1 6537 110 TRANSCRIPTIONAL REGULATOR PRDM12 IS ESSENTIAL FOR HUMAN PAIN PERCEPTION. PAIN PERCEPTION HAS EVOLVED AS A WARNING MECHANISM TO ALERT ORGANISMS TO TISSUE DAMAGE AND DANGEROUS ENVIRONMENTS. IN HUMANS, HOWEVER, UNDESIRABLE, EXCESSIVE OR CHRONIC PAIN IS A COMMON AND MAJOR SOCIETAL BURDEN FOR WHICH AVAILABLE MEDICAL TREATMENTS ARE CURRENTLY SUBOPTIMAL. NEW THERAPEUTIC OPTIONS HAVE RECENTLY BEEN DERIVED FROM STUDIES OF INDIVIDUALS WITH CONGENITAL INSENSITIVITY TO PAIN (CIP). HERE WE IDENTIFIED 10 DIFFERENT HOMOZYGOUS MUTATIONS IN PRDM12 (ENCODING PRDI-BF1 AND RIZ HOMOLOGY DOMAIN-CONTAINING PROTEIN 12) IN SUBJECTS WITH CIP FROM 11 FAMILIES. PRDM PROTEINS ARE A FAMILY OF EPIGENETIC REGULATORS THAT CONTROL NEURAL SPECIFICATION AND NEUROGENESIS. WE DETERMINED THAT PRDM12 IS EXPRESSED IN NOCICEPTORS AND THEIR PROGENITORS AND PARTICIPATES IN THE DEVELOPMENT OF SENSORY NEURONS IN XENOPUS EMBRYOS. MOREOVER, CIP-ASSOCIATED MUTANTS ABROGATE THE HISTONE-MODIFYING POTENTIAL ASSOCIATED WITH WILD-TYPE PRDM12. PRDM12 EMERGES AS A KEY FACTOR IN THE ORCHESTRATION OF SENSORY NEUROGENESIS AND MAY HOLD PROMISE AS A TARGET FOR NEW PAIN THERAPEUTICS. 2015 2 5939 36 TARGETING MECHANOTRANSDUCTION AT THE TRANSCRIPTIONAL LEVEL: YAP AND BRD4 ARE NOVEL THERAPEUTIC TARGETS FOR THE REVERSAL OF LIVER FIBROSIS. LIVER FIBROSIS IS THE RESULT OF A DEREGULATED WOUND HEALING PROCESS CHARACTERIZED BY THE EXCESSIVE DEPOSITION OF EXTRACELLULAR MATRIX. HEPATIC STELLATE CELLS (HSCS), WHICH ARE ACTIVATED IN RESPONSE TO LIVER INJURY, ARE THE MAJOR SOURCE OF EXTRACELLULAR MATRIX AND DRIVE THE WOUND HEALING PROCESS. HOWEVER, CHRONIC LIVER DAMAGE LEADS TO PERPETUAL HSC ACTIVATION, PROGRESSIVE FORMATION OF PATHOLOGICAL SCAR TISSUE AND ULTIMATELY, CIRRHOSIS AND ORGAN FAILURE. HSC ACTIVATION IS TRIGGERED LARGELY IN RESPONSE TO MECHANOSIGNALING FROM THE MICROENVIRONMENT, WHICH INDUCES A PROFIBROTIC NUCLEAR TRANSCRIPTION PROGRAM THAT PROMOTES HSC PROLIFERATION AND EXTRACELLULAR MATRIX SECRETION THEREBY SETTING UP A POSITIVE FEEDBACK LOOP LEADING TO MATRIX STIFFENING AND SELF-SUSTAINED, PATHOLOGICAL, HSC ACTIVATION. DESPITE THE SIGNIFICANT PROGRESS IN OUR UNDERSTANDING OF LIVER FIBROSIS, THE MOLECULAR MECHANISMS THROUGH WHICH THE EXTRACELLULAR MATRIX PROMOTES HSC ACTIVATION ARE NOT WELL UNDERSTOOD AND NO EFFECTIVE THERAPIES HAVE BEEN APPROVED TO DATE THAT CAN TARGET THIS EARLY, REVERSIBLE, STAGE IN LIVER FIBROSIS. SEVERAL NEW LINES OF INVESTIGATION NOW PROVIDE IMPORTANT INSIGHT INTO THIS AREA OF STUDY AND IDENTIFY TWO NUCLEAR TARGETS WHOSE INHIBITION HAS THE POTENTIAL OF REVERSING LIVER FIBROSIS BY INTERFERING WITH HSC ACTIVATION: YES-ASSOCIATED PROTEIN (YAP), A TRANSCRIPTIONAL CO-ACTIVATOR AND EFFECTOR OF THE MECHANOSENSITIVE HIPPO PATHWAY, AND BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4), AN EPIGENETIC REGULATOR