1 4501 88 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 2 699 30 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 3 1764 30 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 4 6757 46 WNT SIGNALING IN LIVER FIBROSIS: PROGRESS, CHALLENGES AND POTENTIAL DIRECTIONS. LIVER FIBROSIS IS A COMMON WOUND-HEALING RESPONSE TO CHRONIC LIVER INJURIES, INCLUDING ALCOHOLIC OR DRUG TOXICITY, PERSISTENT VIRAL INFECTION, AND GENETIC FACTORS. MYOFIBROBLASTIC TRANSDIFFERENTIATION (MTD) IS THE PIVOTAL EVENT DURING LIVER FIBROGENESIS, AND RESEARCH IN THE PAST FEW YEARS HAS IDENTIFIED KEY MEDIATORS AND MOLECULAR MECHANISMS RESPONSIBLE FOR MTD OF HEPATIC STELLATE CELLS (HSCS). HSCS ARE UNDIFFERENTIATED CELLS WHICH PLAY AN IMPORTANT ROLE IN LIVER REGENERATION. RECENT EVIDENCE DEMONSTRATES THAT HSCS DERIVE FROM MESODERM AND AT LEAST IN PART VIA SEPTUM TRANSVERSUM AND MESOTHELIUM, AND HSCS EXPRESS MARKERS FOR DIFFERENT CELL TYPES WHICH DERIVE FROM MULTIPOTENT MESENCHYMAL PROGENITORS. THERE IS A REGULATORY COMMONALITY BETWEEN DIFFERENTIATION OF ADIPOCYTES AND THAT OF HSC, AND THE SHIFT FROM ADIPOGENIC TO MYOGENIC OR NEURONAL PHENOTYPE CHARACTERIZES HSC MTD. CENTRAL OF THIS SHIFT IS A LOSS OF EXPRESSION OF THE MASTER ADIPOGENIC REGULATOR PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA (PPARGAMMA). RESTORED EXPRESSION OF PPARGAMMA AND/OR OTHER ADIPOGENIC TRANSCRIPTION GENES CAN REVERSE MYOFIBROBLASTIC HSCS TO DIFFERENTIATED CELLS. VERTEBRATE WNT AND DROSOPHILA WINGLESS ARE HOMOLOGOUS GENES, AND THEIR TRANSLATED PROTEINS HAVE BEEN SHOWN TO PARTICIPATE IN THE REGULATION OF CELL PROLIFERATION, CELL POLARITY, CELL DIFFERENTIATION, AND OTHER BIOLOGICAL ROLES. MORE RECENTLY, WNT SIGNALING IS IMPLICATED IN HUMAN FIBROSING DISEASES, SUCH AS PULMONARY FIBROSIS, RENAL FIBROSIS, AND LIVER FIBROSIS. BLOCKING THE CANONICAL WNT SIGNAL PATHWAY WITH THE CO-RECEPTOR ANTAGONIST DICKKOPF-1 (DKK1) ABROGATES THESE EPIGENETIC REPRESSIONS AND RESTORES THE GENE PPARGAMMA EXPRESSION AND HSC DIFFERENTIATION. THE IDENTIFIED MORPHOGEN MEDIATED EPIGENETIC REGULATION OF PPARGAMMA AND HSC DIFFERENTIATION ALSO SERVES AS NOVEL THERAPEUTIC TARGETS FOR LIVER FIBROSIS AND LIVER REGENERATION. IN CONCLUSION, THE WNT SIGNALING PROMOTES LIVER FIBROSIS BY ENHANCING HSC ACTIVATION AND SURVIVAL, AND WE HEREIN DISCUSS WHAT WE CURRENTLY KNOW AND WHAT WE EXPECT WILL COME IN THIS FIELD IN THE NEXT FUTURE. 2013 5 692 29 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 6 5939 39 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 7 4199 35 METABOLIC REPROGRAMMING AND CELL FATE REGULATION IN ALCOHOLIC LIVER DISEASE. ALCOHOLIC LIVER DISEASE (ALD) SHOULD BE DEFINED AS A LIFE-STYLE METABOLIC DISEASE. ITS PATHOGENESIS IS DRIVEN BY ALTERED CELL FATE OF BOTH PARENCHYMAL AND NON-PARENCHYMAL LIVER CELL TYPES, CONTRIBUTING TO DIFFERENT PATHOLOGIC SPECTRA. A CRITICAL TURNING POINT IN PROGRESSION OF ALD IS CHRONIC ALCOHOLIC STEATOHEPATITIS (ASH) OR ALCOHOLIC