1 81 100 A NEW TYPE OF DENTAL ANOMALY: MOLAR-INCISOR MALFORMATION (MIM). A MOLAR-INCISOR MALFORMATION (MIM) IS A NEWLY DISCOVERED TYPE OF DENTAL ANOMALY OF THE PERMANENT FIRST MOLARS, DECIDUOUS SECOND MOLARS, AND PERMANENT MAXILLARY CENTRAL INCISORS. MIM ANOMALIES OF THE PERMANENT FIRST MOLARS AND DECIDUOUS SECOND MOLARS MAY INCLUDE NORMAL CROWNS WITH A CONSTRICTED CERVICAL REGION AND THIN, NARROW, AND SHORT ROOTS, WHEREAS THE AFFECTED MAXILLARY CENTRAL INCISORS MAY EXHIBIT A HYPOPLASTIC ENAMEL NOTCH NEAR THE CERVICAL THIRD OF THE CLINICAL CROWN. ALTHOUGH THE ETIOLOGY OF MIM REMAINS TO BE DETERMINED, IT IS THOUGHT TO BE ATTRIBUTABLE TO AN EPIGENETIC FACTOR LINKED TO BRAIN- AND CENTRAL NERVOUS SYSTEM-RELATED SYSTEMIC DISEASES AT AROUND AGE 1 TO 2 YEARS. MIM TEETH ARE ASSOCIATED WITH CLINICAL PROBLEMS SUCH AS IMPACTION, EARLY EXFOLIATION, SPACE LOSS, SPONTANEOUS PAIN, PERIAPICAL ABSCESS, AND POOR INCISOR ESTHETICS. CHILDREN WITH MIM TEETH SHOULD BE OBSERVED CLOSELY WITH RESPECT TO THEIR MEDICAL HISTORY, AND DENTISTS SHOULD FORMULATE A WIDER-RANGING TREATMENT PLAN. 2014 2 1274 18 DACH1 PROTECTS PODOCYTES FROM EXPERIMENTAL DIABETIC INJURY AND MODULATES PTIP-H3K4ME3 ACTIVITY. DACHSHUND HOMOLOG 1 (DACH1), A KEY CELL-FATE DETERMINANT, REGULATES TRANSCRIPTION BY DNA SEQUENCE-SPECIFIC BINDING. WE IDENTIFIED DIMINISHED DACH1 EXPRESSION IN A LARGE-SCALE SCREEN FOR MUTATIONS THAT CONVERT INJURY-RESISTANT PODOCYTES INTO INJURY-SUSCEPTIBLE PODOCYTES. IN DIABETIC KIDNEY DISEASE (DKD) PATIENTS, PODOCYTE DACH1 EXPRESSION LEVELS ARE DIMINISHED, A CONDITION THAT STRONGLY CORRELATES WITH POOR CLINICAL OUTCOMES. GLOBAL DACH1 KO MICE MANIFEST RENAL HYPOPLASIA AND DIE PERINATALLY. PODOCYTE-SPECIFIC DACH1 KO MICE, HOWEVER, MAINTAIN NORMAL GLOMERULAR ARCHITECTURE AT BASELINE, BUT RAPIDLY EXHIBIT PODOCYTE INJURY AFTER DIABETES ONSET. FURTHERMORE, PODOCYTE-SPECIFIC AUGMENTATION OF DACH1 EXPRESSION IN MICE PROTECTS FROM DKD. COMBINED RNA SEQUENCING AND IN SILICO PROMOTER ANALYSIS REVEAL CONVERSELY OVERLAPPING GLOMERULAR TRANSCRIPTOMIC SIGNATURES BETWEEN PODOCYTE-SPECIFIC DACH1 AND PAX TRANSACTIVATION-DOMAIN INTERACTING PROTEIN (PTIP) KO MICE, WITH UPREGULATED GENES POSSESSING HIGHER-THAN-EXPECTED NUMBERS OF PROMOTER DACH1-BINDING SITES. PTIP, AN ESSENTIAL COMPONENT OF THE ACTIVATING HISTONE H3 LYSINE 4 TRIMETHYLATION (H3K4ME3) COMPLEX, INTERACTS WITH DACH1 AND IS RECRUITED BY DACH1 TO ITS PROMOTER-BINDING SITES. DACH1-PTIP RECRUITMENT REPRESSES TRANSCRIPTION AND REDUCES PROMOTER H3K4ME3 LEVELS. DACH1 KNOCKDOWN IN PODOCYTES COMBINED WITH HYPERGLYCEMIA TRIGGERS TARGET GENE UPREGULATION AND INCREASES PROMOTER H3K4ME3. THESE FINDINGS REVEAL THAT IN DKD, DIMINISHED DACH1 EXPRESSION ENHANCES PODOCYTE INJURY VULNERABILITY VIA EPIGENETIC DEREPRESSION OF ITS TARGET GENES. 