OF GENE EXPRESSION. YAP AND BRD4 ACTIVITY IS INDUCED IN RESPONSE TO MECHANICAL STIMULATION OF HSCS AND EACH PROTEIN INDEPENDENTLY CONTROLS WAVES OF EARLY GENE EXPRESSION NECESSARY FOR HSC ACTIVATION. SIGNIFICANTLY, INHIBITION OF EITHER PROTEIN CAN REVERT THE CHRONIC ACTIVATION OF HSCS AND IMPEDE PATHOLOGICAL PROGRESSION OF LIVER FIBROSIS IN CLINICALLY RELEVANT MODEL SYSTEMS. IN THIS REVIEW WE WILL DISCUSS THE ROLES OF THESE NUCLEAR CO-ACTIVATORS IN HSC ACTIVATION, THEIR MECHANISM OF ACTION IN THE FIBROTIC PROCESS IN THE LIVER AND OTHER ORGANS, AND THE POTENTIAL OF TARGETING THEIR ACTIVITY WITH SMALL MOLECULE DRUGS FOR FIBROSIS REVERSAL. 2016 3 5155 31 PRDM12 MODULATES PAIN-RELATED BEHAVIOR BY REMODELING GENE EXPRESSION IN MATURE NOCICEPTORS. PRDM12 IS A CONSERVED EPIGENETIC TRANSCRIPTIONAL REGULATOR THAT DISPLAYS RESTRICTED EXPRESSION IN NOCICEPTORS OF THE DEVELOPING PERIPHERAL NERVOUS SYSTEM. IN MICE, PRDM12 IS REQUIRED FOR THE DEVELOPMENT OF THE ENTIRE NOCICEPTIVE LINEAGE. IN HUMANS, PRDM12 MUTATIONS CAUSE CONGENITAL INSENSITIVITY TO PAIN, LIKELY BECAUSE OF THE LOSS OF NOCICEPTORS. PRDM12 EXPRESSION IS MAINTAINED IN MATURE NOCICEPTORS SUGGESTING A YET-TO-BE EXPLORED FUNCTIONAL ROLE IN ADULTS. USING PRDM12 INDUCIBLE CONDITIONAL KNOCKOUT MOUSE MODELS, WE REPORT THAT IN ADULT NOCICEPTORS PRDM12 IS NO LONGER REQUIRED FOR CELL SURVIVAL BUT CONTINUES TO PLAY A ROLE IN THE TRANSCRIPTIONAL CONTROL OF A NETWORK OF GENES, MANY OF THEM ENCODING ION CHANNELS AND RECEPTORS. WE FOUND THAT DISRUPTION OF PRDM12 ALTERS THE EXCITABILITY OF DORSAL ROOT GANGLION NEURONS IN CULTURE. PHENOTYPICALLY, WE OBSERVED THAT MICE LACKING PRDM12 EXHIBIT NORMAL RESPONSES TO THERMAL AND MECHANICAL NOCICEPTIVE STIMULI BUT A REDUCED RESPONSE TO CAPSAICIN AND HYPERSENSITIVITY TO FORMALIN-INDUCED INFLAMMATORY PAIN. TOGETHER, OUR DATA INDICATE THAT PRDM12 REGULATES PAIN-RELATED BEHAVIOR IN A COMPLEX WAY BY MODULATING GENE EXPRESSION IN ADULT NOCICEPTORS AND CONTROLLING THEIR EXCITABILITY. THE RESULTS ENCOURAGE FURTHER STUDIES TO ASSESS THE POTENTIAL OF PRDM12 AS A TARGET FOR ANALGESIC DEVELOPMENT. 2022 4 4732 31 NOVEL BIOMARKERS FOR INFLAMMATORY BOWEL DISEASE AND COLORECTAL CANCER: AN INTERPLAY BETWEEN METABOLIC DYSREGULATION AND EXCESSIVE INFLAMMATION. PERSISTENT INFLAMMATION CAN TRIGGER ALTERED EPIGENETIC, INFLAMMATORY, AND BIOENERGETIC STATES. INFLAMMATORY BOWEL DISEASE (IBD) IS AN IDIOPATHIC DISEASE CHARACTERIZED BY CHRONIC INFLAMMATION OF THE GASTROINTESTINAL TRACT, WITH EVIDENCE OF SUBSEQUENT METABOLIC SYNDROME DISORDER. STUDIES HAVE DEMONSTRATED THAT AS MANY AS 42% OF PATIENTS WITH ULCERATIVE COLITIS (UC) WHO ARE FOUND TO HAVE HIGH-GRADE DYSPLASIA, EITHER ALREADY HAD COLORECTAL CANCER (CRC) OR DEVELOP IT WITHIN A SHORT TIME. THE PRESENCE OF LOW-GRADE DYSPLASIA IS ALSO PREDICTIVE OF CRC. MANY SIGNALING PATHWAYS