1 6023 139 THE BET PROTAC INHIBITOR DBET6 PROTECTS AGAINST RETINAL DEGENERATION AND INHIBITS THE CGAS-STING IN RESPONSE TO LIGHT DAMAGE. BACKGROUND: CHRONIC INFLAMMATION SIGNIFICANTLY CONTRIBUTES TO PHOTORECEPTOR DEATH IN BLINDING RETINAL DISEASES SUCH AS AGE-RELATED MACULAR DEGENERATION (AMD) AND RETINITIS PIGMENTOSA (RP). BROMODOMAIN AND EXTRATERMINAL DOMAIN (BET) PROTEINS ARE EPIGENETIC READERS THAT ACT AS KEY PROINFLAMMATORY FACTORS. WE RECENTLY FOUND THE FIRST-GENERATION BET INHIBITOR JQ1 ALLEVIATED SODIUM IODATE-INDUCED RETINAL DEGENERATION BY SUPPRESSING CGAS-STING INNATE IMMUNITY. HERE, WE INVESTIGATED THE EFFECTS AND MECHANISM OF DBET6, A PROTEOLYSIS?TARGETING CHIMERA (PROTAC) SMALL MOLECULE THAT SELECTIVELY DEGRADES BET BY THE UBIQUITIN?PROTEASOME SYSTEM, IN LIGHT-INDUCED RETINAL DEGENERATION. METHODS: MICE WERE EXPOSED TO BRIGHT LIGHT TO INDUCE RETINAL DEGENERATION, AND THE ACTIVATION OF CGAS-STING WAS DETERMINED BY RNA-SEQUENCING AND MOLECULAR BIOLOGY. RETINAL FUNCTION, MORPHOLOGY, PHOTORECEPTOR VIABILITY AND RETINAL INFLAMMATION WERE EXAMINED IN THE PRESENCE AND ABSENCE OF DBET6 TREATMENT. RESULTS: INTRAPERITONEAL INJECTION OF DBET6 LED TO THE RAPID DEGRADATION OF BET PROTEIN IN THE RETINA WITHOUT DETECTABLE TOXICITY. DBET6 IMPROVED RETINAL RESPONSIVENESS AND VISUAL ACUITY AFTER LIGHT DAMAGE (LD). DBET6 ALSO REPRESSED LD-INDUCED RETINAL MACROPHAGES/MICROGLIA ACTIVATION, MULLER CELL GLIOSIS, PHOTORECEPTOR DEATH AND RETINAL DEGENERATION. ANALYSIS OF SINGLE-CELL RNA-SEQUENCING RESULTS REVEALED CGAS-STING COMPONENTS WERE EXPRESSED IN RETINAL MICROGLIA. LD LED TO DRAMATIC ACTIVATION OF THE CGAS-STING PATHWAY, WHEREAS DBET6 SUPPRESSED LD-INDUCED STING EXPRESSION IN REACTIVE MACROPHAGES/MICROGLIA AND THE RELATED INFLAMMATORY RESPONSE. CONCLUSIONS: THIS STUDY INDICATES TARGETED DEGRADATION OF BET BY DBET6 EXERTS NEUROPROTECTIVE EFFECTS BY INHIBITING CGAS-STING IN REACTIVE RETINAL MACROPHAGES/MICROGLIA, AND IS EXPECTED TO BECOME A NEW STRATEGY FOR TREATMENT OF RETINAL DEGENERATION. 2023 2 2113 35 EPIGENETIC HALLMARKS OF AGE-RELATED MACULAR DEGENERATION ARE RECAPITULATED IN A PHOTOSENSITIVE MOUSE MODEL. AGE-RELATED MACULAR DEGENERATION (AMD) IS A CHRONIC, MULTIFACTORIAL DISORDER AND A LEADING CAUSE OF BLINDNESS IN THE ELDERLY. CHARACTERIZED BY PROGRESSIVE PHOTORECEPTOR DEGENERATION IN THE CENTRAL RETINA, DISEASE PROGRESSION INVOLVES EPIGENETIC CHANGES IN CHROMATIN ACCESSIBILITY RESULTING FROM ENVIRONMENTAL EXPOSURES AND CHRONIC STRESS. HERE, WE REPORT THAT A PHOTOSENSITIVE MOUSE MODEL OF ACUTE STRESS-INDUCED PHOTORECEPTOR DEGENERATION RECAPITULATES THE EPIGENETIC HALLMARKS OF HUMAN AMD. GLOBAL EPIGENOMIC PROFILING WAS ACCOMPLISHED BY EMPLOYING AN ASSAY FOR TRANSPOSASE-ACCESSIBLE CHROMATIN USING SEQUENCING (ATAC-SEQ), WHICH REVEALED AN ASSOCIATION BETWEEN DECREASED CHROMATIN ACCESSIBILITY AND STRESS-INDUCED PHOTORECEPTOR CELL DEATH IN OUR MOUSE MODEL. THE EPIGENOMIC CHANGES INDUCED BY LIGHT DAMAGE INCLUDE REDUCED EUCHROMATIN AND INCREASED HETEROCHROMATIN ABUNDANCE, RESULTING IN TRANSCRIPTIONAL AND TRANSLATIONAL DYSREGULATION THAT ULTIMATELY DRIVES PHOTORECEPTOR APOPTOSIS AND AN INFLAMMATORY REACTIVE GLIOSIS IN THE RETINA. OF PARTICULAR INTEREST, PHARMACOLOGICAL INHIBITION OF HISTONE DEACETYLASE 11 (HDAC11) AND SUPPRESSOR OF VARIEGATION 3-9 HOMOLOG 2 (SUV39H2), KEY HISTONE-MODIFYING ENZYMES INVOLVED IN PROMOTING REDUCED CHROMATIN ACCESSIBILITY, AMELIORATED LIGHT DAMAGE IN OUR MOUSE MODEL, SUPPORTING A CAUSAL LINK BETWEEN DECREASED CHROMATIN ACCESSIBILITY AND PHOTORECEPTOR DEGENERATION, THEREBY ELUCIDATING A POTENTIAL NEW THERAPEUTIC STRATEGY TO COMBAT AMD. 2020 3 6567 33 TRANSLATOMIC RESPONSE OF RETINAL MULLER GLIA TO ACUTE AND CHRONIC STRESS. ANALYSIS OF RETINA CELL TYPE-SPECIFIC EPIGENETIC AND TRANSCRIPTOMIC SIGNATURES IS CRUCIAL TO UNDERSTANDING THE PATHOPHYSIOLOGY OF RETINAL DEGENERATIONS SUCH AS AGE-RELATED MACULAR DEGENERATION (AMD) AND DELINEATING CELL AUTONOMOUS AND