONTROL INFLAMMATION-TRIGGERED EPIGENETIC REPROGRAMMING IN GLIOMAGENESIS. MECHANISTICALLY, NF-KAPPAB SELECTIVELY DRIVES THE EXPRESSION OF EZH2 BY ACTIVATING ITS TRANSCRIPTION, CONSEQUENTLY RESULTING IN A GLOBAL CHANGE IN H3K27ME3 EXPRESSION AND DISTRIBUTION. FURTHERMORE, WE FIND THAT CO-ACTIVATION OF NF-KAPPAB AND EZH2 CONFERS THE POOREST CLINICAL OUTCOME, AND THAT THE RISK FOR GLIOBLASTOMA CAN BE ACCURATELY MOLECULARLY STRATIFIED BY NF-KAPPAB AND EZH2. IT IS NOTABLE THAT NF-KAPPAB CAN POTENTIALLY COOPERATE WITH EZH2 IN MORE THAN ONE WAY, AND MOST IMPORTANTLY, WE DEMONSTRATE A SYNERGISTIC EFFECT OF CANCER CELLS INDUCED BY COMBINATORY INHIBITION OF NF-KAPPAB AND EZH2, WHICH BOTH ARE FREQUENTLY OVER-ACTIVATED IN GLIOBLASTOMA. IN SUMMARY, WE UNCOVER A FUNCTIONAL COOPERATION BETWEEN CHRONIC INFLAMMATION AND EPIGENETIC REPROGRAMMING IN GLIOBLASTOMA, COMBINED TARGETING OF WHICH BY INHIBITORS GUARANTEED IN SAFETY AND AVAILABILITY FURNISHES A POTENT STRATEGY FOR EFFECTIVE TREATMENT OF THIS FATAL DISEASE. 2022 9 5279 31 PROMOTER-SPECIFIC RELEVANCE OF HISTONE MODIFICATIONS INDUCED BY DEXAMETHASONE DURING THE REGULATION OF PRO-INFLAMMATORY MEDIATORS. GLUCOCORTICOSTEROIDS (GCS) ARE WIDELY USED TO TREAT DIFFERENT KINDS OF CHRONIC INFLAMMATORY AND IMMUNE DISEASES THROUGH TRANSCRIPTIONAL REGULATION OF INFLAMMATORY GENES. MODULATION OF GENE EXPRESSION BY GCS IS KNOWN TO OCCUR THROUGH DIVERSE MECHANISMS OF VARYING RELEVANCE TO SPECIFIC CLASSES OF GENES. EPIGENETIC MODIFICATIONS ARE INDEED A PIVOTAL REGULATORY FEATURE OF GLUCOCORTICOID RECEPTOR AND OTHER TRANSCRIPTION FACTORS. IN THIS STUDY, HISTONE POST-TRANSLATIONAL MODIFICATIONS WERE INVESTIGATED FOR THEIR INVOLVEMENT IN THE REGULATION OF SELECTED PRO-INFLAMMATORY GENES - EXPRESSED IN HUMAN MONOCYTE-DERIVED MACROPHAGES - IN RESPONSE TO TREATMENT WITH SYNTHETIC GC DEXAMETHASONE (DEX). WE SHOW THAT HISTONE TAIL ACETYLATION STATUS IS MODIFIED FOLLOWING DEX ADMINISTRATION, THROUGH DISTINCT AND ALTERNATIVE MECHANISMS AT THE PROMOTERS OF INTERLEUKIN-8 AND INTERLEUKIN-23. IN ADDITION TO HISTONE H3 ACETYLATION, OUR RESULTS DEMONSTRATE THAT H3 LYSINE 4 TRIMETHYLATION IS AFFECTED FOLLOWING DRUG TREATMENT. 