NEUTROPHILIC HEPATITIS (AH), WHICH MARKEDLY PREDISPOSES PATIENTS TO MOST DEVASTATING ALD SEQUELA, CIRRHOSIS AND LIVER CANCER. RESULTS: OUR RESEARCH IDENTIFIES THE PIVOTAL ROLES OF UNIQUE METABOLIC REPROGRAMMING IN M1 ACTIVATION OF HEPATIC MACROPHAGES (HM) AND MYOFIBROBLASTIC ACTIVATION (MF) OF HEPATIC STELLATE CELLS (HSC) IN THE GENESIS OF INFLAMMATION AND FIBROSIS, THE TWO KEY HISTOLOGICAL FEATURES OF CHRONIC ASH AND NEUTROPHILIC AH. FOR M1 HM ACTIVATION, HEIGHTENED PROINFLAMMATORY IRON REDOX SIGNALING IN ENDOSOMES OR CAVEOSOMES RESULTS FROM ALTERED IRON METABOLISM AND STORAGE, PROMOTING IKK/NF-KB ACTIVATION VIA INTERACTIVE ACTIVATION OF P21RAS, TAK1, AND PI3K. FOR MF CELL FATE REGULATION OF HSC, ACTIVATION OF THE MORPHOGEN WNT PATHWAY CAUSED BY THE NUCLEAR PROTEIN NECDIN OR THE SINGLE-PASS TRANS-MEMBRANE PROTEIN DLK1, REPROGRAMS LIPID METABOLISM VIA MECP2-MEDIATED EPIGENETIC REPRESSION OF THE KEY HSC QUIESCENCE GENE PPAR-GAMMA. CONCLUSIONS: THE FINDINGS FROM THESE STUDIES RE-ENFORCE THE IMPORTANCE OF METABOLIC REPROGRAMMING IN CELL FATE REGULATION REQUIRED FOR THE PATHOGENESIS OF ALD. 2015 8 5965 17 TEN-ELEVEN-TRANSLOCATION 2 (TET2) NEGATIVELY REGULATES HOMEOSTASIS AND DIFFERENTIATION OF HEMATOPOIETIC STEM CELLS IN MICE. THE TEN-ELEVEN-TRANSLOCATION 2 (TET2) GENE ENCODES A MEMBER OF TET FAMILY ENZYMES THAT ALTERS THE EPIGENETIC STATUS OF DNA BY OXIDIZING 5-METHYLCYTOSINE TO 5-HYDROXYMETHYLCYTOSINE (5HMC). SOMATIC LOSS-OF-FUNCTION MUTATIONS OF TET2 ARE FREQUENTLY OBSERVED IN PATIENTS WITH DIVERSE MYELOID MALIGNANCIES, INCLUDING MYELODYSPLASTIC SYNDROMES, MYELOPROLIFERATIVE NEOPLASMS, AND CHRONIC MYELOMONOCYTIC LEUKEMIA. BY ANALYZING MICE WITH TARGETED DISRUPTION OF THE TET2 CATALYTIC DOMAIN, WE SHOW HERE THAT TET2 IS A CRITICAL REGULATOR OF SELF-RENEWAL AND DIFFERENTIATION OF HEMATOPOIETIC STEM CELLS (HSCS). TET2 DEFICIENCY LED TO DECREASED GENOMIC LEVELS OF 5HMC AND AUGMENTED THE SIZE OF THE HEMATOPOIETIC STEM/PROGENITOR CELL POOL IN A CELL-AUTONOMOUS MANNER. IN COMPETITIVE TRANSPLANTATION ASSAYS, TET2-DEFICIENT HSCS WERE CAPABLE OF MULTILINEAGE RECONSTITUTION AND POSSESSED A COMPETITIVE ADVANTAGE OVER WILD-TYPE HSCS, RESULTING IN ENHANCED HEMATOPOIESIS INTO BOTH LYMPHOID AND MYELOID LINEAGES. IN VITRO, TET2 DEFICIENCY DELAYED HSC DIFFERENTIATION AND SKEWED DEVELOPMENT TOWARD THE MONOCYTE/MACROPHAGE LINEAGE. OUR DATA INDICATE THAT TET2 HAS A CRITICAL ROLE IN REGULATING THE EXPANSION AND FUNCTION OF HSCS, PRESUMABLY BY CONTROLLING 5HMC LEVELS AT GENES IMPORTANT FOR THE SELF-RENEWAL, PROLIFERATION, AND DIFFERENTIATION OF HSCS. 2011 9 3931 25 LIVER INJURY AND THE ACTIVATION OF THE HEPATIC MYOFIBROBLASTS. LIVER FIBROSIS IS A WOUND HEALING PROCESS, THE END RESULT OF CHRONIC LIVER INJURY ELICITED BY DIFFERENT NOXIOUS STIMULI. ACTIVATED HEPATIC STELLATE CELLS OR MYOFIBROBLASTS AND PORTAL MYOFIBROBLASTS ARE CONSIDERED AS THE MAIN PRODUCERS OF THE EXTRACELLULAR MATRIX IN THE LIVER. UPON LIVER INJURY THE QUIESCENT