CELL-NON-AUTONOMOUS MECHANISMS. WE HAVE DISCOVERED THAT ALDH1L1 IS SPECIFICALLY EXPRESSED IN THE MAJOR MACROGLIA OF THE RETINA, MULLER GLIA, AND, UNLIKE THE BRAIN, IS NOT EXPRESSED IN RETINAL ASTROCYTES. THIS ALLOWS USE OF ALDH1L1 CRE DRIVERS AND NUCLEAR TAGGING AND TRANSLATING RIBOSOME AFFINITY PURIFICATION (NUTRAP) CONSTRUCTS FOR TEMPORALLY CONTROLLED LABELING AND PAIRED ANALYSIS OF MULLER GLIA EPIGENOMES AND TRANSLATOMES. AS VALIDATED THROUGH A VARIETY OF APPROACHES, THE ALDH1L1CRE/ERT2-NUTRAP MODEL PROVIDES MULLER GLIA SPECIFIC TRANSLATOMIC AND EPIGENOMIC PROFILES WITHOUT THE NEED TO ISOLATE WHOLE CELLS. APPLICATION OF THIS APPROACH TO MODELS OF ACUTE INJURY (OPTIC NERVE CRUSH) AND CHRONIC STRESS (AGING) UNCOVERED FEW COMMON MULLER GLIA-SPECIFIC TRANSCRIPTOME CHANGES IN INFLAMMATORY PATHWAYS, AND MOSTLY DIFFERENTIAL SIGNATURES FOR EACH STIMULUS. THE EXPRESSION OF MEMBERS OF THE IL-6 AND INTEGRIN-LINKED KINASE SIGNALING PATHWAYS WAS ENHANCED IN MULLER GLIA IN RESPONSE TO OPTIC NERVE CRUSH BUT NOT AGING. UNIQUE CHANGES IN NEUROINFLAMMATION AND FIBROSIS SIGNALING PATHWAYS WERE OBSERVED IN RESPONSE TO AGING BUT NOT WITH OPTIC NERVE CRUSH. THE ALDH1L1CRE/ERT2-NUTRAP MODEL ALLOWS FOCUSED MOLECULAR ANALYSES OF A SINGLE, MINORITY CELL TYPE WITHIN THE RETINA, PROVIDING MORE SUBSTANTIAL EFFECT SIZES THAN WHOLE TISSUE ANALYSES. THE NUTRAP MODEL, NUCLEIC ACID ISOLATION, AND VALIDATION APPROACHES PRESENTED HERE CAN BE APPLIED TO ANY RETINA CELL TYPE FOR WHICH A CELL TYPE-SPECIFIC CRE IS AVAILABLE. 2022 4 1430 23 DIFFERENTIAL EXPRESSION OF SOX11 AND BDNF MRNA ISOFORMS IN THE INJURED AND REGENERATING NERVOUS SYSTEMS. IN BOTH THE CENTRAL NERVOUS SYSTEM (CNS) AND THE PERIPHERAL NERVOUS SYSTEM (PNS), AXONAL INJURY INDUCES CHANGES IN NEURONAL GENE EXPRESSION. IN THE PNS, A RELATIVELY WELL-CHARACTERIZED ALTERATION IN TRANSCRIPTIONAL ACTIVATION IS KNOWN TO PROMOTE AXONAL REGENERATION. THIS TRANSCRIPTIONAL CASCADE INCLUDES THE NEUROTROPHIN BDNF AND THE TRANSCRIPTION FACTOR SOX11. ALTHOUGH BOTH MOLECULES ACT TO FACILITATE SUCCESSFUL AXON REGENERATION IN THE PNS, THIS PROCESS DOES NOT OCCUR IN THE CNS. THE PRESENT STUDY EXAMINES THE DIFFERENTIAL EXPRESSION OF SOX11 AND BDNF MRNA ISOFORMS IN THE PNS AND CNS USING THREE EXPERIMENTAL PARADIGMS AT DIFFERENT TIME POINTS: (I) THE ACUTELY INJURED CNS (RETINA AFTER OPTIC NERVE CRUSH) AND PNS (DORSAL ROOT GANGLION AFTER SCIATIC NERVE CRUSH), (II) A CNS REGENERATION MODEL (RETINA AFTER OPTIC NERVE CRUSH AND INDUCED REGENERATION); AND (III) THE RETINA DURING A CHRONIC FORM OF CENTRAL NEURODEGENERATION (THE DBA/2J GLAUCOMA MODEL). WE FIND AN INITIAL INCREASE OF SOX11 IN BOTH PNS AND CNS AFTER INJURY; HOWEVER, THE EXPRESSION OF BDNF ISOFORMS IS HIGHER IN THE PNS RELATIVE TO THE CNS. SUSTAINED UPREGULATION OF SOX11 IS SEEN IN THE INJURED RETINA FOLLOWING REGENERATION TREATMENT, WHILE THE EXPRESSION OF TWO BDNF MRNA ISOFORMS IS SUPPRESSED. FURTHERMORE, TWO ISOFORMS OF SOX11 WITH DIFFERENT 3'UTR LENGTHS ARE PRESENT IN THE RETINA, AND THE LONG ISOFORM IS SPECIFICALLY UPREGULATED IN LATER STAGES OF GLAUCOMA. THESE RESULTS PROVIDE INSIGHT INTO THE MOLECULAR CASCADES ACTIVE DURING AXONAL INJURY AND REGENERATION IN MAMMALIAN NEURONS. 2017 5 4106 31 MECHANISM OF INFLAMMATION IN AGE-RELATED MACULAR DEGENERATION. AGE-RELATED MACULAR DEGENERATION (AMD) IS A MULTIFACTORIAL DISEASE THAT REPRESENTS THE MOST COMMON CAUSE OF IRREVERSIBLE VISUAL IMPAIRMENT AMONG PEOPLE OVER THE AGE OF 50 IN EUROPE, THE UNITED STATES, AND AUSTRALIA, ACCOUNTING FOR UP TO 50% OF ALL CASES OF CENTRAL BLINDNESS. RISK FACTORS OF AMD ARE HETEROGENEOUS, MAINLY INCLUDING INCREASING AGE AND DIFFERENT GENETIC PREDISPOSITIONS, TOGETHER WITH SEVERAL ENVIRONMENTAL/EPIGENETIC FACTORS, THAT IS, CIGARETTE SMOKING, DIETARY HABITS, AND PHOTOTOXIC EXPOSURE. IN THE AGING RETINA, FREE RADICALS AND OXIDIZED LIPOPROTEINS ARE CONSIDERED TO BE MAJOR CAUSES OF TISSUE STRESS RESULTING IN LOCAL TRIGGERS FOR PARAINFLAMMATION, A CHRONIC