2014 10 2026 31 EPIGENETIC CHANGES IN BONE MARROW PROGENITOR CELLS INFLUENCE THE INFLAMMATORY PHENOTYPE AND ALTER WOUND HEALING IN TYPE 2 DIABETES. CLASSICALLY ACTIVATED (M1) MACROPHAGES ARE KNOWN TO PLAY A ROLE IN THE DEVELOPMENT OF CHRONIC INFLAMMATION ASSOCIATED WITH IMPAIRED WOUND HEALING IN TYPE 2 DIABETES (T2D); HOWEVER, THE MECHANISM RESPONSIBLE FOR THE DOMINANT PROINFLAMMATORY (M1) MACROPHAGE PHENOTYPE IN T2D WOUNDS IS UNKNOWN. SINCE EPIGENETIC ENZYMES CAN DIRECT MACROPHAGE PHENOTYPES, WE ASSESSED THE ROLE OF HISTONE METHYLATION IN BONE MARROW (BM) STEM/PROGENITOR CELLS IN THE PROGRAMMING OF MACROPHAGES TOWARD A PROINFLAMMATORY PHENOTYPE. WE HAVE FOUND THAT A REPRESSIVE HISTONE METHYLATION MARK, H3K27ME3, IS DECREASED AT THE PROMOTER OF THE IL-12 GENE IN BM PROGENITORS AND THIS EPIGENETIC SIGNATURE IS PASSED DOWN TO WOUND MACROPHAGES IN A MURINE MODEL OF GLUCOSE INTOLERANCE (DIET-INDUCED OBESE). THESE EPIGENETICALLY "PREPROGRAMMED" MACROPHAGES RESULT IN POISED MACROPHAGES IN PERIPHERAL TISSUE AND NEGATIVELY IMPACT WOUND REPAIR. WE FOUND THAT IN DIABETIC CONDITIONS THE H3K27 DEMETHYLASE JMJD3 DRIVES IL-12 PRODUCTION IN MACROPHAGES AND THAT IL-12 PRODUCTION CAN BE MODULATED BY INHIBITING JMJD3. USING HUMAN T2D TISSUE AND MURINE MODELS, WE HAVE IDENTIFIED A PREVIOUSLY UNRECOGNIZED MECHANISM BY WHICH MACROPHAGES ARE PROGRAMMED TOWARD A PROINFLAMMATORY PHENOTYPE, ESTABLISHING A PATTERN OF UNRESTRAINED INFLAMMATION ASSOCIATED WITH NONHEALING WOUNDS. HENCE, HISTONE DEMETHYLASE INHIBITOR-BASED THERAPY MAY REPRESENT A NOVEL TREATMENT OPTION FOR DIABETIC WOUNDS. 2015 11 5975 31 TET1 IS AN IMPORTANT TRANSCRIPTIONAL ACTIVATOR OF TNFALPHA EXPRESSION IN MACROPHAGES. ACTIVATION OF MACROPHAGES AND OVEREXPRESSION OF TNFALPHA IS ASSOCIATED WITH THE PATHOGENESIS OF CHRONIC INFLAMMATORY DISEASES. HOWEVER, THE MECHANISMS LEADING TO TNFALPHA OVEREXPRESSION ARE STILL UNKNOWN. 5-METHYLOCYTOSINE (5-MC) IS AN EPIGENETIC MODIFICATION THAT IS ASSOCIATED WITH SILENCED GENES. RECENT STUDIES SHOWED THAT IT IS CONVERTED TO 5-HYDROXYLMETHYLOCYTOSINE (5-HMC) AND REACTIVATES GENE EXPRESSION THROUGH THE ACTION OF THE FAMILY OF TEN-ELEVEN-TRANSLOCATION (TET1-3) ENZYMES. IN THIS STUDY, WE SHOW THAT 5-HMC LEVELS ARE INCREASED GLOBALLY AND SPECIFICALLY IN THE TNFALPHA PROMOTER DURING THE DIFFERENTIATION OF MONOCYTES TO MACROPHAGES. IN ADDITION, THE LEVELS OF 5-HMC ARE INCREASED UPON LPS STIMULATION OF MACROPHAGES. FURTHERMORE, CRIPSR STABLE KNOCKOUT OF TET1 DECREASES THE EXPRESSION OF TNFALPHA AND OTHER PRO-INFLAMMATORY CYTOKINES. IN CONCLUSION, WE SHOWED THAT TET1 CONTRIBUTES TO THE ACTIVATION OF MACROPHAGES POSSIBLY THROUGH REGULATION OF 5-HYDROXYMETHYLATION IN THE PROMOTER OF PRO-INFLAMMATORY CYTOKINE GENES. THE TET1 ENZYME COULD BE A PROMISING THERAPEUTIC TARGET TO INHIBIT THE PERSISTENT INFLAMMATION CAUSED BY MACROPHAGES IN CHRONIC INFLAMMATORY DISEASES. 