1 700 131 BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4): A KEY PLAYER IN INFLAMMATORY BOWEL DISEASE AND POTENTIAL TO INSPIRE EPIGENETIC THERAPEUTICS. INTRODUCTION: INFLAMMATORY BOWEL DISEASES (IBDS) ARE DEBILITATING CHRONIC INFLAMMATORY DISORDERS WITH INCREASING PREVALENCE WORLDWIDE. EPIGENETIC REGULATOR BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) IS CRITICAL IN CONTROLLING GENE EXPRESSION OF IBD-ASSOCIATED INFLAMMATORY CYTOKINE NETWORKS. BRD4 AS A PROMISING THERAPEUTIC TARGET IS ALSO TIGHTLY ASSOCIATED WITH MANY OTHER DISEASES, SUCH AS AIRWAY INFLAMMATION AND FIBROSIS, CANCERS, INFECTIOUS DISEASES AND CENTRAL NERVOUS SYSTEM DISORDERS. AREAS COVERED: THIS REVIEW BRIEFLY SUMMARIZED THE CRITICAL ROLE OF BRD4 IN THE PATHOGENESIS OF IBDS AND THE CURRENT CLINICAL LANDSCAPE OF DEVELOPING BROMODOMAIN AND EXTRA TERMINAL DOMAIN (BET) INHIBITORS. THE CHALLENGES AND OPPORTUNITIES AS WELL AS FUTURE DIRECTIONS OF TARGETING BRD4 INHIBITION FOR POTENTIAL IBD MEDICATIONS WERE ALSO DISCUSSED. EXPERT OPINION: TARGETING BRD4 WITH POTENT AND SPECIFIC INHIBITORS MAY OFFER NOVEL EFFECTIVE THERAPEUTICS FOR IBD PATIENTS, PARTICULARLY THOSE WHO ARE REFRACTORY TO ANTI-TNFALPHA THERAPY AND IBD-RELATED PROFIBROTIC. DEVELOPING HIGHLY SPECIFIC BRD4 INHIBITORS FOR IBD MEDICATIONS MAY HELP ERASE THE DRAWBACKS OF MOST CURRENT PAN-BET/BRD4 INHIBITORS, SUCH AS OFF-TARGET EFFECTS, POOR ORAL BIOAVAILABILITY, AND LOW GUT MUCOSAL ABSORBANCE. NOVEL STRATEGIES SUCH AS COMBINATORIAL THERAPY, BRD4-BASED DUAL INHIBITORS AND PROTEOLYSIS TARGETING CHIMERAS (PROTACS) MAY ALSO HAVE GREAT POTENTIAL TO MITIGATE SIDE EFFECTS AND OVERCOME DRUG RESISTANCE DURING IBD TREATMENT. 2023 2 923 18 CHRONIC INFECTION DRIVES DNMT3A-LOSS-OF-FUNCTION CLONAL HEMATOPOIESIS VIA IFNGAMMA SIGNALING. AGE-RELATED CLONAL HEMATOPOIESIS (CH) IS A RISK FACTOR FOR MALIGNANCY, CARDIOVASCULAR DISEASE, AND ALL-CAUSE MORTALITY. SOMATIC MUTATIONS IN DNMT3A ARE DRIVERS OF CH, BUT DECADES MAY ELAPSE BETWEEN THE ACQUISITION OF A MUTATION AND CH, SUGGESTING THAT ENVIRONMENTAL FACTORS CONTRIBUTE TO CLONAL EXPANSION. WE TESTED WHETHER INFECTION PROVIDES SELECTIVE PRESSURE FAVORING THE EXPANSION OF DNMT3A MUTANT HEMATOPOIETIC STEM CELLS (HSCS) IN MOUSE CHIMERAS. WE CREATED DNMT3A-MOSAIC MICE BY TRANSPLANTING DNMT3A(-/-) AND WT HSCS INTO WT MICE AND OBSERVED THE SUBSTANTIAL EXPANSION OF DNMT3A(-/-) HSCS DURING CHRONIC MYCOBACTERIAL INFECTION. INJECTION OF RECOMBINANT IFNGAMMA ALONE WAS SUFFICIENT TO PHENOCOPY CH BY DNMT3A(-/-) HSCS UPON INFECTION. TRANSCRIPTIONAL AND EPIGENETIC PROFILING AND FUNCTIONAL STUDIES INDICATE REDUCED DIFFERENTIATION ASSOCIATED WITH WIDESPREAD METHYLATION ALTERATIONS, AND REDUCED SECONDARY STRESS-INDUCED APOPTOSIS ACCOUNTS FOR DNMT3A(-/-) CLONAL EXPANSION DURING INFECTION. DNMT3A MUTANT