STELLATE CELLS TRANSDIFFERENTIATE INTO MYOFIBROBLASTS A PROCESS HIGHLIGHTED BY THE LOSS OF VITAMIN A STORES, UPREGULATION OF INTERSTITIAL TYPE COLLAGENS, SMOOTH MUSCLE ALPHA ACTIN, MATRIX METALLOPROTEINASES, PROTEOGLYCANS, AND THE INDUCTION OF CELL SURVIVAL PATHWAYS. ACTIVATION OF HEPATIC STELLATE CELLS IS A RESULT OF A COMPLEX INTERPLAY BETWEEN THE PARENCHYMAL CELLS, IMMUNE CELLS, EXTRACELLULAR MATRIX MECHANICS AND EXTRAHEPATIC MILIEU SUCH AS THE GUT MICROBIOME. IN THIS REVIEW WE WILL FOCUS ON THE PATHOMECHANISM OF STELLATE CELL ACTIVATION FOLLOWING CHRONIC LIVER INJURY; WITH THE AIM OF IDENTIFYING POSSIBLE TREATMENT TARGETS FOR ANTI-FIBROGENIC AGENTS. 2013 10 3944 28 LNCRNA H19-EZH2 INTERACTION PROMOTES LIVER FIBROSIS VIA REPROGRAMMING H3K27ME3 PROFILES. LIVER FIBROSIS IS A WOUND-HEALING PROCESS CHARACTERIZED BY EXCESS FORMATION OF EXTRACELLULAR MATRIX (ECM) FROM ACTIVATED HEPATIC STELLATE CELLS (HSCS). PREVIOUS STUDIES SHOW THAT BOTH EZH2, AN EPIGENETIC REGULATOR THAT CATALYZES LYSINE 27 TRIMETHYLATION ON HISTONE 3 (H3K27ME3), AND LONG NON-CODING RNA H19 ARE HIGHLY CORRELATED WITH FIBROGENESIS. IN THE CURRENT STUDY, WE INVESTIGATED THE UNDERLYING MECHANISMS. VARIOUS MODELS OF LIVER FIBROSIS INCLUDING MDR2(-/-), BILE DUCT LIGATION (BDL) AND CCL(4) MICE WERE ADAPTED. WE FOUND THAT EZH2 WAS MARKEDLY UPREGULATED AND CORRELATED WITH H19 AND FIBROTIC MARKERS EXPRESSION IN THESE MODELS. ADMINISTRATION OF EZH2 INHIBITOR 3-DZNEP CAUSED SIGNIFICANT PROTECTIVE EFFECTS IN THESE MODELS. FURTHERMORE, TREATMENT WITH 3-DZNEP OR GSK126 SIGNIFICANTLY INHIBITED PRIMARY HSC ACTIVATION AND PROLIFERATION IN TGF-BETA-TREATED HSCS AND H19-OVEREXPREESING LX2 CELLS IN VIVO. USING RNA-PULL DOWN ASSAY COMBINED WITH RNA IMMUNOPRECIPITATION, WE DEMONSTRATED THAT H19 COULD DIRECTLY BIND TO EZH2. INTEGRATED ANALYSIS OF RNA-SEQUENCING (RNA-SEQ) AND CHROMATIN IMMUNOPRECIPITATION SEQUENCING (CHIP-SEQ) FURTHER REVEALED THAT H19 REGULATED THE REPROGRAMMING OF EZH2-MEDIATED H3K27ME3 PROFILES, WHICH EPIGENETICALLY PROMOTED SEVERAL PATHWAYS FAVORING HSCS ACTIVATION AND PROLIFERATION, INCLUDING EPITHELIAL-MESENCHYMAL TRANSITION AND WNT/BETA-CATENIN SIGNALING. IN CONCLUSION, HIGHLY EXPRESSED H19 IN CHRONIC LIVER DISEASES PROMOTES FIBROGENESIS BY REPROGRAMMING EZH2-MEDIATED EPIGENETIC REGULATION OF HSCS ACTIVATION. TARGETING THE H19-EZH2 INTERACTION MAY SERVE AS A NOVEL THERAPEUTIC APPROACH FOR LIVER FIBROSIS. 2023 11 3330 25 HISTONE DEACETYLASE INHIBITOR GIVINOSTAT ALLEVIATES LIVER FIBROSIS BY REGULATING HEPATIC STELLATE CELL ACTIVATION. HEPATIC FIBROSIS, A COMMON PATHOLOGICAL MANIFESTATION OF CHRONIC LIVER INJURY, IS GENERALLY CONSIDERED TO BE THE END RESULT OF AN INCREASE IN EXTRACELLULAR MATRIX PRODUCED BY ACTIVATED HEPATIC STELLATE CELLS (HSCS). THE AIM OF THE PRESENT STUDY WAS TO TARGET THE MECHANISMS UNDERLYING HSC ACTIVATION IN ORDER TO PROVIDE A POWERFUL THERAPEUTIC STRATEGY FOR THE PREVENTION AND TREATMENT OF LIVER FIBROSIS. IN