2019 12 3322 33 HISTONE ACETYLTRANSFERASE P300 INDUCES DE NOVO SUPER-ENHANCERS TO DRIVE CELLULAR SENESCENCE. ACCUMULATION OF SENESCENT CELLS DURING AGING CONTRIBUTES TO CHRONIC INFLAMMATION AND AGE-RELATED DISEASES. WHILE SENESCENCE IS ASSOCIATED WITH PROFOUND ALTERATIONS OF THE EPIGENOME, A SYSTEMATIC VIEW OF EPIGENETIC FACTORS IN REGULATING SENESCENCE IS LACKING. HERE, WE CURATED A LIBRARY OF SHORT HAIRPIN RNAS FOR TARGETED SILENCING OF ALL KNOWN EPIGENETIC PROTEINS AND PERFORMED A HIGH-THROUGHPUT SCREEN TO IDENTIFY KEY CANDIDATES WHOSE DOWNREGULATION CAN DELAY REPLICATIVE SENESCENCE OF PRIMARY HUMAN CELLS. THIS SCREEN IDENTIFIED MULTIPLE NEW PLAYERS INCLUDING THE HISTONE ACETYLTRANSFERASE P300 THAT WAS FOUND TO BE A PRIMARY DRIVER OF THE SENESCENT PHENOTYPE. P300, BUT NOT THE PARALOGOUS CBP, INDUCES A DYNAMIC HYPER-ACETYLATED CHROMATIN STATE AND PROMOTES THE FORMATION OF ACTIVE ENHANCER ELEMENTS IN THE NON-CODING GENOME, LEADING TO A SENESCENCE-SPECIFIC GENE EXPRESSION PROGRAM. OUR WORK ILLUSTRATES A CAUSAL ROLE OF HISTONE ACETYLTRANSFERASES AND ACETYLATION IN SENESCENCE AND SUGGESTS P300 AS A POTENTIAL THERAPEUTIC TARGET FOR SENESCENCE AND AGE-RELATED DISEASES. 2019 13 2493 38 EPIGENETICS AND CHROMATIN REMODELING PLAY A ROLE IN LUNG DISEASE. EPIGENETICS IS DEFINED AS HERITABLE CHANGES THAT AFFECT GENE EXPRESSION WITHOUT ALTERING THE DNA SEQUENCE. EPIGENETIC REGULATION OF GENE EXPRESSION IS FACILITATED THROUGH DIFFERENT MECHANISMS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS AND RNA-ASSOCIATED SILENCING BY SMALL NON-CODING RNAS. ALL THESE MECHANISMS ARE CRUCIAL FOR NORMAL DEVELOPMENT, DIFFERENTIATION AND TISSUE-SPECIFIC GENE EXPRESSION. THESE THREE SYSTEMS INTERACT AND STABILIZE ONE ANOTHER AND CAN INITIATE AND SUSTAIN EPIGENETIC SILENCING, THUS DETERMINING HERITABLE CHANGES IN GENE EXPRESSION. HISTONE ACETYLATION REGULATES DIVERSE CELLULAR FUNCTIONS INCLUDING INFLAMMATORY GENE EXPRESSION, DNA REPAIR AND CELL PROLIFERATION. TRANSCRIPTIONAL COACTIVATORS POSSESS INTRINSIC HISTONE ACETYLTRANSFERASE ACTIVITY AND THIS ACTIVITY DRIVES INFLAMMATORY GENE EXPRESSION. ELEVEN CLASSICAL HISTONE DEACETYLASES (HDACS) ACT TO REGULATE THE EXPRESSION OF DISTINCT SUBSETS OF INFLAMMATORY/IMMUNE GENES. THUS, LOSS OF HDAC ACTIVITY OR THE PRESENCE OF HDAC INHIBITORS CAN FURTHER ENHANCE INFLAMMATORY GENE EXPRESSION BY PRODUCING A GENE-SPECIFIC CHANGE IN HAT ACTIVITY. FOR EXAMPLE, HDAC2 EXPRESSION AND ACTIVITY ARE REDUCED IN LUNG MACROPHAGES, BIOPSY SPECIMENS, AND BLOOD CELLS FROM PATIENTS