STATUS WHICH CONTRIBUTES TO INITIATION AND/OR PROGRESSION OF MANY HUMAN NEURODEGENERATIVE DISEASES SUCH AS AMD. EXPERIMENTAL AND CLINICAL EVIDENCES STRONGLY INDICATE THE PATHOGENETIC ROLE OF IMMUNOLOGIC PROCESSES IN AMD OCCURRENCE, CONSISTING OF PRODUCTION OF INFLAMMATORY RELATED MOLECULES, RECRUITMENT OF MACROPHAGES, COMPLEMENT ACTIVATION, MICROGLIAL ACTIVATION AND ACCUMULATION WITHIN THOSE STRUCTURES THAT COMPOSE AN ESSENTIAL AREA OF THE RETINA KNOWN AS MACULA LUTEA. THIS PAPER REVIEWS SOME ATTRACTIVE ASPECTS OF THE LITERATURE ABOUT THE MECHANISMS OF INFLAMMATION IN AMD, ESPECIALLY FOCUSING ON THOSE FINDINGS OR ARGUMENTS MORE DIRECTLY TRANSLATABLE TO IMPROVE THE CLINICAL MANAGEMENT OF PATIENTS WITH AMD AND TO PREVENT THE SEVERE VISION LOSS CAUSED BY THIS DISEASE. 2012 6 6443 37 THERAPEUTIC APPROACHES TO HISTONE REPROGRAMMING IN RETINAL DEGENERATION. RECENT DATA HAVE REVEALED EPIGENETIC DERANGEMENTS AND SUBSEQUENT CHROMATIN REMODELING AS A POTENT BIOLOGIC SWITCH FOR CHRONIC INFLAMMATION AND CELL SURVIVAL WHICH ARE IMPORTANT THERAPEUTIC TARGETS IN THE PATHOGENESIS OF SEVERAL RETINAL DEGENERATIONS. HISTONE DEACETYLASES (HDACS) ARE A MAJOR COMPONENT OF THIS SYSTEM AND SERVE AS A UNIQUE CONTROL OF THE CHROMATIN REMODELING PROCESS. WITH A MULTITUDE OF TARGETED HDAC INHIBITORS NOW AVAILABLE, THEIR USE IN BOTH BASIC SCIENCE AND CLINICAL STUDIES HAS WIDENED SUBSTANTIALLY. IN THE FIELD OF OCULAR BIOLOGY, THERE ARE DATA TO SUGGEST THAT HDAC INHIBITION MAY SUPPRESS NEOVASCULARIZATION AND MAY BE A POSSIBLE TREATMENT FOR RETINITIS PIGMENTOSA AND DRY AGE-RELATED MACULAR DEGENERATION (AMD). HOWEVER, THE EFFECTS OF THESE INHIBITORS ON CELL SURVIVAL AND CHEMOKINE EXPRESSION IN THE CHORIORETINAL TISSUES REMAIN VERY UNCLEAR. HERE, WE REVIEW THE MULTIFACETED BIOLOGY OF HDAC ACTIVITY AND PHARMACOLOGIC INHIBITION WHILE OFFERING FURTHER INSIGHT INTO THE IMPORTANCE OF THIS EPIGENETIC PATHWAY IN RETINAL DEGENERATIONS. OUR LABORATORY INVESTIGATIONS AIM TO OPEN TRANSLATIONAL AVENUES TO ADVANCE DRY AMD THERAPEUTICS WHILE EXPLORING THE ROLE OF ACETYLATION ON INFLAMMATORY GENE EXPRESSION IN THE AGING AND DEGENERATING RETINA. 2016 7 5690 32 SILENCING OF FEM1CR3 GENE EXPRESSION IN THE DBA/2J MOUSE PRECEDES RETINAL GANGLION CELL DEATH AND IS ASSOCIATED WITH HISTONE DEACETYLASE ACTIVITY. PURPOSE: DOWNREGULATION OF NORMAL GENE EXPRESSION IN DYING RETINAL GANGLION CELLS HAS BEEN DOCUMENTED IN BOTH ACUTE AND CHRONIC MODELS OF OPTIC NERVE DISEASE. THE AUTHORS EXAMINED THE MECHANISM AND TIMING OF THIS PHENOMENON IN DBA/2J MICE, USING GENETICALLY MODIFIED SUBSTRAINS OF THIS INBRED LINE. METHODS: DBA/2J MICE, DOUBLY CONGENIC FOR THE BAX MUTANT ALLELE AND THE GANGLION CELL REPORTER GENE FEM1C(ROSA3) (R3), WERE EVALUATED TO ELUCIDATE THE TIMING OF LOSS OF NORMAL GENE EXPRESSION DURING THE APOPTOTIC PROCESS. THE LOCALIZATION OF HISTONE DEACETYLASE 3 (HDAC3) AND NUCLEAR HISTONE H4 ACETYLATION WERE EXAMINED BY IMMUNOFLUORESCENCE IN DYING CELLS. THE ROLE OF HDACS IN GENE SILENCING DURING GLAUCOMA WAS INTERROGATED USING THE GLOBAL HDAC INHIBITOR TRICHOSTATIN A (TSA). RESULTS: SILENCING OF THE R3 ALLELE OCCURRED IN BAX(-/-) GANGLION CELLS, INDICATING THAT THIS PROCESS PRECEDED THE COMMITTED STEP OF THE INTRINSIC APOPTOTIC PATHWAY. WEEKLY TSA TREATMENT, BETWEEN THE AGES OF 6 AND 10 MONTHS, WAS ABLE TO ATTENUATE THE LOSS OF R3 EXPRESSION IN THE RETINA, BUT HAD NO EFFECT ON OPTIC NERVE DEGENERATION. DYING CELLS IN AGING DBA/2J MICE EXHIBITED NUCLEAR LOCALIZATION OF HDAC3 AND A DECREASE IN THE LEVEL OF H4 ACETYLATION. CONCLUSIONS: RETINAL GANGLION CELLS EXHIBIT A LOSS OF NORMAL GENE EXPRESSION AS AN EARLY (PRE-BAX INVOLVEMENT) PART OF THEIR APOPTOTIC PROGRAM DURING GLAUCOMATOUS DEGENERATION. THIS PROCESS CAN BE AMELIORATED, BUT NOT COMPLETELY BLOCKED, USING HDAC INHIBITORS. EPIGENETIC CHANGES TO ACTIVE CHROMATIN, SUCH AS DEACETYLATION, MAY BE MEDIATED BY HDAC3 IN DYING NEURONS. 