THE PRESENT STUDY, A HIGH?THROUGHPUT SCREENING ASSAY WAS ESTABLISHED, AND THE HISTONE DEACETYLASE INHIBITOR GIVINOSTAT WAS IDENTIFIED AS A POTENT INHIBITOR OF HSC ACTIVATION IN VITRO. GIVINOSTAT SIGNIFICANTLY INHIBITED HSC ACTIVATION IN VIVO, AMELIORATED CARBON TETRACHLORIDE?INDUCED MOUSE LIVER FIBROSIS AND LOWERED PLASMA AMINOTRANSFERASES. TRANSCRIPTOMIC ANALYSIS REVEALED THE MOST SIGNIFICANTLY REGULATED GENES IN THE GIVINOSTAT TREATMENT GROUP IN COMPARISON WITH THOSE IN THE SOLVENT GROUP, AMONG WHICH, DERMOKINE (DMKN), MESOTHELIN (MSLN) AND UROPLAKIN?3B (UPK3B) WERE IDENTIFIED AS POTENTIAL REGULATORS OF HSC ACTIVATION. GIVINOSTAT SIGNIFICANTLY REDUCED THE MRNA EXPRESSION OF DMKN, MSLN AND UPK3B IN BOTH A MOUSE LIVER FIBROSIS MODEL AND IN HSC?LX2 CELLS. KNOCKDOWN OF ANY OF THE AFOREMENTIONED GENES INHIBITED THE TGF?BETA1?INDUCED EXPRESSION OF ALPHA?SMOOTH MUSCLE ACTIN AND COLLAGEN TYPE I, INDICATING THAT THEY ARE CRUCIAL FOR HSC ACTIVATION. IN SUMMARY, USING A NOVEL STRATEGY TARGETING HSC ACTIVATION, THE PRESENT STUDY IDENTIFIED A POTENTIAL EPIGENETIC DRUG FOR THE TREATMENT OF HEPATIC FIBROSIS AND REVEALED NOVEL REGULATORS OF HSC ACTIVATION. 2021 12 6079 21 THE EFFECT OF CXCL12 PROCESSING ON CD34+ CELL MIGRATION IN MYELOPROLIFERATIVE NEOPLASMS. PRIMARY MYELOFIBROSIS (PMF) AND POLYCYTHEMIA VERA (PV) ARE CHRONIC MYELOPROLIFERATIVE NEOPLASMS. PMF AND, TO A LESSER DEGREE, PV ARE CHARACTERIZED BY CONSTITUTIVE MOBILIZATION OF HEMATOPOIETIC STEM CELLS (HSC) AND PROGENITOR CELLS (HPC) INTO THE PERIPHERAL BLOOD (PB). THE INTERACTION BETWEEN THE CHEMOKINE CXCL12 AND ITS RECEPTOR CXCR4 PLAYS A PIVOTAL ROLE IN DETERMINING THE TRAFFICKING OF CD34(+) CELLS BETWEEN THE BONE MARROW (BM) AND THE PB. PMF, BUT NOT PV, IS ASSOCIATED WITH DOWNREGULATION OF CXCR4 BY CD34(+) CELLS DUE TO EPIGENETIC EVENTS. BOTH PV AND PMF PATIENTS HAVE ELEVATED LEVELS OF IMMUNOREACTIVE FORMS OF CXCL12 IN THE BM AND PB. USING ELECTROSPRAY MASS SPECTROMETRY, THE PB AND BM PLASMA OF PV AND PMF PATIENTS WAS SHOWN TO CONTAIN REDUCED AMOUNTS OF INTACT CXCL12 BUT SIGNIFICANT AMOUNTS OF SEVERAL TRUNCATED FORMS OF CXCL12, WHICH ARE LACKING IN NORMAL PB AND BM PLASMA. THESE TRUNCATED FORMS OF CXCL12 ARE THE PRODUCT OF THE ACTION OF SEVERAL SERINE PROTEASES, INCLUDING DIPEPTIDYL PEPTIDASE-IV, NEUTROPHIL ELASTASE, MATRIX METALLOPROTEINASE-2 (MMP-2), MMP-9, AND CATHEPSIN G. UNLIKE CXCL12, THESE TRUNCATES EITHER LACK THE ABILITY TO ACT AS A CHEMOATTRACTANT FOR CD34(+) CELLS AND/OR ACT AS AN ANTAGONIST TO THE ACTION OF CXCL12. THESE DATA SUGGEST THAT PROTEOLYTIC DEGRADATION OF CXCL12 IS CHARACTERISTIC OF BOTH PV AND PMF AND THAT THE RESULTING TRUNCATED FORMS OF CXCL12, IN ADDITION TO THE REDUCED EXPRESSION OF CXCR4 BY CD34(+) CELLS, LEAD TO A PROFOUND MOBILIZATION OF HSC/HPC IN PMF. 2010 13 3158 26 GLYCOGEN SYNTHASE KINASE 3BETA MISSPLICING CONTRIBUTES TO LEUKEMIA STEM CELL GENERATION. RECENT EVIDENCE SUGGESTS THAT A RARE POPULATION OF SELF-RENEWING