HUMAN HSCS SIMILARLY EXHIBIT DEFECTIVE IFNGAMMA-INDUCED DIFFERENTIATION. WE THUS DEMONSTRATE THAT IFNGAMMA SIGNALING INDUCED DURING CHRONIC INFECTION CAN DRIVE DNMT3A-LOSS-OF-FUNCTION CH. 2021 3 693 34 BREAKING BOUNDARIES: PAN BETI DISRUPT 3D CHROMATIN STRUCTURE, BD2-SELECTIVE BETI ARE STRICTLY EPIGENETIC TRANSCRIPTIONAL REGULATORS. BACKGROUND: BROMODOMAIN AND EXTRATERMINAL PROTEINS (BETS) ARE MORE THAN JUST EPIGENETIC REGULATORS OF TRANSCRIPTION. HERE WE HIGHLIGHT A NEW ROLE FOR THE BET PROTEIN BRD4 IN THE MAINTENANCE OF HIGHER ORDER CHROMATIN STRUCTURE AT TOPOLOGICALLY ASSOCIATING DOMAIN BOUNDARIES (TADBS). BD2-SELECTIVE AND PAN (NON-SELECTIVE) BET INHIBITORS (BETI) DIFFERENTIALLY SUPPORT CHROMATIN STRUCTURE, SELECTIVELY AFFECTING TRANSCRIPTION AND CELL VIABILITY. METHODS: USING RNA-SEQ AND BRD4 CHIP-SEQ, THE DIFFERENTIAL EFFECT OF BETI TREATMENT ON THE TRANSCRIPTOME AND BRD4 CHROMATIN OCCUPANCY OF HUMAN AORTIC ENDOTHELIAL CELLS FROM DIABETIC PATIENTS (DHAECS) STIMULATED WITH TNFALPHA WAS EVALUATED. CHROMATIN DECONDENSATION AND DNA FRAGMENTATION WAS ASSESSED BY IMMUNOFLUORESCENCE IMAGING AND QUANTIFICATION. KEY DHAEC FINDINGS WERE VERIFIED IN PROLIFERATING MONOCYTE-LIKE THP-1 CELLS USING REAL TIME-PCR, BRD4 CO-IMMUNOPRECIPITATION STUDIES, WESTERN BLOTS, PROLIFERATION AND APOPTOSIS ASSAYS. FINDINGS: WE DISCOVERED THAT 1) BRD4 CO-LOCALIZES WITH YING-YANG 1 (YY1) AT TADBS, CRITICAL CHROMATIN STRUCTURE COMPLEXES PROXIMAL TO MANY DNA REPAIR GENES. 2) BD2-SELECTIVE BETI ENRICH BRD4/YY1 ASSOCIATIONS, WHILE PAN-BETI DO NOT. 3) FAILURE TO SUPPORT CHROMATIN STRUCTURES THROUGH BRD4/YY1 ENRICHMENT INHIBITS DNA REPAIR GENE TRANSCRIPTION, WHICH INDUCES DNA DAMAGE RESPONSES, AND CAUSES WIDESPREAD CHROMATIN DECONDENSATION, DNA FRAGMENTATION, AND APOPTOSIS. 4) BD2-SELECTIVE BETI MAINTAIN HIGH ORDER CHROMATIN STRUCTURE AND CELL VIABILITY, WHILE REDUCING DELETERIOUS PRO-INFLAMMATORY TRANSCRIPTION. INTERPRETATION: BRD4 PLAYS A PREVIOUSLY UNRECOGNIZED ROLE AT TADBS. BETI DIFFERENTIALLY IMPACT TADB STABILITY. OUR RESULTS PROVIDE TRANSLATIONAL INSIGHT FOR THE DEVELOPMENT OF BETI AS THERAPEUTICS FOR A RANGE OF DISEASES INCLUDING CVD, CHRONIC KIDNEY DISEASE, CANCER, AND COVID-19. 2022 4 6687 27 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 5 595 32 BET PROTEINS REGULATE EXPRESSION OF OSR1 IN EARLY KIDNEY DEVELOPMENT. IN UTERO RENAL DEVELOPMENT IS SUBJECT TO MATERNAL METABOLIC AND ENVIRONMENTAL INFLUENCES AFFECTING LONG-TERM RENAL FUNCTION AND THE RISK OF DEVELOPING CHRONIC KIDNEY FAILURE AND CARDIOVASCULAR DISEASE. EPIGENETIC PROCESSES HAVE BEEN IMPLICATED IN THE ORCHESTRATION OF RENAL DEVELOPMENT AND PRENATAL PROGRAMMING OF NEPHRON NUMBER. HOWEVER, THE ROLE OF MANY EPIGENETIC MODIFIERS FOR KIDNEY DEVELOPMENT IS STILL UNCLEAR. BROMODOMAIN AND EXTRA-TERMINAL DOMAIN (BET) PROTEINS ACT AS HISTONE ACETYLATION READER MOLECULES AND PROMOTE GENE TRANSCRIPTION. BET FAMILY MEMBERS BRD2, BRD3 AND BRD4 ARE EXPRESSED IN THE NEPHROGENIC ZONE DURING KIDNEY DEVELOPMENT. HERE, THE EFFECT OF THE BET INHIBITOR JQ1 ON RENAL DEVELOPMENT IS EVALUATED. INHIBITION OF BET PROTEINS VIA JQ1 LEADS TO REDUCED GROWTH OF METANEPHRIC KIDNEY CULTURES, LOSS OF THE NEPHRON PROGENITOR CELL POPULATION, AND PREMATURE AND DISTURBED NEPHRON DIFFERENTIATION. GENE EXPRESSION OF KEY NEPHRON PROGENITOR TRANSCRIPTION FACTOR OSR1 IS DOWNREGULATED AFTER 24 H BET INHIBITION, WHILE LHX1 AND PAX8 EXPRESSION IS INCREASED. MINING OF BRD4 CHIP-SEQ AND GENE EXPRESSION DATA IDENTIFY OSR1 AS A KEY FACTOR REGULATED BY BRD4-CONTROLLED GENE ACTIVATION. INHIBITION OF BRD4 BY BET INHIBITOR JQ1 LEADS TO DOWNREGULATION OF OSR1, THEREBY CAUSING A DISTURBANCE IN THE BALANCE OF NEPHRON PROGENITOR CELL SELF-RENEWAL AND PREMATURE DIFFERENTIATION OF THE NEPHRON, WHICH ULTIMATELY LEADS TO KIDNEY HYPOPLASIA AND DISTURBED NEPHRON DEVELOPMENT. THIS RAISES QUESTIONS ABOUT THE POTENTIAL TERATOGENIC EFFECTS OF BET INHIBITORS FOR EMBRYONIC DEVELOPMENT. IN SUMMARY, OUR WORK HIGHLIGHTS THE ROLE OF BET PROTEINS FOR PRENATAL PROGRAMMING OF NEPHROGENESIS AND IDENTIFIES OSR1 AS A POTENTIAL TARGET OF BET PROTEINS. 2021 6 592 31 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 7 697 40 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 8 5054 36 PHARMACOPROTEOMICS REVEAL NOVEL PROTECTIVE ACTIVITY OF BROMODOMAIN CONTAINING 4 INHIBITORS ON VASCULAR HOMEOSTASIS IN TLR3-MEDIATED AIRWAY REMODELING. SMALL MOLECULE INHIBITORS OF THE EPIGENETIC REGULATOR BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) ARE POTENTIAL THERAPEUTICS FOR VIRAL AND ALLERGEN-INDUCED AIRWAY REMODELING. A LIMITATION OF THEIR PRECLINICAL ADVANCEMENT IS THE LACK OF DETAILED UNDERSTANDING OF MECHANISMS OF ACTION AND BIOMARKERS OF EFFECT. WE REPORT A SYSTEMS-LEVEL PHARMACOPROTEOMICS IN A STANDARDIZED MURINE MODEL OF TOLL-LIKE RECEPTOR TLR3-NFKAPPAB/RELA INNATE INFLAMMATION IN THE ABSENCE OR PRESENCE OF A HIGHLY SELECTIVE BRD4 INHIBITOR (ZL0454) OR NONSELECTIVE BROMODOMAIN AND EXTRATERMINAL DOMAIN INHIBITOR (JQ1). PROTEOMICS OF BRONCHOALVEOLAR LAVAGE FLUID (BALF) SECRETOME AND EXOSOMAL PROTEINS FROM THIS MURINE MODEL REVEALED INCREASED, SELECTIVE, CAPILLARY LEAK ASSOCIATED WITH PERICYTE-MYOFIBROBLAST TRANSITION, A PHENOMENON BLOCKED BY BRD4 INHIBITORS. BALF PROTEOMICS ALSO SUGGESTED THAT ZL0454 BETTER REDUCED THE VASCULAR LEAKAGE AND EXTRACELLULAR MATRIX DEPOSITION THAN JQ1. A SIGNIFICANT SUBSET OF INFLAMMATION-MEDIATED REMODELING FACTORS WAS ALSO IDENTIFIED IN A MOUSE MODEL OF IDIOPATHIC PULMONARY FIBROSIS PRODUCED BY BLEOMYCIN. BALF EXOSOME ANALYSIS INDICATED THAT BRD4 INHIBITORS REDUCED THE INDUCTION OF