WITH SEVERE ASTHMA AND SMOKING ASTHMATICS, AS WELL AS IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). THIS MAY ACCOUNT, AT LEAST IN PART, FOR THE ENHANCED INFLAMMATION AND REDUCED STEROID RESPONSIVENESS SEEN IN THESE PATIENTS. OTHER PROTEINS, PARTICULARLY TRANSCRIPTION FACTORS, ARE ALSO ACETYLATED AND ARE TARGETS FOR DEACETYLATION BY HDACS AND SIRTUINS, A RELATED FAMILY OF 7 PREDOMINANTLY PROTEIN DEACETYLASES. THUS THE ACETYLATION/DEACETYLATION STATUS OF NF-KAPPAB AND THE GLUCOCORTICOID RECEPTOR CAN ALSO AFFECT THE OVERALL EXPRESSION PATTERN OF INFLAMMATORY GENES AND REGULATE THE INFLAMMATORY RESPONSE. UNDERSTANDING AND TARGETING SPECIFIC ENZYMES INVOLVED IN THIS PROCESS MIGHT LEAD TO NEW THERAPEUTIC AGENTS, PARTICULARLY IN SITUATIONS IN WHICH CURRENT ANTI-INFLAMMATORY THERAPIES ARE SUBOPTIMAL. 2011 14 5795 28 STAT3 INDUCTION OF MIR-146B FORMS A FEEDBACK LOOP TO INHIBIT THE NF-KAPPAB TO IL-6 SIGNALING AXIS AND STAT3-DRIVEN CANCER PHENOTYPES. INTERLEUKIN-6 (IL-6)-MEDIATED ACTIVATION OF SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 (STAT3) IS A MECHANISM BY WHICH CHRONIC INFLAMMATION CAN CONTRIBUTE TO CANCER AND IS A COMMON ONCOGENIC EVENT. WE DISCOVERED A PATHWAY, THE LOSS OF WHICH IS ASSOCIATED WITH PERSISTENT STAT3 ACTIVATION IN HUMAN CANCER. WE FOUND THAT THE GENE ENCODING THE TUMOR SUPPRESSOR MICRORNA MIR-146B IS A DIRECT STAT3 TARGET GENE, AND ITS EXPRESSION WAS INCREASED IN NORMAL BREAST EPITHELIAL CELLS BUT DECREASED IN TUMOR CELLS. METHYLATION OF THE MIR-146B PROMOTER, WHICH INHIBITED STAT3-MEDIATED INDUCTION OF EXPRESSION, WAS INCREASED IN PRIMARY BREAST CANCERS. MOREOVER, WE FOUND THAT MIR-146B INHIBITED NUCLEAR FACTOR KAPPAB (NF-KAPPAB)-DEPENDENT PRODUCTION OF IL-6, SUBSEQUENT STAT3 ACTIVATION, AND IL-6/STAT3-DRIVEN MIGRATION AND INVASION IN BREAST CANCER CELLS, THEREBY ESTABLISHING A NEGATIVE FEEDBACK LOOP. IN ADDITION, HIGHER EXPRESSION OF MIR-146B WAS POSITIVELY CORRELATED WITH PATIENT SURVIVAL IN BREAST CANCER SUBTYPES WITH INCREASED IL6 EXPRESSION AND STAT3 PHOSPHORYLATION. OUR RESULTS IDENTIFY AN EPIGENETIC MECHANISM OF CROSSTALK BETWEEN STAT3 AND NF-KAPPAB RELEVANT TO CONSTITUTIVE STAT3 ACTIVATION IN MALIGNANCY AND THE ROLE OF INFLAMMATION IN ONCOGENESIS. 