2012 8 232 22 ADAPTIVE PLASTICITY IN THE RETINA: PROTECTION AGAINST ACUTE INJURY AND NEURODEGENERATIVE DISEASE BY CONDITIONING STIMULI. ALTHOUGH BOTH PRECLINICAL AND CLINICAL CONDITIONING STUDIES IN HEART AND BRAIN LEAD THE FIELD OF CONDITIONING MEDICINE, INVESTIGATIONS OF RETINAL CONDITIONING STILL NUMBER MORE THAN 100. IN THIS BRIEF REVIEW, WE HIGHLIGHT FINDINGS TO DATE FROM ANIMAL AND CELL CULTURE MODELS OF CONDITIONING THAT PROVIDE DEMONSTRATED PROTECTION IN ACUTE AND CHRONIC RETINAL INJURY AND DISEASE MODELS. THE MULTITUDE OF STIMULI USED TO CONDITION THE RETINA, THE SIGNALING MEDIATORS AND PATHWAYS IDENTIFIED, AND THE INJURY- AND DISEASE-RESILIENT PHENOTYPES DOCUMENTED ARE DISCUSSED HEREIN, ALONG WITH OUR RECOMMENDATIONS FOR THE KINDS OF STUDIES NEEDED TO CONTINUE TO ADVANCE THIS PROMISING FIELD. IN OUR VIEW, THE ROBUST PROTECTION AFFORDED BY THESE ADAPTIVE EPIGENETIC RESPONSES TO CONDITIONING STRESS PROVIDES SIGNIFICANT INCENTIVES FOR BOTH FURTHERING OUR INVESTMENT IN BENCH RESEARCH AND UNDERWRITING CLINICAL TRIALS, SO THAT THE FULL POTENTIAL OF THIS THERAPY CAN BE REALIZED. 2018 9 2206 23 EPIGENETIC MODIFICATIONS AND DIABETIC RETINOPATHY. DIABETIC RETINOPATHY REMAINS ONE OF THE MOST DEBILITATING CHRONIC COMPLICATIONS, BUT DESPITE EXTENSIVE RESEARCH IN THE FIELD, THE EXACT MECHANISM(S) RESPONSIBLE FOR HOW RETINA IS DAMAGED IN DIABETES REMAINS AMBIGUOUS. MANY METABOLIC PATHWAYS HAVE BEEN IMPLICATED IN ITS DEVELOPMENT, AND GENES ASSOCIATED WITH THESE PATHWAYS ARE ALTERED. DIABETIC ENVIRONMENT ALSO FACILITATES EPIGENETICS MODIFICATIONS, WHICH CAN ALTER THE GENE EXPRESSION WITHOUT PERMANENT CHANGES IN DNA SEQUENCE. THE ROLE OF EPIGENETICS IN DIABETIC RETINOPATHY IS NOW AN EMERGING AREA, AND RECENT WORK HAS SHOWN THAT GENES ENCODING MITOCHONDRIAL SUPEROXIDE DISMUTASE (SOD2) AND MATRIX METALLOPROTEINASE-9 (MMP-9) ARE EPIGENETICALLY MODIFIED, ACTIVATES OF EPIGENETIC MODIFICATION ENZYMES, HISTONE LYSINE DEMETHYLASE 1 (LSD1), AND DNA METHYLTRANSFERASE ARE INCREASED, AND THE MICRO RNAS RESPONSIBLE FOR REGULATING NUCLEAR TRANSCRIPTIONAL FACTOR AND VEGF ARE UPREGULATED. WITH THE GROWING EVIDENCE OF EPIGENETIC MODIFICATIONS IN DIABETIC RETINOPATHY, BETTER UNDERSTANDING OF THESE MODIFICATIONS HAS POTENTIAL TO IDENTIFY NOVEL TARGETS TO INHIBIT THIS DEVASTATING DISEASE. FORTUNATELY, THE INHIBITORS AND MIMICS TARGETED TOWARDS HISTONE MODIFICATION, DNA METHYLATION, AND MIRNAS ARE NOW BEING TRIED FOR CANCER AND OTHER CHRONIC DISEASES, AND BETTER UNDERSTANDING OF THE ROLE OF EPIGENETICS IN DIABETIC RETINOPATHY WILL OPEN THE DOOR FOR THEIR POSSIBLE USE IN COMBATING THIS BLINDING DISEASE. 2013 10 5803 30 STING SIGNALING ACTIVATION INHIBITS HBV REPLICATION AND ATTENUATES THE SEVERITY OF LIVER INJURY AND HBV-INDUCED FIBROSIS. THE COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) OF HBV PLAYS A CRUCIAL ROLE IN VIRAL PERSISTENCE AND IS ALSO A RISK FACTOR FOR DEVELOPING HBV-INDUCED DISEASES, INCLUDING LIVER FIBROSIS. STIMULATOR OF INTERFERON GENES (STING), A MASTER REGULATOR OF DNA-MEDIATED INNATE IMMUNE ACTIVATION, IS A POTENTIAL THERAPEUTIC TARGET FOR VIRAL INFECTION AND VIRUS-RELATED DISEASES. IN THIS STUDY, AGONIST-INDUCED STING SIGNALING ACTIVATION IN MACROPHAGES WAS REVEALED TO INHIBIT CCCDNA-MEDIATED TRANSCRIPTION AND HBV REPLICATION VIA EPIGENETIC MODIFICATION IN HEPATOCYTES. NOTABLY, STING ACTIVATION COULD EFFICIENTLY ATTENUATE THE SEVERITY OF LIVER INJURY AND FIBROSIS IN A CHRONIC RECOMBINANT CCCDNA (RCCCDNA) MOUSE MODEL, WHICH IS A PROVEN SUITABLE RESEARCH PLATFORM FOR HBV-INDUCED FIBROSIS. MECHANISTICALLY, STING-ACTIVATED AUTOPHAGIC FLUX COULD SUPPRESS MACROPHAGE INFLAMMASOME ACTIVATION, LEADING TO THE AMELIORATION OF LIVER INJURY AND HBV-INDUCED FIBROSIS. OVERALL, THE ACTIVATION OF STING SIGNALING COULD INHIBIT HBV REPLICATION THROUGH EPIGENETIC SUPPRESSION OF CCCDNA AND ALLEVIATE HBV-INDUCED LIVER FIBROSIS THROUGH THE SUPPRESSION OF MACROPHAGE INFLAMMASOME ACTIVATION BY ACTIVATING AUTOPHAGIC FLUX IN A CHRONIC HBV MOUSE MODEL. THIS STUDY SUGGESTS THAT TARGETING THE STING SIGNALING PATHWAY MAY BE AN IMPORTANT THERAPEUTIC STRATEGY TO PROTECT AGAINST PERSISTENT HBV REPLICATION AND HBV-INDUCED FIBROSIS. 