EXOSOMES ENRICHED IN COAGULATION FACTORS WHOSE PRESENCE CORRELATED WITH INTERSTITIAL FIBRIN DEPOSITION. FINALLY, BALF SAMPLES FROM HUMANS WITH SEVERE ASTHMA DEMONSTRATED SIMILAR UPREGULATIONS OF ORM2, APCS, SPARCL1, FGA, AND FN1, SUGGESTING THEIR POTENTIAL AS BIOMARKERS FOR EARLY DETECTION OF AIRWAY REMODELING AND/OR MONITORING OF THERAPY RESPONSE. SIGNIFICANCE: REPETITIVE AND CHRONIC VIRAL UPPER RESPIRATORY TRACT INFECTIONS TRIGGER TOLL-LIKE RECEPTOR (TLR)3-NFKAPPAB/RELA MEDIATED AIRWAY REMODELING WHICH IS LINKED TO A PROGRESSIVE DECLINE IN PULMONARY FUNCTION IN PATIENTS WITH ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. SMALL MOLECULE INHIBITORS OF THE EPIGENETIC REGULATOR BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) ARE POTENTIAL THERAPEUTICS FOR VIRAL AND ALLERGEN-INDUCED AIRWAY REMODELING. A LIMITATION OF THEIR PRECLINICAL ADVANCEMENT IS THE LACK OF DETAILED UNDERSTANDING OF MECHANISMS OF ACTION AND BIOMARKERS OF EFFECT. OUR STUDY REVEALED THAT THE ACTIVATION OF (TLR)3-NFKAPPAB/RELA PATHWAY IN THE LUNG INDUCED AN ELEVATION IN COAGULATION, COMPLEMENT, AND PLATELET FACTORS, INDICATING THE INCREASED VASCULAR LEAK DURING AIRWAY REMODELING. THE MECHANISM OF VASCULAR LEAKAGE WAS CHRONIC INFLAMMATION-INDUCED PERICYTE-MYOFIBROBLAST TRANSITION, WHICH WAS BLOCKED BY BRD4 INHIBITORS. FINALLY, PROTEOMICS ANALYSIS OF THE BRONCHOALVEOLAR LAVAGE FLUID SAMPLES FROM HUMANS WITH SEVERE ASTHMA DEMONSTRATED SIMILAR FINDINGS THAT WE OBSERVED IN THE ANIMAL MODEL. 2019 9 689 41 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 10 5045 28 PHARMACOLOGIC EPIGENETIC MODULATORS OF ALKALINE PHOSPHATASE IN CHRONIC KIDNEY DISEASE. PURPOSE OF REVIEW: IN CHRONIC KIDNEY DISEASE (CKD), DISTURBANCE OF SEVERAL METABOLIC REGULATORY MECHANISMS CAUSE PREMATURE AGEING, ACCELERATED CARDIOVASCULAR DISEASE (CVD), AND MORTALITY. SINGLE-TARGET INTERVENTIONS HAVE REPEATEDLY FAILED TO IMPROVE THE PROGNOSIS FOR CKD PATIENTS. EPIGENETIC INTERVENTIONS HAVE THE POTENTIAL TO MODULATE SEVERAL PATHOGENETIC PROCESSES SIMULTANEOUSLY. ALKALINE PHOSPHATASE (ALP) IS A ROBUST PREDICTOR OF CVD AND ALL-CAUSE MORTALITY AND IMPLICATED IN PATHOGENIC PROCESSES ASSOCIATED WITH CVD IN CKD. RECENT FINDINGS: IN EXPERIMENTAL STUDIES, EPIGENETIC MODULATION OF ALP BY MICRORNAS OR BROMODOMAIN AND EXTRATERMINAL (BET) PROTEIN INHIBITION HAS SHOWN PROMISING RESULTS FOR THE TREATMENT OF CVD AND OTHER CHRONIC METABOLIC DISEASES. THE BET INHIBITOR APABETALONE IS CURRENTLY BEING EVALUATED FOR CARDIOVASCULAR RISK REDUCTION IN A PHASE III CLINICAL STUDY IN HIGH-RISK CVD PATIENTS, INCLUDING PATIENTS WITH CKD (CLINICALTRIALS.GOV IDENTIFIER: NCT02586155). PHASE II STUDIES DEMONSTRATE AN ALP-LOWERING POTENTIAL OF APABETALONE, WHICH WAS ASSOCIATED WITH IMPROVED CARDIOVASCULAR AND RENAL OUTCOMES. SUMMARY: ALP IS A PREDICTOR OF CVD AND MORTALITY IN CKD. EPIGENETIC MODULATION OF ALP HAS THE POTENTIAL TO AFFECT SEVERAL PATHOGENETIC PROCESSES IN CKD AND THEREBY IMPROVE CARDIOVASCULAR OUTCOME. 