2014 15 1383 34 DIABETES AND ITS CARDIOVASCULAR COMPLICATIONS: POTENTIAL ROLE OF THE ACETYLTRANSFERASE P300. DIABETES HAS BEEN SHOWN TO ACCELERATE VASCULAR SENESCENCE, WHICH IS ASSOCIATED WITH CHRONIC INFLAMMATION AND OXIDATIVE STRESS, BOTH IMPLICATED IN THE DEVELOPMENT OF ENDOTHELIAL DYSFUNCTION. THIS CONDITION REPRESENTS THE INITIAL ALTERATION LINKING DIABETES TO RELATED CARDIOVASCULAR (CV) COMPLICATIONS. RECENTLY, IT HAS BEEN HYPOTHESISED THAT THE ACETYLTRANSFERASE, P300, MAY CONTRIBUTE TO ESTABLISHING AN EARLY VASCULAR SENESCENT PHENOTYPE, PLAYING A RELEVANT ROLE IN DIABETES-ASSOCIATED INFLAMMATION AND OXIDATIVE STRESS, WHICH DRIVE ENDOTHELIAL DYSFUNCTION. SPECIFICALLY, P300 CAN MODULATE VASCULAR INFLAMMATION THROUGH EPIGENETIC MECHANISMS AND TRANSCRIPTION FACTORS ACETYLATION. INDEED, IT REGULATES THE INFLAMMATORY PATHWAY BY INTERACTING WITH NUCLEAR FACTOR KAPPA-LIGHT-CHAIN-ENHANCER OF ACTIVATED B CELLS P65 SUBUNIT (NF-KAPPAB P65) OR BY INDUCING ITS ACETYLATION, SUGGESTING A CRUCIAL ROLE OF P300 AS A BRIDGE BETWEEN NF-KAPPAB P65 AND THE TRANSCRIPTIONAL MACHINERY. ADDITIONALLY, P300-MEDIATED EPIGENETIC MODIFICATIONS COULD BE UPSTREAM OF THE ACTIVATION OF INFLAMMATORY CYTOKINES, AND THEY MAY INDUCE OXIDATIVE STRESS BY AFFECTING THE PRODUCTION OF REACTIVE OXYGEN SPECIES (ROS). BECAUSE SEVERAL IN VITRO AND IN VIVO STUDIES SHED LIGHT ON THE POTENTIAL USE OF ACETYLTRANSFERASE INHIBITORS, A BETTER UNDERSTANDING OF THE MECHANISMS UNDERLYING THE ROLE OF P300 IN DIABETIC VASCULAR DYSFUNCTION COULD HELP IN FINDING NEW STRATEGIES FOR THE CLINICAL MANAGEMENT OF CV DISEASES RELATED TO DIABETES. 2023 16 1667 41 DOWNREGULATION OF PCAF BY MIR-181A/B PROVIDES FEEDBACK REGULATION TO TNF-ALPHA-INDUCED TRANSCRIPTION OF PROINFLAMMATORY GENES IN LIVER EPITHELIAL CELLS. ABERRANT CELLULAR RESPONSES TO PROINFLAMMATORY CYTOKINES, SUCH AS TNF-ALPHA, ARE PATHOGENIC FEATURES IN MOST CHRONIC INFLAMMATORY DISEASES. A VARIETY OF EXTRACELLULAR AND INTRACELLULAR FEEDBACK PATHWAYS HAS EVOLVED TO PREVENT AN INAPPROPRIATE CELLULAR REACTION TO THESE PROINFLAMMATORY CYTOKINES. IN THIS STUDY, WE REPORT THAT TNF-ALPHA TREATMENT OF HUMAN AND MOUSE CHOLANGIOCYTES AND HEPATOCYTES DOWNREGULATED EXPRESSION OF P300/CBP-ASSOCIATED FACTOR (PCAF), A COACTIVATOR AND AN ACETYLTRANSFERASE THAT PROMOTES HISTONE ACETYLATION AND GENE TRANSCRIPTION. OF THESE UPREGULATED MICRORNAS IN TNF-ALPHA-TREATED CELLS, MIR-181A/B (MIR-181A AND MIR-181B) SUPPRESSED TRANSLATION OF PCAF MRNA. FUNCTIONAL MANIPULATION OF MIR-181A/B CAUSED RECIPROCAL ALTERATIONS IN PCAF PROTEIN EXPRESSION IN CULTURED CHOLANGIOCYTES AND HEPATOCYTES. INHIBITION OF MIR-181A/B FUNCTION WITH ANTI-MIRS BLOCKED TNF-ALPHA-INDUCED SUPPRESSION OF PCAF EXPRESSION. PROMOTER RECRUITMENT OF PCAF WAS SHOWN TO BE ASSOCIATED WITH TNF-ALPHA-INDUCED TRANSCRIPTION OF INFLAMMATORY