2022 11 279 25 AGE-RELATED MACULAR DEGENERATION: FROM EPIGENETICS TO THERAPEUTIC IMPLICATIONS. ABERRANT REGULATION OF EPIGENETIC MECHANISMS, INCLUDING THE TWO MOST COMMON TYPES; DNA METHYLATION AND HISTONE MODIFICATION HAVE BEEN IMPLICATED IN COMMON CHRONIC PROGRESSIVE CONDITIONS, INCLUDING ALZHEIMER DISEASE, CARDIOVASCULAR DISEASE, AND AGE-RELATED MACULAR DEGENERATION (AMD). ALL THESE CONDITIONS ARE COMPLEX, MEANING THAT ENVIRONMENTAL FACTORS, GENETIC FACTORS, AND THEIR INTERACTIONS PLAY A ROLE IN DISEASE PATHOPHYSIOLOGY. ALTHOUGH GENOME WIDE ASSOCIATION STUDIES (GWAS), AND STUDIES ON TWINS DEMONSTRATE THE GENETIC/HEREDITARY COMPONENT TO THESE COMPLEX DISEASES, INCLUDING AMD, THIS CONTRIBUTION IS MUCH LESS THAN 100%. MOREOVER, THE CONTRIBUTION OF THE HEREDITARY COMPONENT DECREASES IN THE ADVANCED, LATER ONSET FORMS OF THESE CHRONIC DISEASES INCLUDING AMD. THIS UNDERSCORES THE NEED TO ELUCIDATE HOW THE GENETIC AND ENVIRONMENTAL FACTORS FUNCTION TO EXERT THEIR INFLUENCE ON DISEASE PATHOPHYSIOLOGY. BY TEASING OUT EPIGENETIC MECHANISMS AND HOW THEY EXERT THEIR INFLUENCE ON AMD, THERAPEUTIC TARGETS CAN BE TAILORED TO PREVENT AND/OR SLOW DOWN DISEASE PROGRESSION. EPIGENETIC STUDIES THAT INCORPORATE WELL-CHARACTERIZED PATIENT TISSUE SAMPLES (INCLUDING AFFECTED TISSUES AND PERIPHERAL BLOOD), SIMILAR TO THOSE RELEVANT TO GENE EXPRESSION STUDIES, ALONG WITH GENETIC AND EPIDEMIOLOGICAL INFORMATION, CAN BE THE FIRST STEP IN DEVELOPING APPROPRIATE FUNCTIONAL ASSAYS TO VALIDATE FINDINGS AND IDENTIFY POTENTIAL THERAPIES. 2021 12 697 36 BROMODOMAIN AND EXTRATERMINAL PROTEINS AS NOVEL EPIGENETIC TARGETS FOR RENAL DISEASES. EPIGENETIC MECHANISMS, ESPECIALLY DNA METHYLATION AND HISTONE MODIFICATIONS, ARE DYNAMIC PROCESSES THAT REGULATE THE GENE EXPRESSION TRANSCRIPTIONAL PROGRAM IN NORMAL AND DISEASED STATES. THE BROMODOMAIN AND EXTRATERMINAL (BET) PROTEIN FAMILY (BRD2, BRD3, BRD4, AND BRDT) ARE EPIGENETIC READERS THAT, VIA BROMODOMAINS, REGULATE GENE TRANSCRIPTION BY BINDING TO ACETYLATED LYSINE RESIDUES ON HISTONES AND MASTER TRANSCRIPTIONAL FACTORS. EXPERIMENTAL DATA HAVE DEMONSTRATED THE INVOLVEMENT OF SOME BET PROTEINS IN MANY PATHOLOGICAL CONDITIONS, INCLUDING TUMOR DEVELOPMENT, INFECTIONS, AUTOIMMUNITY, AND INFLAMMATION. SELECTIVE BROMODOMAIN INHIBITORS ARE EPIGENETIC DRUGS THAT BLOCK THE INTERACTION BETWEEN BET PROTEINS AND ACETYLATED PROTEINS, THUS EXERTING BENEFICIAL EFFECTS. RECENT DATA HAVE DESCRIBED THE BENEFICIAL EFFECT OF BET INHIBITION ON EXPERIMENTAL RENAL DISEASES. EMERGING EVIDENCE UNDERSCORES THE IMPORTANCE OF ENVIRONMENTAL MODIFICATIONS IN THE ORIGIN OF PATHOLOGICAL FEATURES IN CHRONIC KIDNEY DISEASES (CKD). SEVERAL CELLULAR PROCESSES SUCH AS OXIDATION, METABOLIC DISORDERS, CYTOKINES, INFLAMMATION, OR ACCUMULATED UREMIC TOXINS MAY INDUCE EPIGENETIC MODIFICATIONS THAT REGULATE KEY PROCESSES INVOLVED IN RENAL DAMAGE AND IN OTHER PATHOLOGICAL CONDITIONS OBSERVED IN CKD PATIENTS. HERE, WE REVIEW HOW TARGETING BROMODOMAINS IN BET PROTEINS MAY REGULATE ESSENTIAL PROCESSES INVOLVED IN RENAL DISEASES AND IN ASSOCIATED COMPLICATIONS FOUND IN CKD PATIENTS, SUCH AS CARDIOVASCULAR DAMAGE, HIGHLIGHTING THE POTENTIAL OF EPIGENETIC THERAPEUTIC STRATEGIES AGAINST BET PROTEINS FOR CKD TREATMENT AND ASSOCIATED RISKS. 