ARE SHARED AMONG IBD AND CRC, INCLUDING CELL SURVIVAL, CELL PROLIFERATION, ANGIOGENESIS, AND INFLAMMATORY SIGNALING PATHWAYS. CURRENT IBD THERAPEUTICS TARGET A SMALL SUBSET OF MOLECULAR DRIVERS OF IBD, WITH MANY FOCUSED ON THE INFLAMMATORY ASPECT OF THE PATHWAYS. THUS, THERE IS A GREAT NEED TO IDENTIFY BIOMARKERS OF BOTH IBD AND CRC, THAT CAN BE PREDICTIVE OF THERAPEUTIC EFFICACY, DISEASE SEVERITY, AND PREDISPOSITION TO CRC. IN THIS STUDY, WE EXPLORED THE CHANGES IN BIOMARKERS SPECIFIC FOR INFLAMMATORY, METABOLIC, AND PROLIFERATIVE PATHWAYS, TO HELP DETERMINE THE RELEVANCE TO BOTH IBD AND CRC. OUR ANALYSIS DEMONSTRATED, FOR THE FIRST TIME IN IBD, THE LOSS OF THE TUMOR SUPPRESSOR PROTEIN RAS ASSOCIATED FAMILY PROTEIN 1A (RASSF1A), VIA EPIGENETIC CHANGES, THE HYPERACTIVATION OF THE OBLIGATE KINASE OF THE NOD2 PATHOGEN RECOGNITION RECEPTOR (RECEPTOR INTERACTING PROTEIN KINASE 2 [RIPK2]), THE LOSS OF ACTIVATION OF THE METABOLIC KINASE, AMP ACTIVATED PROTEIN KINASE (AMPKALPHA1), AND, LASTLY, THE ACTIVATION OF THE TRANSCRIPTION FACTOR AND KINASE YES ASSOCIATED PROTEIN (YAP) KINASE, THAT IS INVOLVED IN PROLIFERATION OF CELLS. THE EXPRESSION AND ACTIVATION STATUS OF THESE FOUR ELEMENTS ARE MIRRORED IN IBD, CRC, AND IBD-CRC PATIENTS AND, IMPORTANTLY, IN MATCHED BLOOD AND BIOPSY SAMPLES. THE LATTER WOULD SUGGEST THAT BIOMARKER ANALYSIS CAN BE PERFORMED NON-INVASIVELY, TO UNDERSTAND IBD AND CRC, WITHOUT THE NEED FOR INVASIVE AND COSTLY ENDOSCOPIC ANALYSIS. THIS STUDY, FOR THE FIRST TIME, ILLUSTRATES THE NEED TO UNDERSTAND IBD OR CRC BEYOND AN INFLAMMATORY PERSPECTIVE AND THE VALUE OF THERAPEUTICS DIRECTED TO RESET ALTERED PROLIFERATIVE AND METABOLIC STATES WITHIN THE COLON. THE USE OF SUCH THERAPEUTICS MAY TRULY DRIVE PATIENTS INTO REMISSION. 2023 5 699 18 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 6 6687 20 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 7 1764 23 EARLY-IMMEDIATE GENE EGR1 IS ASSOCIATED WITH TGFBETA1 REGULATION OF EPIGENETIC READER BROMODOMAIN-CONTAINING PROTEIN 4 VIA THE CANONICAL SMAD3 SIGNALING IN HEPATIC STELLATE CELLS IN VITRO AND IN VIVO. UPON CHRONIC DAMAGE TO THE LIVER, MULTIPLE CYTOKINES STIMULATE HEPATIC STELLATE CELLS (HSCS), CAUSING THE ALTERATIONS OF GENE EXPRESSION PROFILES AND THUS LEADING TO HSC ACTIVATION, A KEY STEP IN LIVER FIBROGENESIS. ACTIVATED HSCS ARE THE DOMINANT CONTRIBUTORS TO LIVER FIBROSIS. BROMODOMAIN CONTAINING PROTEIN 4 (BRD4), AN IMPORTANT EPIGENETIC READER, WAS DEMONSTRATED TO CONCENTRATE ON HUNDREDS OF ENHANCERS ASSOCIATED WITH GENES INVOLVED IN MULTIPLE PROFIBROTIC PATHWAYS, THEREBY DIRECTING HSC ACTIVATION AND THE FIBROTIC RESPONSES. THE PRESENT STUDIES WERE DESIGNED TO EXAMINE THE EFFECT OF TRANSFORMING GROWTH FACTOR BETA-1 (TGFBETA1), THE MOST POTENT PRO-FIBROTIC CYTOKINE, ON BRD4 EXPRESSION IN HSCS AND, IF