GENES. INTRIGUINGLY, PRETREATMENT OF CELLS WITH TNF-ALPHA INHIBITED TRANSCRIPTION OF INFLAMMATORY GENES IN RESPONSE TO SUBSEQUENT TNF-ALPHA STIMULATION. OVEREXPRESSION OF PCAF OR INHIBITION OF MIR-181A/B FUNCTION WITH ANTI-MIRS ATTENUATED THE INHIBITORY EFFECTS OF TNF-ALPHA PRETREATMENT ON EPITHELIAL INFLAMMATORY RESPONSE TO SUBSEQUENT TNF-ALPHA STIMULATION. DOWNREGULATION OF PCAF AND THE INHIBITORY EFFECTS OF TNF-ALPHA PRETREATMENT ON LIVER EPITHELIAL INFLAMMATORY RESPONSE WERE FURTHER CONFIRMED IN A MOUSE MODEL OF TNF-ALPHA I.P. INJECTION. THESE DATA SUGGEST THAT PCAF IS A TARGET FOR MIR-181A/B, AND DOWNREGULATION OF PCAF BY TNF-ALPHA PROVIDES NEGATIVE FEEDBACK REGULATION TO INFLAMMATORY REACTIONS IN LIVER EPITHELIAL CELLS, A PROCESS THAT MAY BE RELEVANT TO THE EPIGENETIC FINE-TUNING OF EPITHELIAL INFLAMMATORY PROCESSES IN GENERAL. 2012 17 4284 26 MICRORNA CIRCUITS REGULATE THE CANCER-INFLAMMATION LINK. GENETIC AND EPIGENETIC PERTURBATIONS ARE REQUIRED TO TRANSFORM NORMAL CELLS INTO CANCER CELLS. INFLAMMATORY SIGNALING PATHWAYS ARE ACTIVATED IN VARIOUS CANCERS, LINKING CHRONIC INFLAMMATION TO ONCOGENESIS. HOWEVER, THE MOLECULAR CIRCUITS THAT RESULT IN SUSTAINED ACTIVATION OF THESE INFLAMMATORY FACTORS ARE NOT YET WELL UNDERSTOOD. IN THE 28 JANUARY 2014 ISSUE OF SCIENCE SIGNALING, XIANG ET AL. IDENTIFIED A MICRORNA-MEDIATED ANTI-INFLAMMATORY CIRCUIT THAT IS REPRESSED EPIGENETICALLY IN RECEPTOR-NEGATIVE BREAST CANCERS. A HIGH-THROUGHPUT SCREEN FOR SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 (STAT3)-REGULATED MICRORNAS REVEALED MICRORNA MIR-146B AS A DIRECT STAT3 TARGET IN MAMMARY EPITHELIAL CELLS, BUT DNA METHYLATION IN ITS PROMOTER AREA SUPPRESSED MIR-146B EXPRESSION IN CANCER CELLS. OVEREXPRESSION OF MIR-146B SUPPRESSED NUCLEAR FACTOR KAPPAB (NF-KAPPAB)-DEPENDENT EXPRESSION OF IL6 AND SUBSEQUENT STAT3 ACTIVATION AND DECREASED THE STAT3-INDUCED INVASIVENESS AND MESENCHYMAL PHENOTYPE OF BREAST CANCER CELLS. OVERALL, THIS STUDY CONTRIBUTES TO OUR UNDERSTANDING OF HOW INFLAMMATION IS INVOLVED IN ONCOGENIC TRANSFORMATION. FURTHER STUDIES COULD EVALUATE THE THERAPEUTIC POTENTIAL OF TARGETING THIS CIRCUIT IN ESTROGEN RECEPTOR-NEGATIVE BREAST CANCERS. 