2020 11 4582 30 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 12 6450 32 THERAPEUTIC TARGETS FOR INFLAMMATION-MEDIATED AIRWAY REMODELING IN CHRONIC LUNG DISEASE. ACUTE EXACERBATIONS OF CHRONIC LUNG DISEASE ACCOUNT FOR SUBSTANTIAL MORBIDITY AND HEALTH COSTS. REPEATED INFLAMMATORY EPISODES AND ATTENDANT BRONCHOCONSTRICTION CAUSE STRUCTURAL REMODELING OF THE AIRWAY. REMODELING IS A MULTICELLULAR RESPONSE TO MUCOSAL INJURY THAT RESULTS IN EPITHELIAL CELL-STATE CHANGES, ENHANCED EXTRACELLULAR DEPOSITION, AND EXPANSION OF PRO-FIBROTIC MYOFIBROBLAST POPULATIONS. AREAS COVERED: THIS MANUSCRIPT OVERVIEWS MECHANISTIC STUDIES IDENTIFYING KEY SENTINEL CELL POPULATIONS IN THE AIRWAY AND HOW PATTERN RECOGNITION SIGNALING INDUCES MALADAPTIVE MUCOSAL CHANGES AND AIRWAY REMODELING. STUDIES ELUCIDATING HOW NFKAPPAB COUPLES WITH AN ATYPICAL HISTONE ACETYLTRANSFERASE, BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) THAT REPROGRAMS MUCOSAL FIBROGENIC RESPONSES, ARE DESCRIBED. THE APPROACHES TO DEVELOPMENT AND CHARACTERIZATION OF SELECTIVE INHIBITORS OF EPIGENETIC REPROGRAMMING ON INNATE INFLAMMATION AND STRUCTURAL REMODELING IN PRECLINICAL MODELS ARE DETAILED. EXPERT COMMENTARY: BRONCHIOLAR CELLS DERIVED FROM SCGB1A1-EXPRESSING PROGENITORS FUNCTION AS MAJOR SENTINEL CELLS OF THE AIRWAY, RESPONSIBLE FOR INITIATING ANTIVIRAL AND AEROALLERGEN RESPONSES. IN THESE SENTINEL CELLS, ACTIVATION OF INNATE INFLAMMATION IS COUPLED TO NEUTROPHILIC RECRUITMENT, MESENCHYMAL TRANSITION AND MYOFIBROBLAST EXPANSION. THERAPEUTICS TARGETING THE NFKB-BRD4 MAY BE EFFICACIOUS IN REDUCING PATHOLOGICAL EFFECTS OF ACUTE EXACERBATIONS IN CHRONIC LUNG DISEASE. 2018 13 1650 32 DOMAIN-SELECTIVE TARGETING OF BET PROTEINS IN CANCER AND IMMUNOLOGICAL DISEASES. CANCER AND INFLAMMATION ARE STRONGLY INTERCONNECTED PROCESSES. CHRONIC INFLAMMATORY PATHOLOGIES CAN BE AT THE HEART OF TUMOR DEVELOPMENT; SIMILARLY, TUMOR-ELICITED INFLAMMATION IS A CONSEQUENCE OF MANY CANCERS. THE MECHANISTIC INTERDEPENDENCE BETWEEN CANCER AND INFLAMMATORY PATHOLOGIES POINTS TOWARD COMMON PROTEIN EFFECTORS WHICH REPRESENT POTENTIAL SHARED TARGETS FOR PHARMACOLOGICAL INTERVENTION. EPIGENETIC MECHANISMS OFTEN DRIVE RESISTANCE TO CANCER THERAPY AND IMMUNOMODULATORY STRATEGIES. THE BROMODOMAIN AND EXTRATERMINAL DOMAIN (BET) PROTEINS ARE EPIGENETIC ADAPTERS WHICH PLAY A MAJOR ROLE IN CONTROLLING CELL PROLIFERATION AND THE PRODUCTION OF INFLAMMATORY MEDIATORS. A PLETHORA OF SMALL MOLECULES AIMED AT INHIBITING BET PROTEIN FUNCTION TO TREAT CANCER AND INFLAMMATORY DISEASES HAVE POPULATED ACADEMIC AND INDUSTRY EFFORTS IN THE LAST 10 YEARS. IN THIS REVIEW, WE WILL DISCUSS RECENT PHARMACOLOGICAL APPROACHES AIMED AT TARGETING A SINGLE OR A SUBSET OF THE EIGHT BROMODOMAINS WITHIN THE BET FAMILY WHICH HAVE THE POTENTIAL TO TEASE APART CLINICAL EFFICACY AND SAFETY SIGNALS OF BET INHIBITORS. 