SO, ELUCIDATED THE UNDERLYING MECHANISMS IN VITRO AND IN VIVO. THE EXPERIMENTS EMPLOYED THE HETEROGENEOUS TGFBETA1 KNOCKOUT (TGFBETA1(+/-) ) MICE, GENE KNOCKDOWN IN VIVO, AND A MODEL OF THIOACETAMIDE (TAA)-INDUCED LIVER INJURY. THE RESULTS REVEALED THAT TGFBETA1 ENHANCED BRD4 EXPRESSION IN HSCS, WHICH WAS MEDIATED, AT LEAST, BY SMAD3 SIGNALING AND EARLY-IMMEDIATE GENE EGR1 (EARLY GROWTH RESPONSE-1). TGFBETA1-INDUCED SMAD3 SIGNALING INCREASED EGR1 EXPRESSION AND PROMOTED EGR1 BINDING TO BRD4 PROMOTER AT A SITE AROUND -111 BP, PROMOTING BRD4 EXPRESSION. EGR1 KNOCKDOWN REDUCED BRD4 EXPRESSION IN HSCS IN A MOUSE MODEL OF TAA-INDUCED LIVER INJURY AND LESSENED LIVER FIBROSIS. DOUBLE FLUORESCENCE STAINING DEMONSTRATED A STRONG INCREASE IN BRD4 EXPRESSION IN ACTIVATED HSCS IN FIBROTIC AREAS OF THE HUMAN LIVERS, PARALLELING THE UPREGULATION OF P-SMAD3 AND EGR1. THIS RESEARCH SUGGESTED NOVEL MOLECULAR EVENTS UNDERLYING THE ROLES OF THE MASTER PRO-FIBROTIC CYTOKINE TGFBETA1 IN HSC ACTIVATION AND LIVER FIBROGENESIS. 2022 8 692 23 BRD4 PROMOTES HEPATIC STELLATE CELLS ACTIVATION AND HEPATIC FIBROSIS VIA MEDIATING P300/H3K27AC/PLK1 AXIS. HEPATIC FIBROSIS (HF) IS A REVERSIBLE WOUND-HEALING RESPONSE CHARACTERIZED BY EXCESSIVE EXTRACELLULAR MATRIX (ECM) DEPOSITION AND SECONDARY TO PERSISTENT CHRONIC INJURY. BROMODOMAIN PROTEIN 4 (BRD4) COMMONLY FUNCTIONS AS A "READER" TO REGULATE EPIGENETIC MODIFICATIONS INVOLVED IN VARIOUS BIOLOGICAL AND PATHOLOGICAL EVENTS, BUT THE MECHANISM OF HF REMAINS UNCLEAR. IN THIS STUDY, WE ESTABLISHED A CCL(4)-INDUCED HF MODEL AND SPONTANEOUS RECOVERY MODEL IN MICE AND FOUND ABERRANT BRD4 EXPRESSION, WHICH WAS CONSISTENT WITH THE RESULTS IN HUMAN HEPATIC STELLATE CELLS (HSCS)- LX2 CELLS IN VITRO. SUBSEQUENTLY, WE FOUND THAT DISTRICTION AND INHIBITION OF BRD4 RESTRAINED TGFBETA-INDUCED TRANS-DIFFERENTIATION OF LX2 CELLS INTO ACTIVATED, PROLIFERATIVE MYOFIBROBLASTS AND ACCELERATED APOPTOSIS, AND BRD4 OVEREXPRESSION BLOCKED MDI-INDUCED LX2 CELLS INACTIVATION AND PROMOTED THE PROLIFERATION AND INHIBITED APOPTOSIS OF INACTIVATED CELLS. ADDITIONALLY, ADENO-ASSOCIATED VIRUS SEROTYPE 8-LOADED SHORT HAIRPIN RNA-MEDIATED BRD4 KNOCKDOWN IN MICE SIGNIFICANTLY ATTENUATED CCL(4)-INDUCED FIBROTIC RESPONSES INCLUDING HSCS ACTIVATION AND COLLAGEN DEPOSITION. MECHANISTICALLY, BRD4 DEFICIENCY INHIBITED PLK1 EXPRESSION IN ACTIVATED LX2 CELLS, AND CHIP AND CO-IP ASSAYS REVEALED THAT BRD4 REGULATION OF PLK1 WAS DEPENDENT ON P300-MEDIATED ACETYLATION MODIFICATION FOR H3K27 ON THE PLK1 PROMOTER. IN CONCLUSION, BRD4 DEFICIENCY IN THE LIVER ALLEVIATES CCL(4)-INDUCED HF IN MICE, AND BRD4 PARTICIPATES IN THE ACTIVATION AND REVERSAL OF HSCS THROUGH POSITIVELY REGULATING THE P300/H3K27AC/PLK1 AXIS, PROVIDING A POTENTIAL INSIGHT FOR HF THERAPY. 