2019 13 1105 37 COMBINED INHIBITION OF HISTONE DEACETYLASES AND BET FAMILY PROTEINS AS EPIGENETIC THERAPY FOR NERVE INJURY-INDUCED NEUROPATHIC PAIN. CURRENT TREATMENTS FOR NEUROPATHIC PAIN HAVE OFTEN MODERATE EFFICACY AND PRESENT UNWANTED EFFECTS SHOWING THE NEED TO DEVELOP EFFECTIVE THERAPIES. ACCUMULATING EVIDENCE SUGGESTS THAT HISTONE ACETYLATION PLAYS ESSENTIAL ROLES IN CHRONIC PAIN AND THE ANALGESIC ACTIVITY OF HISTONE DEACETYLASES (HDACS) INHIBITORS IS DOCUMENTED. BROMODOMAIN AND EXTRA-TERMINAL DOMAIN (BET) PROTEINS ARE EPIGENETIC READERS THAT INTERACT WITH ACETYLATED LYSINE RESIDUES ON HISTONES, BUT LITTLE IS KNOWN ABOUT THEIR IMPLICATION IN NEUROPATHIC PAIN. THUS, THE CURRENT STUDY WAS AIMED TO INVESTIGATE THE EFFECT OF THE COMBINATION OF HDAC AND BET INHIBITORS IN THE SPARED NERVE INJURY (SNI) MODEL IN MICE. INTRANASAL ADMINISTRATION OF I-BET762 (BET INHIBITOR) OR SAHA (HDAC INHIBITOR) ATTENUATED THERMAL AND MECHANICAL HYPERSENSITIVITY AND THIS ANTIALLODYNIC ACTIVITY WAS IMPROVED BY CO-ADMINISTRATION OF BOTH DRUGS. SPINAL CORD SECTIONS OF SNI MICE SHOWED AN INCREASED EXPRESSION OF HDAC1 AND BRD4 PROTEINS AND COMBINATION PRODUCED A STRONGER REDUCTION COMPARED TO EACH EPIGENETIC AGENT ALONE. SAHA AND I-BET762, ADMINISTERED ALONE OR IN COMBINATION, COUNTERACTED THE SNI-INDUCED MICROGLIA ACTIVATION BY INHIBITING THE EXPRESSION OF IBA1, CD11B, INDUCIBLE NITRIC OXIDE SYNTHASE (INOS), THE ACTIVATION OF NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) AND SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION-1 (STAT1) WITH COMPARABLE EFFICACY. CONVERSELY, THE EPIGENETIC INHIBITORS SHOWED A MODEST EFFECT ON SPINAL PROINFLAMMATORY CYTOKINES CONTENT THAT WAS SIGNIFICANTLY POTENTIATED BY THEIR COMBINATION. PRESENT RESULTS INDICATE A KEY ROLE OF ACETYLATED HISTONES AND THEIR RECRUITMENT BY BET PROTEINS ON MICROGLIA-MEDIATED SPINAL NEUROINFLAMMATION. TARGETING NEUROPATHIC PAIN WITH THE COMBINATION OF HDAC AND BET INHIBITORS MAY REPRESENT A PROMISING NEW THERAPEUTIC OPTION. 2021 14 1904 37 ENHANCED RETINAL GANGLION CELL SURVIVAL IN GLAUCOMA BY HYPOXIC POSTCONDITIONING AFTER DISEASE ONSET. THE NEUROPROTECTIVE EFFICACY OF ADAPTIVE EPIGENETICS, WHEREIN BENEFICIAL GENE EXPRESSION CHANGES ARE INDUCED BY NONHARMFUL "CONDITIONING" STIMULI, IS NOW WELL ESTABLISHED IN SEVERAL ACUTE, PRECLINICAL CENTRAL NERVOUS SYSTEM INJURY MODELS. RECENTLY, IN A MOUSE MODEL OF GLAUCOMA, WE DEMONSTRATED RETINAL GANGLION CELL (RGC) PROTECTION BY REPETITIVELY "PRECONDITIONING" WITH HYPOXIA PRIOR TO DISEASE ONSET, INDICATING AN EPIGENETIC APPROACH MAY ALSO YIELD BENEFITS IN CHRONIC NEURODEGENERATIVE DISEASE. HEREIN, WE DETERMINED WHETHER PRESENTING THE REPETITIVE HYPOXIC STIMULUS AFTER DISEASE INITIATION [REPETITIVE HYPOXIC "POSTCONDITIONING" (RH-POST)] COULD AFFORD SIMILAR FUNCTIONAL AND MORPHOLOGIC PROTECTION AGAINST GLAUCOMATOUS RGC INJURY. CHRONIC ELEVATIONS IN INTRAOCULAR PRESSURE (IOP) WERE INDUCED UNILATERALLY IN ADULT MALE C57BL/6 MICE BY EPISCLERAL VEIN LIGATION. MICE WERE RANDOMIZED TO AN RH-POST [1 H OF SYSTEMIC HYPOXIA (11% OXYGEN) EVERY OTHER DAY, STARTING 4 DAYS AFTER IOP ELEVATION] OR AN UNTREATED CONTROL GROUP. AFTER 3 WEEKS OF EXPERIMENTAL GLAUCOMA, THE 21-27% REDUCTION AND 5-25% PROLONGATION IN FLASH VISUAL-EVOKED POTENTIAL AMPLITUDES AND LATENCIES, RESPECTIVELY, AND THE 30% IMPAIRMENT IN VISUAL ACUITY WERE ROBUSTLY IMPROVED IN RH-POST-TREATED MICE, AS WAS THE 17% LOSS IN RGC SOMA NUMBER AND 20% REDUCTION IN AXON INTEGRITY. THESE PROTECTIVE EFFECTS WERE OBSERVED WITHOUT RH-POST AFFECTING IOP. THE PRESENT FINDINGS DEMONSTRATE THAT FUNCTIONAL AND MORPHOLOGIC PROTECTION OF RGCS CAN BE REALIZED BY STIMULATING EPIGENETIC RESPONSES DURING THE EARLY STAGES OF DISEASE, AND THUS CONSTITUTE A NEW CONCEPTUAL APPROACH TO GLAUCOMA THERAPEUTICS. 2015 15 4582 37 N-TERMINAL BET BROMODOMAIN INHIBITORS DISRUPT A BRD4-P65 INTERACTION AND REDUCE INDUCIBLE NITRIC OXIDE SYNTHASE TRANSCRIPTION IN PANCREATIC BETA-CELLS. CHRONIC INFLAMMATION OF PANCREATIC ISLETS IS A KEY DRIVER OF BETA-CELL DAMAGE THAT CAN LEAD TO AUTOREACTIVITY AND THE EVENTUAL ONSET OF AUTOIMMUNE DIABETES (T1D). IN THE ISLET, ELEVATED LEVELS OF PROINFLAMMATORY CYTOKINES INDUCE THE TRANSCRIPTION OF THE INDUCIBLE NITRIC OXIDE SYNTHASE (INOS) GENE, NOS2, ULTIMATELY RESULTING IN INCREASED NITRIC OXIDE (NO). EXCESSIVE OR PROLONGED EXPOSURE TO NO CAUSES BETA-CELL DYSFUNCTION AND FAILURE ASSOCIATED WITH DEFECTS IN MITOCHONDRIAL RESPIRATION. RECENT STUDIES SHOWED THAT INHIBITION