CANCER STEM CELLS (CSC) IS RESPONSIBLE FOR CANCER PROGRESSION AND THERAPEUTIC RESISTANCE. CHRONIC MYELOID LEUKEMIA (CML) REPRESENTS AN IMPORTANT PARADIGM FOR UNDERSTANDING THE GENETIC AND EPIGENETIC EVENTS INVOLVED IN CSC PRODUCTION. CML PROGRESSES FROM A CHRONIC PHASE (CP) IN HEMATOPOIETIC STEM CELLS (HSC) THAT HARBOR THE BCR-ABL TRANSLOCATION, TO BLAST CRISIS (BC), CHARACTERIZED BY ABERRANT ACTIVATION OF BETA-CATENIN WITHIN GRANULOCYTE-MACROPHAGE PROGENITORS (GMP). A MAJOR BARRIER TO PREDICTING AND INHIBITING BLAST CRISIS TRANSFORMATION HAS BEEN THE IDENTIFICATION OF MECHANISMS DRIVING BETA-CATENIN ACTIVATION. HERE WE SHOW THAT BC CML MYELOID PROGENITORS, IN PARTICULAR GMP, SERIALLY TRANSPLANT LEUKEMIA IN IMMUNOCOMPROMISED MICE AND THUS ARE ENRICHED FOR LEUKEMIA STEM CELLS (LSC). NOTABLY, CDNA SEQUENCING OF WNT/BETA-CATENIN PATHWAY REGULATORY GENES, INCLUDING ADENOMATOUS POLYPOSIS COLI, GSK3BETA, AXIN 1, BETA-CATENIN, LYMPHOID ENHANCER FACTOR-1, CYCLIN D1, AND C-MYC, REVEALED A NOVEL IN-FRAME SPLICE DELETION OF THE GSK3BETA KINASE DOMAIN IN THE GMP OF BC SAMPLES THAT WAS NOT DETECTABLE BY SEQUENCING IN BLASTS OR NORMAL PROGENITORS. MOREOVER, BC CML PROGENITORS WITH MISSPLICED GSK3BETA HAVE ENHANCED BETA-CATENIN EXPRESSION AS WELL AS SERIAL ENGRAFTMENT POTENTIAL WHILE REINTRODUCTION OF FULL-LENGTH GSK3BETA REDUCES BOTH IN VITRO REPLATING AND LEUKEMIC ENGRAFTMENT. WE PROPOSE THAT CP CML IS INITIATED BY BCR-ABL EXPRESSION IN AN HSC CLONE BUT THAT PROGRESSION TO BC MAY INCLUDE MISSPLICING OF GSK3BETA IN GMP LSC, ENABLING UNPHOSPHORYLATED BETA-CATENIN TO PARTICIPATE IN LSC SELF-RENEWAL. MISSPLICING OF GSK3BETA REPRESENTS A UNIQUE MECHANISM FOR THE EMERGENCE OF BC CML LSC AND MIGHT PROVIDE A NOVEL DIAGNOSTIC AND THERAPEUTIC TARGET. 2009 14 98 29 A PROOF-OF-CONCEPT FOR EPIGENETIC THERAPY OF TISSUE FIBROSIS: INHIBITION OF LIVER FIBROSIS PROGRESSION BY 3-DEAZANEPLANOCIN A. THE PROGRESSION OF FIBROSIS IN CHRONIC LIVER DISEASE IS DEPENDENT UPON HEPATIC STELLATE CELLS (HSCS) TRANSDIFFERENTIATING TO A MYOFIBROBLAST-LIKE PHENOTYPE. THIS PIVOTAL PROCESS IS CONTROLLED BY ENZYMES THAT REGULATE HISTONE METHYLATION AND CHROMATIN STRUCTURE, WHICH MAY BE TARGETS FOR DEVELOPING ANTI-FIBROTICS. THERE IS LIMITED PRE-CLINICAL EXPERIMENTAL SUPPORT FOR THE POTENTIAL TO THERAPEUTICALLY MANIPULATE EPIGENETIC REGULATORS IN FIBROSIS. IN ORDER TO LEARN IF EPIGENETIC TREATMENT CAN HALT THE PROGRESSION OF PRE-ESTABLISHED LIVER FIBROSIS, WE TREATED MICE WITH THE HISTONE METHYLTRANSFERASE INHIBITOR 3-DEAZANEPLANOCIN A (DZNEP) IN A NAKED FORM OR BY SELECTIVELY TARGETING HSC-DERIVED MYOFIBROBLASTS VIA AN ANTIBODY-LIPOSOME-DZNEP TARGETING VEHICLE. WE DISCOVERED THAT DZNEP TREATMENT INHIBITED MULTIPLE HISTONE METHYLATION MODIFICATIONS, INDICATIVE OF A BROADER SPECIFICITY THAN PREVIOUSLY REPORTED. THIS BROAD EPIGENETIC REPRESSION WAS ASSOCIATED WITH THE SUPPRESSION OF FIBROSIS PROGRESSION AS ASSESSED BOTH HISTOLOGICALLY AND BIOCHEMICALLY. THE