2023 9 5907 33 TARGET-BASED SMALL MOLECULE DRUG DISCOVERY TOWARDS NOVEL THERAPEUTICS FOR INFLAMMATORY BOWEL DISEASES. INFLAMMATORY BOWEL DISEASE (IBD), INCLUDING ULCERATIVE COLITIS (UC) AND CROHN'S DISEASE (CD), IS A CLASS OF SEVERE AND CHRONIC DISEASES OF THE GASTROINTESTINAL (GI) TRACT WITH RECURRENT SYMPTOMS AND SIGNIFICANT MORBIDITY. LONG-TERM PERSISTENCE OF CHRONIC INFLAMMATION IN IBD IS A MAJOR CONTRIBUTING FACTOR TO NEOPLASTIC TRANSFORMATION AND THE DEVELOPMENT OF COLITIS-ASSOCIATED COLORECTAL CANCER. CONVERSELY, PERSISTENCE OF TRANSMURAL INFLAMMATION IN CD IS ASSOCIATED WITH FORMATION OF FIBROSING STRICTURES, RESULTING IN SUBSTANTIAL MORBIDITY. THE RECENT INTRODUCTION OF BIOLOGICAL RESPONSE MODIFIERS AS IBD THERAPIES, SUCH AS ANTIBODIES NEUTRALIZING TUMOR NECROSIS FACTOR (TNF)-ALPHA, HAVE REPLACED NONSELECTIVE ANTI-INFLAMMATORY CORTICOSTEROIDS IN DISEASE MANAGEMENT. HOWEVER, A LARGE PROPORTION (~40%) OF PATIENTS WITH THE TREATMENT OF ANTI-TNF-ALPHA ANTIBODIES ARE DISCONTINUED OR WITHDRAWN FROM THERAPY BECAUSE OF (1) PRIMARY NONRESPONSE, (2) SECONDARY LOSS OF RESPONSE, (3) OPPORTUNISTIC INFECTION, OR (4) ONSET OF CANCER. THEREFORE, THE DEVELOPMENT OF NOVEL AND EFFECTIVE THERAPEUTICS TARGETING SPECIFIC SIGNALING PATHWAYS IN THE PATHOGENESIS OF IBD IS URGENTLY NEEDED. IN THIS COMPREHENSIVE REVIEW, WE SUMMARIZE THE RECENT ADVANCES IN DRUG DISCOVERY OF NEW SMALL MOLECULES IN PRECLINICAL OR CLINICAL DEVELOPMENT FOR TREATING IBD THAT TARGET BIOLOGICALLY RELEVANT PATHWAYS IN MUCOSAL INFLAMMATION. THESE INCLUDE INTRACELLULAR ENZYMES (JANUS KINASES, RECEPTOR INTERACTING PROTEIN, PHOSPHODIESTERASE 4, IKAPPAB KINASE), INTEGRINS, G PROTEIN-COUPLED RECEPTORS (S1P, CCR9, CXCR4, CB2) AND INFLAMMASOME MEDIATORS (NLRP3), ETC. WE WILL ALSO DISCUSS EMERGING EVIDENCE OF A DISTINCT MECHANISM OF ACTION, BROMODOMAIN-CONTAINING PROTEIN 4, AN EPIGENETIC REGULATOR OF PATHWAYS INVOLVED IN THE ACTIVATION, COMMUNICATION, AND TRAFFICKING OF IMMUNE CELLS. WE HIGHLIGHT THEIR CHEMOTYPES, MODE OF ACTIONS, STRUCTURE-ACTIVITY RELATIONSHIPS, CHARACTERIZATIONS, AND THEIR IN VITRO/IN VIVO ACTIVITIES AND THERAPEUTIC POTENTIAL. THE PERSPECTIVES ON THE RELEVANT CHALLENGES, NEW OPPORTUNITIES, AND FUTURE DIRECTIONS IN THIS FIELD ARE ALSO DISCUSSED. 2021 10 700 26 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 11 3245 20 HEPATIC STELLATE CELLS AS KEY TARGET IN LIVER FIBROSIS. PROGRESSIVE LIVER FIBROSIS, INDUCED BY CHRONIC VIRAL AND METABOLIC DISORDERS, LEADS TO MORE THAN ONE MILLION DEATHS ANNUALLY VIA DEVELOPMENT OF CIRRHOSIS, ALTHOUGH NO ANTIFIBROTIC THERAPY HAS BEEN APPROVED TO DATE. TRANSDIFFERENTIATION (OR "ACTIVATION") OF HEPATIC STELLATE CELLS IS THE MAJOR CELLULAR SOURCE OF MATRIX PROTEIN-SECRETING MYOFIBROBLASTS, THE MAJOR DRIVER OF LIVER FIBROGENESIS. PARACRINE SIGNALS FROM INJURED EPITHELIAL CELLS, FIBROTIC TISSUE MICROENVIRONMENT, IMMUNE AND SYSTEMIC METABOLIC