2020 14 699 28 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 15 591 32 BET BROMODOMAIN PROTEINS AND EPIGENETIC REGULATION OF INFLAMMATION: IMPLICATIONS FOR TYPE 2 DIABETES AND BREAST CANCER. CHRONIC INFLAMMATION DRIVES PATHOLOGIES ASSOCIATED WITH TYPE 2 DIABETES (T2D) AND BREAST CANCER. OBESITY-DRIVEN INFLAMMATION MAY EXPLAIN INCREASED RISK AND MORTALITY OF BREAST CANCER WITH T2D REPORTED IN THE EPIDEMIOLOGY LITERATURE. THERAPEUTIC APPROACHES TO TARGET INFLAMMATION IN BOTH T2D AND CANCER HAVE SO FAR FALLEN SHORT OF THE EXPECTED IMPROVEMENTS IN DISEASE PATHOGENESIS OR OUTCOMES. THE TARGETING OF EPIGENETIC REGULATORS OF CYTOKINE TRANSCRIPTION AND CYTOKINE SIGNALING OFFERS ONE PROMISING, UNTAPPED APPROACH TO TREATING DISEASES DRIVEN BY INFLAMMATION. RECENT WORK HAS DEEPLY IMPLICATED THE BROMODOMAIN AND EXTRA-TERMINAL DOMAIN (BET) PROTEINS, WHICH ARE ACETYLATED HISTONE "READERS", IN EPIGENETIC REGULATION OF INFLAMMATION. THIS REVIEW FOCUSES ON INFLAMMATION ASSOCIATED WITH T2D AND BREAST CANCER, AND THE POSSIBILITY OF TARGETING BET PROTEINS AS AN APPROACH TO REGULATING INFLAMMATION IN THE CLINIC. UNDERSTANDING INFLAMMATION IN THE CONTEXT OF BET PROTEIN REGULATION MAY PROVIDE A BASIS FOR DESIGNING PROMISING THERAPEUTICS FOR T2D AND BREAST CANCER. 2017 16 2245 34 EPIGENETIC MODULATION OF GREMLIN-1/NOTCH PATHWAY IN EXPERIMENTAL CRESCENTIC IMMUNE-MEDIATED GLOMERULONEPHRITIS. CRESCENTIC GLOMERULONEPHRITIS IS A DEVASTATING AUTOIMMUNE DISEASE THAT WITHOUT EARLY AND PROPERLY TREATMENT MAY RAPIDLY PROGRESS TO END-STAGE RENAL DISEASE AND DEATH. CURRENT IMMUNOSUPPRESSIVE TREATMENT PROVIDES LIMITED EFFICACY AND AN IMPORTANT BURDEN OF ADVERSE EVENTS. EPIGENETIC DRUGS ARE A SOURCE OF NOVEL THERAPEUTIC TOOLS. AMONG THEM, BROMODOMAIN AND EXTRATERMINAL DOMAIN (BET) INHIBITORS (IBETS) BLOCK THE INTERACTION BETWEEN BROMODOMAINS AND ACETYLATED PROTEINS, INCLUDING HISTONES AND TRANSCRIPTION FACTORS. IBETS HAVE DEMONSTRATED PROTECTIVE EFFECTS ON MALIGNANCY, INFLAMMATORY DISORDERS AND EXPERIMENTAL KIDNEY DISEASE. RECENTLY, GREMLIN-1 WAS PROPOSED AS A URINARY BIOMARKER OF DISEASE PROGRESSION IN HUMAN ANTI-NEUTROPHIL CYTOPLASMIC ANTIBODY (ANCA)-ASSOCIATED CRESCENTIC GLOMERULONEPHRITIS. WE HAVE NOW EVALUATED WHETHER IBETS COULD REGULATE GREMLIN-1 IN EXPERIMENTAL ANTI-GLOMERULAR BASEMENT MEMBRANE NEPHRITIS INDUCED BY NEPHROTOXIC SERUM (NTS) IN MICE, A MODEL RESEMBLING HUMAN CRESCENTIC GLOMERULONEPHRITIS. IN NTS-INJECTED MICE, THE IBET JQ1 INHIBITED RENAL GREMLIN-1 OVEREXPRESSION AND DIMINISHED GLOMERULAR DAMAGE, RESTORING PODOCYTE