OF THE BROMODOMAIN AND EXTRATERMINAL DOMAIN (BET) FAMILY OF PROTEINS, A DRUGGABLE CLASS OF EPIGENETIC READER PROTEINS, PREVENTS THE ONSET AND PROGRESSION OF T1D IN THE NON-OBESE DIABETIC MOUSE MODEL. WE HYPOTHESIZED THAT BET PROTEINS CO-ACTIVATE TRANSCRIPTION OF CYTOKINE-INDUCED INFLAMMATORY GENE TARGETS IN BETA-CELLS AND THAT SELECTIVE, CHEMOTHERAPEUTIC INHIBITION OF BET BROMODOMAINS COULD REDUCE SUCH TRANSCRIPTION. HERE, WE INVESTIGATED THE ABILITY OF BET BROMODOMAIN SMALL MOLECULE INHIBITORS TO REDUCE THE BETA-CELL RESPONSE TO THE PROINFLAMMATORY CYTOKINE INTERLEUKIN 1 BETA (IL-1BETA). BET BROMODOMAIN INHIBITION ATTENUATED IL-1BETA-INDUCED TRANSCRIPTION OF THE INFLAMMATORY MEDIATOR NOS2 AND CONSEQUENT INOS PROTEIN AND NO PRODUCTION. REDUCED NOS2 TRANSCRIPTION IS CONSISTENT WITH INHIBITION OF NF-KAPPAB FACILITATED BY DISRUPTING THE INTERACTION OF A SINGLE BET FAMILY MEMBER, BRD4, WITH THE NF-KAPPAB SUBUNIT, P65. USING RECENTLY REPORTED SELECTIVE INHIBITORS OF THE FIRST AND SECOND BET BROMODOMAINS, INHIBITION OF ONLY THE FIRST BROMODOMAIN WAS NECESSARY TO REDUCE THE INTERACTION OF BRD4 WITH P65 IN BETA-CELLS. MOREOVER, INHIBITION OF THE FIRST BROMODOMAIN WAS SUFFICIENT TO MITIGATE IL-1BETA-DRIVEN DECREASES IN MITOCHONDRIAL OXYGEN CONSUMPTION RATES AND BETA-CELL VIABILITY. BY IDENTIFYING A ROLE FOR THE INTERACTION BETWEEN BRD4 AND P65 IN CONTROLLING THE RESPONSE OF BETA-CELLS TO PROINFLAMMATORY CYTOKINES, WE PROVIDE MECHANISTIC INFORMATION ON HOW BET BROMODOMAIN INHIBITION CAN DECREASE INFLAMMATION. THESE STUDIES ALSO SUPPORT THE POTENTIAL THERAPEUTIC APPLICATION OF MORE SELECTIVE BET BROMODOMAIN INHIBITORS IN ATTENUATING BETA-CELL INFLAMMATION. 2022 16 5546 27 ROLE OF EPIGENETIC MECHANISMS IN THE DEVELOPMENT OF CHRONIC COMPLICATIONS OF DIABETES. THERE IS GROWING EVIDENCE THAT EPIGENETIC REGULATION OF GENE EXPRESSION INCLUDING POST-TRANSLATIONAL HISTONE MODIFICATIONS (PTHMS), DNA METHYLATION AND MICRORNA (MIRNA)-REGULATION OF MRNA TRANSLATION COULD PLAY A CRUCIAL ROLE IN THE DEVELOPMENT OF CHRONIC, DIABETIC COMPLICATIONS. HYPERGLYCEMIA CAN INDUCE AN ABNORMAL ACTION OF PTHMS AND DNA METHYLTRANSFERASES AS WELL AS ALTER THE LEVELS OF NUMEROUS MIRNAS IN ENDOTHELIAL CELLS, VASCULAR SMOOTH MUSCLE CELLS, CARDIOMYOCYTES, RETINA, AND RENAL CELLS. THESE EPIGENETIC ABNORMALITIES RESULT IN CHANGES IN THE EXPRESSION OF NUMEROUS GENES CONTRIBUTING TO EFFECTS SUCH AS DEVELOPMENT OF CHRONIC INFLAMMATION, IMPAIRED CLEARANCE OF REACTIVE OXYGEN SPECIES (ROS), ENDOTHELIAL CELL DYSFUNCTION AND/OR THE ACCUMULATION OF EXTRACELLULAR MATRIX IN THE KIDNEY, WHICH CAUSING THE DEVELOPMENT OF RETINOPATHY, NEPHROPATHY OR CARDIOMYOPATHY. SOME EPIGENETIC MODIFICATIONS, FOR EXAMPLE PTHMS AND DNA METHYLATION, BECOME IRREVERSIBLE OVER TIME. THEREFORE, THESE PROCESSES HAVE GAINED MUCH ATTENTION IN EXPLAINING THE LONG-LASTING DETRIMENTAL CONSEQUENCES OF HYPERGLYCAEMIA CAUSING THE DEVELOPMENT OF CHRONIC COMPLICATIONS EVEN AFTER IMPROVED GLYCAEMIC CONTROL IS ACHIEVED. OUR REVIEW SUGGESTS THAT THE TREATMENT OF CHRONIC COMPLICATIONS SHOULD FOCUS ON ERASING METABOLIC MEMORY BY TARGETING CHROMATIN MODIFICATION ENZYMES AND BY RESTORING MIRNA LEVELS. 2014 17 689 37 BRD4 AS A THERAPEUTIC TARGET IN PULMONARY DISEASES. BROMODOMAIN AND EXTRA-TERMINAL DOMAIN (BET) PROTEINS ARE EPIGENETIC MODULATORS THAT REGULATE GENE TRANSCRIPTION THROUGH INTERACTING WITH ACETYLATED LYSINE RESIDUES OF HISTONE PROTEINS. BET PROTEINS HAVE MULTIPLE ROLES IN REGULATING KEY CELLULAR FUNCTIONS SUCH AS CELL PROLIFERATION, DIFFERENTIATION, INFLAMMATION, OXIDATIVE AND REDOX BALANCE, AND IMMUNE RESPONSES. AS A RESULT, BET PROTEINS HAVE BEEN FOUND TO BE ACTIVELY INVOLVED IN A BROAD RANGE OF HUMAN LUNG DISEASES INCLUDING ACUTE LUNG INFLAMMATION, ASTHMA, PULMONARY ARTERIAL HYPERTENSION, PULMONARY FIBROSIS, AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). DUE TO THE IDENTIFICATION OF SPECIFIC SMALL MOLECULAR INHIBITORS OF BET PROTEINS, TARGETING BET IN THESE