DYSREGULATION, ENTERIC DYSBIOSIS, AND HEPATITIS VIRAL PRODUCTS CAN DIRECTLY OR INDIRECTLY INDUCE STELLATE CELL ACTIVATION. DYSREGULATED INTRACELLULAR SIGNALING, EPIGENETIC CHANGES, AND CELLULAR STRESS RESPONSE REPRESENT CANDIDATE TARGETS TO DEACTIVATE STELLATE CELLS BY INDUCING REVERSION TO INACTIVATED STATE, CELLULAR SENESCENCE, APOPTOSIS, AND/OR CLEARANCE BY IMMUNE CELLS. CELL TYPE- AND TARGET-SPECIFIC PHARMACOLOGICAL INTERVENTION TO THERAPEUTICALLY INDUCE THE DEACTIVATION WILL ENABLE MORE EFFECTIVE AND LESS TOXIC PRECISION ANTIFIBROTIC THERAPIES. 2017 12 4582 29 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 13 5602 24 RORGAMMAT(+) HEMATOPOIETIC CELLS ARE NECESSARY FOR TUMOR CELL PROLIFERATION DURING COLITIS-ASSOCIATED TUMORIGENESIS IN MICE. COLORECTAL CANCER (CRC) IS ONE OF THE MOST COMMON TUMOR ENTITIES. IN PATIENTS WITH INFLAMMATORY BOWEL DISEASES, THE DEVELOPMENT OF COLITIS-ASSOCIATED COLON CANCER IS CONSIDERED A DANGEROUS LONG-TERM COMPLICATION. IL-17A AND THE TRANSCRIPTION FACTOR RETINOIC ACID RECEPTOR-RELATED ORPHAN RECEPTOR GAMMAT (RORGAMMAT) PLAY FUNDAMENTAL ROLES IN THE PATHOGENESIS OF INFLAMMATORY BOWEL DISEASES; IN HUMAN STUDIES, WE DETECTED A DENSE INFILTRATION OF RORGAMMAT-DEPENDENT CD4(+) IL17A(+) T HELPER (TH)17 CELLS IN SPECIMENS OF CRC, ULCERATIVE COLITIS, AND ULCERATIVE COLITIS-ASSOCIATED COLORECTAL CANCER. HOWEVER, THE MECHANISTIC ROLE OF RORGAMMAT(+) HEMATOPOIETIC CELLS IN COLITIS-ASSOCIATED TUMORIGENESIS REMAINS UNCLEAR. TO INVESTIGATE COLITIS-ASSOCIATED COLON TUMORIGENESIS, WE CONDUCTED STUDIES IN THE AOM+DSS MOUSE MODEL THAT REVEALED THE IMPORTANCE OF RORGAMMAT FOR COLON TUMOR PROGRESSION. IN THE ABSENCE OF RORGAMMAT-DEPENDENT TH17 LYMPHOCYTES, MICE SHOWED SIGNS OF INTENSE CHRONIC COLITIS, BUT DEVELOPED SIGNIFICANTLY FEWER MACROSCOPIC TUMOR NODULES. THE REDUCTION OF TUMOR DEVELOPMENT IN RORGAMMAT(-/-) MICE WAS NOT DUE TO REDUCED COLON TUMOR INITIATION. HOWEVER, THE PROLIFERATION RATE OF TUMOR CELLS WAS REDUCED IN THE ABSENCE OF RORGAMMAT-DEPENDENT TH17 CELLS AND TUMOR CELLS SHOWED PRONOUNCED SIGNS OF SENESCENCE-ASSOCIATED EPIGENETIC AND LYSOSOMAL CHANGES. THESE RESULTS INDICATE AN IMPORTANT ROLE FOR THE IMMUNOLOGICAL MILIEU IN COLITIS-ASSOCIATED CANCER, WHICH IS SHAPED IN-PART BY RORGAMMAT-DEPENDENT TH17 LYMPHOCYTES THAT SUPPORT CRC GROWTH. 2015 14 689 31 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 15 4448 32 MOLECULAR MECHANISM AND TREATMENT OF VIRAL HEPATITIS-RELATED LIVER FIBROSIS. HEPATIC FIBROSIS IS A WOUND-HEALING RESPONSE TO VARIOUS CHRONIC STIMULI, INCLUDING VIRAL HEPATITIS B OR C INFECTION. ACTIVATED MYOFIBROBLASTS, PREDOMINANTLY DERIVED FROM THE HEPATIC STELLATE CELLS (HSCS), REGULATE THE BALANCE BETWEEN MATRIX METALLOPROTEINASES AND THEIR TISSUE INHIBITORS TO MAINTAIN EXTRACELLULAR MATRIX HOMEOSTASIS. TRANSFORMING GROWTH