ANTI-FIBROTIC EFFECT OF DZNEP WAS REPRODUCED WHEN THE DRUG WAS SELECTIVELY TARGETED TO HSC-DERIVED MYOFIBROBLASTS. THEREFORE, THE IN VIVO MODULATION OF HSC HISTONE METHYLATION IS SUFFICIENT TO HALT PROGRESSION OF FIBROSIS IN THE CONTEXT OF CONTINUOUS LIVER DAMAGE. THIS DISCOVERY AND OUR NOVEL HSC-TARGETING VEHICLE, WHICH AVOIDS THE UNWANTED EFFECTS OF EPIGENETIC DRUGS ON PARENCHYMAL LIVER CELLS, REPRESENTS AN IMPORTANT PROOF-OF-CONCEPT FOR EPIGENETIC TREATMENT OF LIVER FIBROSIS. 2017 15 3702 22 INFLAMMATORY SIGNALING PATHWAYS IN PRELEUKEMIC AND LEUKEMIC STEM CELLS. HEMATOPOIETIC STEM CELLS (HSCS) ARE A RARE SUBSET OF BONE MARROW CELLS THAT USUALLY EXIST IN A QUIESCENT STATE, ONLY ENTERING THE CELL CYCLE TO REPLENISH THE BLOOD COMPARTMENT, THEREBY LIMITING THE POTENTIAL FOR ERRORS IN REPLICATION. INFLAMMATORY SIGNALS THAT ARE RELEASED IN RESPONSE TO ENVIRONMENTAL STRESSORS, SUCH AS INFECTION, TRIGGER ACTIVE CYCLING OF HSCS. THESE INFLAMMATORY SIGNALS CAN ALSO DIRECTLY INDUCE HSCS TO RELEASE CYTOKINES INTO THE BONE MARROW ENVIRONMENT, PROMOTING MYELOID DIFFERENTIATION. AFTER STRESS MYELOPOIESIS IS TRIGGERED, HSCS REQUIRE INTRACELLULAR SIGNALING PROGRAMS TO DEACTIVATE THIS RESPONSE AND RETURN TO STEADY STATE. PROLONGED OR EXCESSIVE EXPOSURE TO INFLAMMATORY CYTOKINES, SUCH AS IN PROLONGED INFECTION OR IN CHRONIC RHEUMATOLOGIC CONDITIONS, CAN LEAD TO CONTINUED HSC CYCLING AND EVENTUAL HSC LOSS. THIS PROMOTES BONE MARROW FAILURE, AND CAN PRECIPITATE PRELEUKEMIC STATES OR LEUKEMIA THROUGH THE ACQUISITION OF GENETIC AND EPIGENETIC CHANGES IN HSCS. THIS CAN OCCUR THROUGH THE INITIATION OF CLONAL HEMATOPOIESIS, FOLLOWED BY THE EMERGENCE PRELEUKEMIC STEM CELLS (PRE-LSCS). IN THIS REVIEW, WE DESCRIBE THE ROLES OF MULTIPLE INFLAMMATORY SIGNALING PATHWAYS IN THE GENERATION OF PRE-LSCS AND IN PROGRESSION TO MYELODYSPLASTIC SYNDROME (MDS), MYELOPROLIFERATIVE NEOPLASMS, AND ACUTE MYELOID LEUKEMIA (AML). IN AML, ACTIVATION OF SOME INFLAMMATORY SIGNALING PATHWAYS CAN PROMOTE THE CYCLING AND DIFFERENTIATION OF LSCS, AND THIS CAN BE EXPLOITED THERAPEUTICALLY. WE ALSO DISCUSS THE THERAPEUTIC POTENTIAL OF MODULATING INFLAMMATORY SIGNALING FOR THE TREATMENT OF MYELOID MALIGNANCIES. 2017 16 2545 31 EPIGENETICS IN LIVER FIBROSIS: COULD HDACS BE A THERAPEUTIC TARGET? CHRONIC LIVER DISEASES (CLD) REPRESENT A WORLDWIDE HEALTH PROBLEM. WHILE CLDS MAY HAVE DIVERSE ETIOLOGIES, A COMMON PATHOGENIC DENOMINATOR IS THE PRESENCE OF LIVER FIBROSIS. CIRRHOSIS, THE END-STAGE OF CLD, IS CHARACTERIZED BY EXTENSIVE FIBROSIS AND IS MARKEDLY ASSOCIATED WITH THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA. THE MOST IMPORTANT EVENT IN HEPATIC FIBROGENESIS IS THE ACTIVATION OF HEPATIC STELLATE CELLS (HSC) FOLLOWING LIVER INJURY. ACTIVATED HSCS ACQUIRE A MYOFIBROBLAST-LIKE PHENOTYPE BECOMING PROLIFERATIVE, FIBROGENIC, AND CONTRACTILE CELLS. WHILE TRANSIENT ACTIVATION OF HSCS IS PART OF THE PHYSIOLOGICAL MECHANISMS OF TISSUE REPAIR, PROTRACTED