2014 18 911 27 CHRONIC EXPOSURE TO TNF REPROGRAMS CELL SIGNALING PATHWAYS IN FIBROBLAST-LIKE SYNOVIOCYTES BY ESTABLISHING LONG-TERM INFLAMMATORY MEMORY. FIBROBLAST-LIKE SYNOVIOCYTES (FLS) PLAY A CRITICAL ROLE IN THE PATHOGENESIS OF RHEUMATOID ARTHRITIS (RA). CHRONIC INFLAMMATION INDUCES TRANSCRIPTOMIC AND EPIGENETIC MODIFICATIONS THAT IMPARTS A PERSISTENT CATABOLIC PHENOTYPE TO THE FLS, DESPITE THEIR DISSOCIATION FROM THE INFLAMMATORY ENVIRONMENT. WE ANALYZED HIGH THROUGHPUT GENE EXPRESSION AND CHROMATIN ACCESSIBILITY DATA FROM HUMAN AND MOUSE FLS FROM OUR AND OTHER STUDIES AVAILABLE ON PUBLIC REPOSITORIES, WITH THE GOAL OF IDENTIFYING THE PERSISTENTLY REPROGRAMMED SIGNALING PATHWAYS DRIVEN BY CHRONIC INFLAMMATION. WE FOUND THAT THE GENE EXPRESSION CHANGES INDUCED BY SHORT-TERM TUMOR NECROSIS FACTOR-ALPHA (TNF) TREATMENT WERE LARGELY SUSTAINED IN THE FLS EXPOSED TO CHRONIC INFLAMMATION. THESE CHANGES THAT INCLUDED BOTH ACTIVATION AND REPRESSION OF GENE EXPRESSION, WERE ACCOMPANIED BY THE REMODELING OF CHROMATIN ACCESSIBILITY. THE SUSTAINED ACTIVATED GENES (SAGS) INCLUDED ESTABLISHED PRO-INFLAMMATORY SIGNALING COMPONENTS KNOWN TO ACT AT MULTIPLE LEVELS OF NF-KAPPAB, STAT AND AP-1 SIGNALING CASCADES. INTERESTINGLY, THE SUSTAINED REPRESSED GENES (SRGS) INCLUDED CRITICAL MEDIATORS AND TARGETS OF THE BMP SIGNALING PATHWAY. WE THUS IDENTIFIED SUSTAINED REPRESSION OF BMP SIGNALING AS A UNIQUE CONSTITUENT OF THE LONG-TERM INFLAMMATORY MEMORY INDUCED BY CHRONIC INFLAMMATION. WE POSTULATE THAT SIMULTANEOUS TARGETING OF THESE ACTIVATED AND REPRESSED SIGNALING PATHWAYS MAY BE NECESSARY TO COMBAT RA PERSISTENCE. 2020 19 4969 37 PATHOLOGICAL NEUROINFLAMMATORY CONVERSION OF REACTIVE ASTROCYTES IS INDUCED BY MICROGLIA AND INVOLVES CHROMATIN REMODELING. FOLLOWING BRAIN INJURY OR IN NEURODEGENERATIVE DISEASES, ASTROCYTES BECOME REACTIVE AND MAY SUFFER PATHOLOGICAL REMODELING, FEATURES OF WHICH ARE THE LOSS OF THEIR HOMEOSTATIC FUNCTIONS AND A PRO-INFLAMMATORY GAIN OF FUNCTION THAT FACILITATES NEURODEGENERATION. PHARMACOLOGICAL INTERVENTION TO MODULATE THIS ASTROGLIAL RESPONSE AND NEUROINFLAMMATION IS AN INTERESTING NEW THERAPEUTIC RESEARCH STRATEGY, BUT IT STILL REQUIRES A DEEPER UNDERSTANDING OF THE UNDERLYING CELLULAR AND MOLECULAR MECHANISMS OF THE PHENOMENON. BASED ON THE KNOWN MICROGLIAL-ASTROGLIAL INTERACTION, THE PROMINENT ROLE OF THE NUCLEAR FACTOR KAPPA B (NF-KAPPAB) PATHWAY IN MEDIATING ASTROGLIAL PATHOLOGICAL PRO-INFLAMMATORY GAIN OF FUNCTION, AND ITS ABILITY TO RECRUIT CHROMATIN-REMODELING ENZYMES, WE FIRST EXPLORED THE MICROGLIAL ROLE IN THE INITIATION OF ASTROGLIAL PRO-INFLAMMATORY CONVERSION AND THEN MONITORED THE PROGRESSION OF EPIGENETIC CHANGES IN THE ASTROCYTIC CHROMATIN. DIFFERENT CONFIGURATIONS OF PRIMARY GLIAL CULTURE WERE USED TO MODULATE MICROGLIA-ASTROCYTE CROSSTALK WHILE INDUCING PRO-INFLAMMATORY