FACTOR-BETA AND PLATELET-DERIVED GROWTH FACTOR ARE CLASSIC PROFIBROGENIC SIGNALS THAT ACTIVATE HSC PROLIFERATION. IN ADDITION, PROINFLAMMATORY CYTOKINES AND CHEMOKINES COORDINATE MACROPHAGES, T CELLS, NK/NKT CELLS, AND LIVER SINUSOIDAL ENDOTHELIAL CELLS IN COMPLEX FIBROGENIC AND REGRESSION PROCESSES. IN ADDITION, FIBROGENESIS INVOLVES ANGIOGENESIS, METABOLIC REPROGRAMMING, AUTOPHAGY, MICRORNA, AND EPIGENETIC REGULATIONS. HEPATIC INFLAMMATION IS THE DRIVING FORCE BEHIND LIVER FIBROSIS; HOWEVER, HOST SINGLE NUCLEOTIDE POLYMORPHISMS AND VIRAL FACTORS, INCLUDING THE GENOTYPE, VIRAL LOAD, VIRAL MUTATION, AND VIRAL PROTEINS, HAVE BEEN ASSOCIATED WITH FIBROSIS PROGRESSION. ELIMINATING THE UNDERLYING ETIOLOGY IS THE MOST CRUCIAL ANTIFIBROTIC THERAPY. GROWING EVIDENCE HAS INDICATED THAT PERSISTENT VIRAL SUPPRESSION WITH ANTIVIRAL THERAPY CAN RESULT IN FIBROSIS REGRESSION, REDUCED LIVER DISEASE PROGRESSION, DECREASED HEPATOCELLULAR CARCINOMA, AND IMPROVED CHANCES OF SURVIVAL. PRECLINICAL STUDIES AND CLINICAL TRIALS ARE CURRENTLY EXAMINING SEVERAL INVESTIGATIONAL AGENTS THAT TARGET KEY FIBROGENIC PATHWAYS; THE RESULTS ARE PROMISING AND SHED LIGHT ON THIS DEBILITATING ILLNESS. 2014 16 4501 25 MORPHOGENS AND HEPATIC STELLATE CELL FATE REGULATION IN CHRONIC LIVER DISEASE. HEPATIC STELLATE CELLS (HSC) ARE THE LIVER MESENCHYMAL CELL TYPE WHICH RESPONDS TO HEPATOCELLULAR DAMAGE AND PARTICIPATES IN WOUND HEALING. ALTHOUGH HSC MYOFIBROBLASTIC TRANS-DIFFERENTIATION (ACTIVATION) IS IMPLICATED IN EXCESSIVE EXTRACELLULAR MATRIX DEPOSITION, MOLECULAR UNDERSTANDING OF THIS PHENOTYPIC SWITCH FROM THE VIEWPOINT OF CELL FATE REGULATION IS LIMITED. RECENT STUDIES DEMONSTRATE THE ROLES OF ANTI-ADIPOGENIC MORPHOGENS (WNT, NECDIN, SHH) IN EPIGENETIC REPRESSION OF THE HSC DIFFERENTIATION GENE PPARGAMMA AS A CAUSAL EVENT IN HSC ACTIVATION. THESE MORPHOGENS HAVE POSITIVE CROSS-INTERACTIONS WHICH CONVERGE TO EPIGENETIC REPRESSION OF PPARGAMMA INVOLVING THE METHYL-CPG BINDING PROTEIN MECP2. HOWEVER, THESE MORPHOGENS EXPRESSED BY ACTIVATED HSC MAY ALSO PARTICIPATE IN CROSS-TALK BETWEEN HSC AND HEPATOBLASTS/HEPATOCYTES TO SUPPORT LIVER REGENERATION, AND THEIR ABERRANT REGULATION MAY CONTRIBUTE TO LIVER TUMORIGENESIS. IMPLICATIONS OF HSC-DERIVED MORPHOGENS IN THESE POSSIBILITIES ARE DISCUSSED. 2012 17 5013 27 PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA AS A THERAPEUTIC TARGET FOR HEPATIC FIBROSIS: FROM BENCH TO BEDSIDE. HEPATIC FIBROSIS IS A DYNAMIC CHRONIC LIVER DISEASE OCCURRING AS A CONSEQUENCE OF WOUND-HEALING RESPONSES TO VARIOUS HEPATIC INJURIES. THIS DISORDER IS ONE OF PRIMARY PREDICTORS FOR LIVER-ASSOCIATED MORBIDITY AND MORTALITY WORLDWIDE. TO DATE, NO PHARMACOLOGICAL AGENT HAS BEEN APPROVED FOR HEPATIC FIBROSIS OR COULD BE RECOMMENDED FOR ROUTINE USE IN CLINICAL CONTEXT. CELLULAR AND MOLECULAR