ACTIVATION OF A WOUND HEALING REACTION LEADS TO ORGAN FIBROSIS. THE PHENOTYPIC CHANGES OF ACTIVATED HSCS INVOLVE EPIGENETIC MECHANISMS MEDIATED BY NON-CODING RNAS (NCRNA) AS WELL AS BY CHANGES IN DNA METHYLATION AND HISTONE MODIFICATIONS. DURING CLD THESE EPIGENETIC MECHANISMS BECOME DEREGULATED, WITH ALTERATIONS IN THE EXPRESSION AND ACTIVITY OF EPIGENETIC MODULATORS. HERE WE PROVIDE AN OVERVIEW OF THE EPIGENETIC ALTERATIONS INVOLVED IN FIBROGENIC HSCS TRANSDIFFERENTIATION WITH PARTICULAR FOCUS ON HISTONES ACETYLATION CHANGES. WE ALSO DISCUSS RECENT STUDIES SUPPORTING THE PROMISING THERAPEUTIC POTENTIAL OF HISTONE DEACETYLASE INHIBITORS IN LIVER FIBROSIS. 2020 17 4838 21 ONCOGENIC N-RAS AND TET2 HAPLOINSUFFICIENCY COLLABORATE TO DYSREGULATE HEMATOPOIETIC STEM AND PROGENITOR CELLS. CONCURRENT GENETIC LESIONS EXIST IN A MAJORITY OF PATIENTS WITH HEMATOLOGIC MALIGNANCIES. AMONG THESE, SOMATIC MUTATIONS THAT ACTIVATE RAS ONCOGENES AND INACTIVATE THE EPIGENETIC MODIFIER TEN-ELEVEN TRANSLOCATION 2 (TET2) FREQUENTLY CO-OCCUR IN HUMAN CHRONIC MYELOMONOCYTIC LEUKEMIAS (CMMLS) AND ACUTE MYELOID LEUKEMIAS, SUGGESTING A COOPERATIVITY IN MALIGNANT TRANSFORMATION. TO TEST THIS, WE APPLIED A CONDITIONAL MURINE MODEL THAT ENDOGENOUSLY EXPRESSED ONCOGENIC NRAS(G12D) AND MONOALLELIC LOSS OF TET2 AND EXPLORED THE COLLABORATIVE ROLE SPECIFICALLY WITHIN HEMATOPOIETIC STEM AND PROGENITOR CELLS (HSPCS) AT DISEASE INITIATION. WE DEMONSTRATE THAT THE 2 MUTATIONS COLLABORATED TO ACCELERATE A TRANSPLANTABLE CMML-LIKE DISEASE IN VIVO, WITH AN OVERALL SHORTENED SURVIVAL AND INCREASED DISEASE PENETRANCE COMPARED WITH SINGLE MUTANTS. AT PRELEUKEMIC STAGE, N-RAS(G12D) AND TET2 HAPLOINSUFFICIENCY TOGETHER INDUCED BALANCED HEMATOPOIETIC STEM CELL (HSC) PROLIFERATION AND ENHANCED COMPETITIVENESS. NRAS(G12D/+)/TET2(+/-) HSCS DISPLAYED INCREASED SELF-RENEWAL IN PRIMARY AND SECONDARY TRANSPLANTATIONS, WITH SIGNIFICANTLY HIGHER RECONSTITUTION THAN SINGLE MUTANTS. STRIKINGLY, THE 2 MUTATIONS TOGETHER CONFERRED LONG-TERM RECONSTITUTION AND SELF-RENEWAL POTENTIAL TO MULTIPOTENT PROGENITORS, A POOL OF CELLS THAT USUALLY HAVE LIMITED SELF-RENEWAL COMPARED WITH HSCS. MOREOVER, HSPCS FROM NRAS(G12D/+)/TET2(+/-) MICE DISPLAYED INCREASED CYTOKINE SENSITIVITY IN RESPONSE TO THROMBOPOIETIN. THEREFORE, OUR STUDIES ESTABLISH A NOVEL TRACTABLE CMML MODEL AND PROVIDE INSIGHTS INTO HOW DYSREGULATED SIGNALING PATHWAYS AND EPIGENETIC MODIFIERS COLLABORATE TO MODULATE HSPC FUNCTION AND PROMOTE LEUKEMOGENESIS. 2018 18 2219 36 EPIGENETIC MODIFICATIONS IN HEPATIC STELLATE CELLS CONTRIBUTE TO LIVER FIBROSIS. LIVER FIBROSIS REPRESENTS THE FINAL COMMON PATHWAY OF VIRTUALLY ALL TYPES OF CHRONIC LIVER DISEASES, AND IT HAS BEEN A MAJOR PUBLIC HEALTH CONCERN. MANY GENES HAVE BEEN DEMONSTRATED TO BE INVOLVED IN THE PATHOGENESIS OF LIVER FIBROSIS, WHILE THE MECHANISMS UNDERLYING GENE REGULATION STILL NEEDS FURTHER RESEARCH. ON THE OTHER HAND, HEPATIC STELLATE CELLS (HSCS) ARE QUIESCENT CELLS IN THE PERISINUSOIDAL SPACE IN LIVER. HSCS FACILITATE HEPATOCYTES INTERACTIONS VIA RELEASING SOLUBLE INFLAMMATORY FACTORS AND PRODUCING EXTRACELLULAR MATRIX. HSCS CAN BE ACTIVATED IN RESPONSE TO LIVER INJURY, AND THEY DIFFERENTIATE TO MYOFIBROBLASTS, WHICH GREATLY CONTRIBUTE TO THE FIBROGENESIS PROCESS. VARIOUS EPIGENETIC PROCEDURES, INCLUDING DNA METHYLATION, HISTONE MODIFICATION AND FORMATION OF PARTICULAR CHROMATIN STRUCTURE, PLAY CRUCIAL ROLES IN THE GENE TRANSCRIPTIONAL EXPRESSION IN HSCS, REGULATING VARIOUS VITAL PROCESSES. FOR INSTANCE, EPIGENETIC MODULATION ON THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA (PPAR-GAMMA) GENE PROMOTER ACCOUNTS FOR HSC DIFFERENTIATION THROUGH INTERACTING PATHWAYS. ABERRANT EXPRESSION OF A SERIES OF HISTONES AND CHEMOKINES IN ACTIVATED HSCS CAN AGGRAVATE INFLAMMATION AND OXIDATIVE STRESS, WHICH IN TURN PROMOTES DIFFERENTIATION OF HSCS TO MYOFIBROBLASTS AND ENHANCES THE WHOLE FIBROGENESIS PROCESS. DEGRADATION OF EXTRACELLULAR MATRIX IS ALSO REGULATED THROUGH EPIGENETIC MODULATION ON MATRIX ASSOCIATED ENZYMES. MOREOVER, FIBROSIS-RELATED EPIGENETIC MODIFICATIONS IN THE PARENTAL GENERATION MAY BE INHERITED TO THEIR OFFSPRING. IN THIS REVIEW, WE FIRSTLY SUMMARIZE THE VITAL EPIGENETIC MODIFICATIONS OF FIBROSIS-RELATED GENES IN HSCS, AND HIGHLIGHT SPECIFIC NUCLEIC ACID SEQUENCES AND STRUCTURES IN GENE PROMOTERS AS IMPORTANT ACTION SITES, WHICH MAY PROVIDE INDICATORS FOR LIVER FIBROSIS DIAGNOSIS IN THE FUTURE. 2013 19 5953 18 TARGETS IN MPNS AND POTENTIAL THERAPEUTICS. PHILADELPHIA-NEGATIVE CLASSICAL MYELOPROLIFERATIVE NEOPLASMS (MPNS), INCLUDING POLYCYTHEMIA VERA (PV), ESSENTIAL THROMBOCYTHEMIA (ET) AND PRIMARY MYELOFIBROSIS (PMF), ARE CLONAL HEMOPATHIES THAT EMERGE IN THE HEMATOPOIETIC STEM CELL (HSC) COMPARTMENT. MPN DRIVER MUTATIONS ARE RESTRICTED TO SPECIFIC EXONS (14 AND 12) OF JANUS KINASE 2 (JAK2), THROMBOPOIETIN RECEPTOR (MPL/TPOR) AND CALRETICULIN (CALR) GENES, ARE INVOLVED DIRECTLY IN CLONAL MYELOPROLIFERATION AND GENERATE THE MPN PHENOTYPE. AS A RESULT, AN INCREASED NUMBER OF FULLY FUNCTIONAL ERYTHROCYTES, PLATELETS AND LEUKOCYTES IS OBSERVED IN THE PERIPHERAL BLOOD. NEVERTHELESS, THE COMPLEXITY AND HETEROGENEITY OF MPN CLINICAL PHENOTYPES CANNOT BE SOLELY EXPLAINED BY THE TYPE OF DRIVER MUTATION. OTHER FACTORS, SUCH AS ADDITIONAL SOMATIC MUTATIONS AFFECTING EPIGENETIC REGULATORS OR SPLICEOSOMES COMPONENTS, MUTANT ALLELE BURDENS AND MODIFIERS OF SIGNALING BY DRIVER MUTANTS, CLONAL ARCHITECTURE AND THE ORDER OF MUTATION ACQUISITION, SIGNALING EVENTS THAT OCCUR DOWNSTREAM OF A DRIVER MUTATION, THE PRESENCE OF SPECIFIC GERM-LINE VARIANTS, THE INTERACTION OF THE NEOPLASTIC CLONE WITH BONE MARROW MICROENVIRONMENT AND CHRONIC INFLAMMATION, ALL CAN MODULATE THE DISEASE PHENOTYPE, INFLUENCE THE MPN CLINICAL COURSE AND THEREFORE, MIGHT BE USEFUL THERAPEUTIC TARGETS. 2022 20 4448 30 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