NUMBERS. CHROMATIN IMMUNOPRECIPITATION ASSAY DEMONSTRATED BRD4 ENRICHMENT OF THE GREM-1 GENE PROMOTER IN INJURED KIDNEYS, CONSISTENT WITH GREMLIN-1 EPIGENETIC REGULATION. MOREOVER, JQ1 BLOCKED BRD4 BINDING AND INHIBITED GREM-1 GENE TRANSCRIPTION. THE BENEFICIAL EFFECT OF IBETS WAS ALSO MEDIATED BY MODULATION OF NOTCH PATHWAY. JQ1 INHIBITED THE GENE EXPRESSION OF THE NOTCH EFFECTORS HES-1 AND HEY-1 IN NTS-INJURED KIDNEYS. OUR RESULTS FURTHER SUPPORT THE ROLE FOR EPIGENETIC DRUGS, SUCH AS IBETS, IN THE TREATMENT OF RAPIDLY PROGRESSIVE CRESCENTIC GLOMERULONEPHRITIS. 2022 17 1455 33 DISCOVERY OF THIENO[2,3-D]PYRIMIDINE-BASED HYDROXAMIC ACID DERIVATIVES AS BROMODOMAIN-CONTAINING PROTEIN 4/HISTONE DEACETYLASE DUAL INHIBITORS INDUCE AUTOPHAGIC CELL DEATH IN COLORECTAL CARCINOMA CELLS. BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) AND HISTONE DEACETYLASES (HDAC) ARE BOTH ATTRACTIVE EPIGENETIC TARGETS IN CANCER AND OTHER CHRONIC DISEASES. BASED ON THE INTEGRATED FRAGMENT-BASED DRUG DESIGN, SYNTHESIS, AND IN VITRO AND IN VIVO EVALUATIONS, A SERIES OF NOVEL THIENO[2,3-D]PYRIMIDINE-BASED HYDROXAMIC ACID DERIVATIVES ARE DISCOVERED AS SELECTIVE BRD4-HDAC DUAL INHIBITORS. COMPOUND 17C IS THE MOST POTENT INHIBITOR FOR BRD4 AND HDAC WITH IC(50) VALUES AT NANOMOLAR LEVELS, AS WELL AS THE EXPRESSION LEVEL OF C-MYC, AND INCREASES THE ACETYLATION OF HISTONE H3. MOREOVER, 17C PRESENTS INHIBITORY EFFECTS ON THE PROLIFERATION OF COLORECTAL CARCINOMA (CRC) CELLS VIA INDUCING AUTOPHAGIC CELL DEATH. IT ALSO HAS A GOOD PHARMACOKINETIC PROFILE IN RATS AND ORAL BIOAVAILABILITY OF 40.5%. IN THE HCT-116 XENOGRAFT IN VIVO MODELS, 17C DISPLAYS POTENT INHIBITORY EFFICIENCY ON TUMOR GROWTH BY INDUCING AUTOPHAGIC CELL DEATH AND SUPPRESSING IL6-JAK-STAT SIGNALING PATHWAYS. OUR RESULTS SUGGEST THAT THE BRD4-HDAC DUAL INHIBITION MIGHT BE AN ATTRACTIVE THERAPEUTIC STRATEGY FOR CRC. 2020 18 596 35 BET PROTEINS: AN APPROACH TO FUTURE THERAPIES IN TRANSPLANTATION. IN ORDER TO DEVELOP NEW EFFICIENT THERAPIES FOR ORGAN TRANSPLANTATION, IT IS ESSENTIAL TO ACQUIRE A COMPREHENSIVE KNOWLEDGE OF THE MOLECULAR MECHANISMS AND PROCESSES, SUCH AS IMMUNE ACTIVATION, CHRONIC INFLAMMATION, AND FIBROSIS, WHICH LEAD TO REJECTION AND LONG-TERM GRAFT LOSS. RECENT EFFORTS HAVE SHED SOME LIGHT ON THE EPIGENETIC REGULATION ASSOCIATED WITH THESE PROCESSES. IN THIS CONTEXT, THE BROMO AND EXTRATERMINAL (BET) FAMILY OF BROMODOMAIN PROTEINS (BRD2, BRD3, BRD4, AND BRDT) HAVE EMERGED AS MAJOR EPIGENETIC PLAYERS, CONNECTING CHROMATIN STRUCTURE WITH GENE EXPRESSION CHANGES. THESE PROTEINS RECOGNIZE ACETYLATED LYSINES IN HISTONES AND MASTER TRANSCRIPTION FACTORS TO RECRUIT REGULATORY COMPLEX AND, FINALLY, MODIFY THE TRANSCRIPTIONAL PROGRAM. RECENT STUDIES INDICATE THAT BET PROTEINS ARE ESSENTIAL IN THE