UNDERSTANDING OF HEPATIC FIBROSIS HAS REVEALED THAT PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA (PPARGAMMA), THE FUNCTIONING RECEPTOR FOR ANTIDIABETIC THIAZOLIDINEDIONES, PLAYS A PIVOTAL ROLE IN THE PATHOBIOLOGY OF HEPATIC STELLATE CELLS (HSCS), WHOSE ACTIVATION IS THE CENTRAL EVENT IN THE PATHOGENESIS OF HEPATIC FIBROSIS. ACTIVATION OF PPARGAMMA INHIBITS HSC COLLAGEN PRODUCTION AND MODULATES HSC ADIPOGENIC PHENOTYPE AT TRANSCRIPTIONAL AND EPIGENETIC LEVELS. THESE MOLECULAR INSIGHTS INDICATE PPARGAMMA AS A PROMISING DRUG TARGET FOR ANTIFIBROTIC CHEMOTHERAPY. INTENSIVE ANIMAL STUDIES HAVE DEMONSTRATED THAT STIMULATION OF PPARGAMMA REGULATORY SYSTEM THROUGH GENE THERAPY APPROACHES AND PPARGAMMA LIGANDS HAS THERAPEUTIC PROMISE FOR HEPATIC FIBROSIS INDUCED BY A VARIETY OF ETIOLOGIES. AT THE SAME TIME, THIAZOLIDINEDIONE AGENTS HAVE BEEN INVESTIGATED FOR THEIR CLINICAL BENEFITS PRIMARILY IN PATIENTS WITH NONALCOHOLIC STEATOHEPATITIS, A COMMON METABOLIC LIVER DISORDER WITH HIGH POTENTIAL TO PROGRESS TO FIBROSIS AND LIVER-RELATED DEATH. ALTHOUGH SOME STUDIES HAVE SHOWN INITIAL PROMISE, NONE HAS ESTABLISHED LONG-TERM EFFICACY IN WELL-CONTROLLED RANDOMIZED CLINICAL TRIALS. THIS COMPREHENSIVE REVIEW COVERS THE 10-YEAR DISCOVERIES OF THE MOLECULAR BASIS FOR PPARGAMMA REGULATION OF HSC PATHOPHYSIOLOGY AND THEN FOCUSES ON THE ANIMAL INVESTIGATIONS AND CLINICAL TRIALS OF VARIOUS THERAPEUTIC MODALITIES TARGETING PPARGAMMA FOR HEPATIC FIBROSIS. 2013 18 596 34 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 2817 22 FIBROSIS IN THE LIVER: ACUTE PROTECTION AND CHRONIC DISEASE. THE UNDERSTANDING OF THE CELLULAR AND MOLECULAR MECHANISMS OF THE FIBROTIC WOUND-HEALING RESPONSE OF THE LIVER HAS MADE DRAMATIC PROGRESS IN THE PAST 20 YEARS. HEPATIC STELLATE CELLS (HSCS), WHICH AFTER LIVER INJURY PROLIFERATE AND TRANSDIFFERENTIATE TO MYOFIBROBLASTS, HAVE EMERGED AS THE PRIMARY SOURCE OF THE FIBROTIC RESPONSE, EVEN THOUGH OTHER FIBROGENIC CELLS MAY ALSO CONTRIBUTE TO THE PRODUCTION OF EXTRACELLULAR MATRIX (ECM). ADVANCES IN THE UNDERSTANDING OF HSC REGULATION INCLUDE APOPTOTIC SIGNALING, ANGIOGENIC SIGNALING, AND RESPONSES TO OXIDATIVE STRESS. THE ECM HAS EMERGED NOT ONLY AS A STRUCTURAL SCAFFOLD, BUT ALSO AS A DYNAMIC AND INTERACTIVE MATRIX REGULATING STELLATE CELL ACTIVATION. ADDITIONALLY, THE INNATE IMMUNE SYSTEM AND IMMUNE SIGNALING, AS WELL AS A BROADENING UNDERSTANDING OF THE TRANSCRIPTIONAL REGULATION INCLUDING MICRORNAS AND EPIGENETIC EVENTS OFFER POTENTIAL THERAPEUTIC TARGETS. UNRAVELING GENETIC DETERMINANTS RELATED TO MECHANISMS OF HEPATIC FIBROGENESIS PROMISE INDIVIDUALIZED THERAPY OR PREVENTION. HEPATIC FIBROSIS AND CIRRHOSIS HAVE EMERGED AS TREATABLE AND POTENTIALLY REVERSIBLE CONSEQUENCE OF CHRONIC LIVER DISEASE. 2010 20 697 33 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