LUNG DISEASES HAS BECOME AN AREA OF INCREASING INTEREST. EMERGING EVIDENCE HAS DEMONSTRATED THE BENEFICIAL EFFECTS OF BET INHIBITORS IN PRECLINICAL MODELS OF VARIOUS HUMAN LUNG DISEASES. THIS IS, IN GENERAL, LARGELY RELATED TO THE ABILITY OF BET PROTEINS TO BIND TO PROMOTERS OF GENES THAT ARE CRITICAL FOR INFLAMMATION, DIFFERENTIATION, AND BEYOND. BY MODULATING THESE CRITICAL GENES, BET PROTEINS ARE INTEGRATED INTO THE PATHOGENESIS OF DISEASE PROGRESSION. THE INTRINSIC HISTONE ACETYLTRANSFERASE ACTIVITY OF BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) IS OF PARTICULAR INTEREST, SEEMS TO ACT INDEPENDENTLY OF ITS BROMODOMAIN BINDING ACTIVITY, AND HAS IMPLICATION IN SOME CONTEXTS. IN THIS REVIEW, WE PROVIDE A BRIEF OVERVIEW OF THE RESEARCH ON BET PROTEINS WITH A FOCUS ON BRD4 IN SEVERAL MAJOR HUMAN LUNG DISEASES, THE UNDERLYING MOLECULAR MECHANISMS, AS WELL AS FINDINGS OF TARGETING BET PROTEINS USING PHARMACEUTICAL INHIBITORS IN DIFFERENT LUNG DISEASES PRECLINICALLY. 2023 18 6687 22 VALIDATION OF THE EPIGENETIC READER BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) AS A THERAPEUTIC TARGET FOR TREATMENT OF AIRWAY REMODELING. STRUCTURAL REMODELING IS CENTRAL TO THE INITIATION AND PROGRESSION OF MANY CHRONIC LUNG DISEASES, REPRESENTING AN IMPORTANT UNMET NEED. WE EXAMINE THE EVIDENCE SUPPORTING BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) AS A VALIDATED BIOLOGICAL TARGET FOR TREATMENT OF AIRWAY REMODELING. IN EPITHELIAL CELLS AND FIBROBLASTS, BRD4 SERVES AS A SCAFFOLD FOR CHROMATIN REMODELING COMPLEXES IN ACTIVE SUPER-ENHANCERS. IN RESPONSE TO INFLAMMATORY STIMULI, BRD4 IS REPOSITIONED TO INNATE AND MESENCHYMAL GENES ACTIVATING THEIR PRODUCTION. PROOF-OF-CONCEPT STUDIES SHOW PROMISING BENEFIT OF SELECTIVE BRD4 INHIBITORS IN DISRUPTING EPITHELIAL MESENCHYMAL TRANSITION AND MYOFIBROBLAST TRANSITION IN DIVERSE MODELS OF LUNG INJURY. RECENT IDENTIFICATION OF BIOMARKERS OF BRD4 PROVIDES A BASIS FOR FURTHER DRUG DEVELOPMENT FOR APPLICATION IN VIRAL-INDUCED AIRWAY INFLAMMATION, COPD AND INTERSTITIAL LUNG DISEASES. 2020 19 592 35 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 20 699 34 BROMODOMAIN PROTEIN 4 IS A KEY MOLECULAR DRIVER OF TGFBETA1-INDUCED HEPATIC STELLATE CELL ACTIVATION. LIVER FIBROSIS IS CHARACTERIZED BY THE EXCESSIVE DEPOSITION OF EXTRACELLULAR MATRIX IN LIVER. CHRONIC LIVER INJURY INDUCES THE ACTIVATION OF HEPATIC STELLATE CELL (HSCS), A KEY STEP IN LIVER FIBROGENESIS. THE ACTIVATED HSC IS THE PRIMARY SOURCE OF ECM AND CONTRIBUTES SIGNIFICANTLY TO LIVER FIBROSIS. TGFBETA1 IS THE MOST POTENT PRO-FIBROTIC CYTOKINE. BROMODOMAIN PROTEIN 4 (BRD4), AN EPIGENETIC READER OF HISTONE ACETYLATION MARKS, WAS CRUCIAL FOR PROFIBROTIC GENE EXPRESSION IN HSCS. THE PRESENT STUDY AIMED TO INVESTIGATE THE ROLES OF BRD4 IN TGFBETA1-DEPENDENT HSC ACTIVATION AND LIVER FIBROSIS, FOCUSING ON TGFBETA1-INDUCED ALTERATIONS OF THE LEVELS OF THE FIBROTIC-RELATED IMPORTANT PROTEINS IN HSCS BY EMPLOYING THE HETEROZYGOUS TGFBETA1 KNOCKOUT MICE AND BRD4 KNOCKDOWN IN VIVO AND IN VITRO. RESULTS REVEALED THAT BRD4 PROTEIN LEVEL WAS SIGNIFICANTLY UPREGULATED BY TGFBETA1 AND BRD4 KNOCKDOWN REDUCED TGFBETA1-INDUCED HSC ACTIVATION AND LIVER FIBROSIS. BRD4 WAS REQUIRED FOR THE INFLUENCES OF TGFBETA1 ON PDGFBETA RECEPTOR AND ON THE PATHWAYS OF SMAD3, STAT3, AND AKT. BRD4 ALSO MEDIATED TGFBETA1-INDUCED INCREASES IN HISTONE ACETYLTRANSFERASE P300, THE PIVOTAL PRO-INFLAMMATORY NFKB P65, AND TISSUE INHIBITOR OF METALLOPROTEINASE 1 WHEREAS BRD4 REDUCED CASPASE-3 PROTEIN LEVELS IN HSCS DURING LIVER INJURY, INDEPENDENT OF TGFBETA1. FURTHER EXPERIMENTS INDICATED THE INTERACTION BETWEEN TGFBETA1-INDUCED BRD4 AND NFKB P65 IN HSCS AND IN LIVER OF TAA-INDUCED LIVER INJURY. HUMAN CIRRHOTIC LIVERS WERE DEMONSTRATED A PARALLEL INCREASE IN THE PROTEIN LEVELS OF BRD4 AND NFKB P65 IN HSCS. THIS STUDY REVEALED THAT BRD4 WAS A KEY MOLECULAR DRIVER OF TGFBETA1-INDUCED HSC ACTIVATION AND LIVER FIBROSIS. 2023