GAIN OF FUNCTION BY LIPOPOLYSACCHARIDE (LPS) EXPOSURE. IN VIVO, BRAIN ISCHEMIA BY CORTICAL DEVASCULARIZATION (PIAL DISRUPTION) WAS PERFORMED TO VERIFY THE PRESENCE OF EPIGENETIC MARKS IN REACTIVE ASTROCYTES. OUR RESULTS SHOWED THAT 1) MICROGLIA IS REQUIRED TO INITIATE THE PATHOLOGICAL CONVERSION OF ASTROCYTES BY TRIGGERING THE NF-KAPPAB SIGNALING PATHWAY; 2) THIS INTERACTION IS MEDIATED BY SOLUBLE FACTORS AND INDUCES STABLE ASTROGLIAL PHENOTYPIC CHANGES; 3) THE PATHOLOGICAL CONVERSION PROMOTES CHROMATIN REMODELING WITH STABLE INCREASE IN H3K9K14AC, TEMPORARY INCREASE IN H3K27AC, AND TEMPORARY REDUCTION IN HETEROCHROMATIN MARK H3K9ME3; AND 4) IN VIVO REACTIVE ASTROCYTES SHOW INCREASED H3K27AC MARK IN THE NEUROINFLAMMATORY MILIEU FROM THE ISCHEMIC PENUMBRA. OUR FINDINGS INDICATE THAT ASTROGLIAL PATHOLOGICAL PRO-INFLAMMATORY GAIN OF FUNCTION IS ASSOCIATED WITH PROFOUND CHANGES IN THE CONFIGURATION OF ASTROCYTIC CHROMATIN, WHICH IN TURN ARE INITIATED BY MICROGLIA-DERIVED CUES. THESE RESULTS OPEN A NEW AVENUE IN THE STUDY OF POTENTIAL PHARMACOLOGICAL INTERVENTIONS THAT MODIFY THE INITIATION AND STABILIZATION OF ASTROGLIAL PATHOLOGICAL REMODELING, WHICH WOULD BE USEFUL IN ACUTE AND CHRONIC CNS INJURY. EPIGENETIC CHANGES REPRESENT A PLAUSIBLE PHARMACOLOGICAL TARGET TO INTERFERE WITH THE STABILIZATION OF THE PATHOLOGICAL ASTROGLIAL PHENOTYPE. 2021 20 5293 24 PROTEASOMAL DEGRADATION OF THE HISTONE ACETYL TRANSFERASE P300 CONTRIBUTES TO BETA-CELL INJURY IN A DIABETES ENVIRONMENT. IN TYPE 2 DIABETES, AMYLOID OLIGOMERS, CHRONIC HYPERGLYCEMIA, LIPOTOXICITY, AND PRO-INFLAMMATORY CYTOKINES ARE DETRIMENTAL TO BETA-CELLS, CAUSING APOPTOSIS AND IMPAIRED INSULIN SECRETION. THE HISTONE ACETYL TRANSFERASE P300, INVOLVED IN REMODELING OF CHROMATIN STRUCTURE BY EPIGENETIC MECHANISMS, IS A KEY UBIQUITOUS ACTIVATOR OF THE TRANSCRIPTIONAL MACHINERY. IN THIS STUDY, WE REPORT THAT LOSS OF P300 ACETYL TRANSFERASE ACTIVITY AND EXPRESSION LEADS TO BETA-CELL APOPTOSIS, AND MOST IMPORTANTLY, THAT STRESS SITUATIONS KNOWN TO BE ASSOCIATED WITH DIABETES ALTER P300 LEVELS AND FUNCTIONAL INTEGRITY. WE FOUND THAT PROTEASOMAL DEGRADATION IS THE MECHANISM SUBSERVING P300 LOSS IN BETA-CELLS EXPOSED TO HYPERGLYCEMIA OR PRO-INFLAMMATORY CYTOKINES. WE ALSO REPORT THAT MELATONIN, A HORMONE PRODUCED IN THE PINEAL GLAND AND KNOWN TO PLAY KEY ROLES IN BETA-CELL HEALTH, PRESERVES P300 LEVELS ALTERED BY THESE TOXIC CONDITIONS. COLLECTIVELY, THESE DATA IMPLY AN IMPORTANT ROLE FOR P300 IN THE PATHOPHYSIOLOGY OF DIABETES. 2018