NF-KB-MEDIATED INFLAMMATORY RESPONSE, DURING THE ACTIVATION AND DIFFERENTIATION OF TH17-IMMUNE CELLS, AND IN PROFIBROTIC PROCESSES. HERE, WE REVIEW THIS NEW BODY OF DATA AND HIGHLIGHT THE EFFICIENCY OF BET INHIBITORS IN SEVERAL MODELS OF DISEASES. THE PROMISING RESULTS OBTAINED FROM THESE PRECLINICAL MODELS INDICATE THAT IT MAY BE TIME TO TRANSLATE THESE OUTCOMES TO THE TRANSPLANTATION FIELD, WHERE EPIGENETICS WILL BE OF INCREASING VALUE IN THE COMING YEARS. 2017 19 2397 28 EPIGENETIC REPROGRAMMING OF AIRWAY MACROPHAGES PROMOTES POLARIZATION AND INFLAMMATION IN MUCO-OBSTRUCTIVE LUNG DISEASE. LUNG DISEASES, SUCH AS CYSTIC FIBROSIS AND COPD, ARE CHARACTERIZED BY MUCUS OBSTRUCTION AND CHRONIC AIRWAY INFLAMMATION, BUT THEIR MECHANISTIC LINK REMAINS POORLY UNDERSTOOD. HERE, WE FOCUS ON THE FUNCTION OF THE MUCOSTATIC AIRWAY MICROENVIRONMENT ON EPIGENETIC REPROGRAMMING OF AIRWAY MACROPHAGES (AM) AND RESULTING TRANSCRIPTOMIC AND PHENOTYPICAL CHANGES. USING A MOUSE MODEL OF MUCO-OBSTRUCTIVE LUNG DISEASE (SCNN1B-TRANSGENIC), WE IDENTIFY EPIGENETICALLY CONTROLLED, DIFFERENTIALLY REGULATED PATHWAYS AND TRANSCRIPTION FACTORS INVOLVED IN INFLAMMATORY RESPONSES AND MACROPHAGE POLARIZATION. FUNCTIONALLY, AMS FROM SCNN1B-TRANSGENIC MICE HAVE REDUCED EFFEROCYTOSIS AND PHAGOCYTOSIS, AND EXCESSIVE INFLAMMATORY RESPONSES UPON LIPOPOLYSACCHARIDE CHALLENGE, MEDIATED THROUGH ENHANCED IRF1 FUNCTION AND EXPRESSION. EX VIVO STIMULATION OF WILD-TYPE AMS WITH NATIVE MUCUS IMPAIRS EFFEROCYTOSIS AND PHAGOCYTOSIS CAPACITIES. IN ADDITION, MUCUS INDUCES GENE EXPRESSION CHANGES, COMPARABLE WITH THOSE OBSERVED IN AMS FROM SCNN1B-TRANSGENIC MICE. OUR DATA SHOW THAT MUCOSTASIS INDUCES EPIGENETIC REPROGRAMMING OF AMS, LEADING TO CHANGES FAVORING TISSUE DAMAGE AND DISEASE PROGRESSION. TARGETING THESE ALTERED AMS MAY SUPPORT THERAPEUTIC APPROACHES IN PATIENTS WITH MUCO-OBSTRUCTIVE LUNG DISEASES. 2021 20 4703 23 NIK AS A DRUGGABLE MEDIATOR OF TISSUE INJURY. NF-KAPPAB-INDUCING KINASE (NIK, MAP3K14) IS BEST KNOWN AS THE APICAL KINASE THAT TRIGGERS NON-CANONICAL NF-KAPPAB ACTIVATION AND BY ITS ROLE IN THE IMMUNE SYSTEM. RECENT DATA INDICATE A ROLE FOR NIK EXPRESSED BY NON-LYMPHOID CELLS IN CANCER, KIDNEY DISEASE, LIVER INJURY, GLUCOSE HOMEOSTASIS, OSTEOSARCOPENIA, VASCULAR CALCIFICATION, HEMATOPOIESIS, AND ENDOTHELIAL FUNCTION. THE SPECTRUM OF NIK-ASSOCIATED DISEASE NOW RANGES FROM IMMUNODEFICIENCY (WHEN NIK IS DEFECTIVE) TO AUTOIMMUNITY, CANCER, STERILE INFLAMMATION, FIBROSIS, AND METABOLIC DISEASE WHEN NIK IS OVERACTIVE. THE DEVELOPMENT OF NOVEL SMALL-MOLECULE NIK INHIBITORS HAS PAVED THE WAY TO TEST NIK TARGETING TO TREAT DISEASE IN VIVO, AND MAY EVENTUALLY LEAD TO NIK TARGETING IN THE CLINIC. IN ADDITION, NIK ACTIVATORS ARE BEING EXPLORED FOR SPECIFIC CONDITIONS SUCH AS MYELOID LEUKEMIA. 2019