2021 3 550 16 AUTOIMMUNE POLYENDOCRINOPATHY-CANDIDIASIS-ECTODERMAL DYSTROPHY IN TWO SIBLINGS: SAME MUTATIONS BUT VERY DIFFERENT PHENOTYPES. AUTOIMMUNE POLYENDOCRINOPATHY-CANDIDIASIS-ECTODERMAL DYSTROPHY (APECED), CAUSED BY MUTATIONS IN THE AIRE GENE, IS MAINLY CHARACTERIZED BY THE TRIAD OF HYPOPARATHYROIDISM, PRIMARY ADRENOCORTICAL INSUFFICIENCY AND CHRONIC MUCOCUTANEOUS CANDIDIASIS, BUT CAN INCLUDE MANY OTHER MANIFESTATIONS, WITH NO CURRENTLY CLEAR GENOTYPE-PHENOTYPE CORRELATION. WE PRESENT THE CLINICAL FEATURES OF TWO SIBLINGS, A MALE AND A FEMALE, WITH THE SAME MUTATIONS IN THE AIRE GENE ASSOCIATED WITH TWO VERY DIFFERENT PHENOTYPES. INTERESTINGLY, THE BROTHER RECENTLY EXPERIENCED COVID-19 INFECTION WITH PNEUMONIA, COMPLICATED BY HYPERTENSION, HYPOKALEMIA AND HYPERCALCEMIA. ALTHOUGH APECED IS A MONOGENIC DISEASE, ITS EXPRESSIVENESS CAN BE EXTREMELY DIFFERENT. IN ADDITION TO THE GENETIC BASIS, EPIGENETIC AND ENVIRONMENTAL FACTORS MIGHT INFLUENCE THE PHENOTYPIC EXPRESSION, ALTHOUGH THEIR EXACT ROLE REMAINS TO BE ELUCIDATED. 2021 4 595 13 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 5 5842 13 STRUCTURE OF HUMAN SP140 PHD FINGER: AN ATYPICAL FOLD INTERACTING WITH PIN1. SP140 IS A NUCLEAR LEUKOCYTE-SPECIFIC PROTEIN INVOLVED IN PRIMARY BILIARY CIRRHOSIS AND A RISK FACTOR IN CHRONIC LYMPHOCYTIC LEUKEMIA. THE PRESENCE OF SEVERAL CHROMATIN RELATED MODULES SUCH AS PLANT HOMEODOMAIN (PHD), BROMODOMAIN AND SAND DOMAIN SUGGESTS A ROLE IN CHROMATIN-MEDIATED REGULATION OF GENE EXPRESSION; HOWEVER, ITS REAL FUNCTION IS STILL ELUSIVE. HEREIN WE PRESENT THE SOLUTION STRUCTURE OF SP140-PHD FINGER AND INVESTIGATE ITS ROLE AS EPIGENETIC READER IN VITRO. SP140-PHD PRESENTS AN ATYPICAL PHD FINGER FOLD WHICH DOES NOT BIND TO HISTONE H3 TAILS BUT IS RECOGNIZED BY PEPTIDYLPROLYL ISOMERASE PIN1. PIN1 SPECIFICALLY BINDS TO A PHOSPHOPEPTIDE CORRESPONDING TO THE L3 LOOP OF SP140-PHD AND CATALYZES CIS-TRANS ISOMERIZATION OF A PTHR-PRO BOND. MOREOVER CO-IMMUNOPRECIPITATION EXPERIMENTS DEMONSTRATE FLAG-SP140 INTERACTION WITH ENDOGENOUS PIN1 IN VIVO. OVERALL THESE DATA INCLUDE SP140 IN THE LIST OF THE INCREASING NUMBER OF PIN1 BINDERS AND EXPAND THE REGULATORY POTENTIAL OF PHD FINGERS AS VERSATILE STRUCTURAL PLATFORMS FOR DIVERSIFIED INTERACTIONS. 2014 6 2245 16 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 7 5442 15 RENIN-ANGIOTENSIN BLOCKADE RESETS PODOCYTE EPIGENOME THROUGH KRUPPEL-LIKE FACTOR 4 AND ATTENUATES PROTEINURIA. PROTEINURIA IS A CENTRAL COMPONENT OF CHRONIC KIDNEY DISEASE AND AN INDEPENDENT RISK FACTOR FOR CARDIOVASCULAR DISEASE. KIDNEY PODOCYTES HAVE AN ESSENTIAL ROLE AS A FILTRATION BARRIER AGAINST PROTEINURIA. KRUPPEL-LIKE FACTOR 4 (KLF4) IS EXPRESSED IN PODOCYTES AND DECREASED IN GLOMERULAR DISEASES LEADING TO METHYLATION OF THE NEPHRIN PROMOTER, DECREASED NEPHRIN EXPRESSION AND PROTEINURIA. TREATMENT WITH AN ANGIOTENSIN RECEPTOR BLOCKER (ARB) REDUCED METHYLATION OF THE NEPHRIN PROMOTER IN MURINE GLOMERULI OF AN ADRIAMYCIN NEPHROPATHY MODEL WITH RECOVERY OF KLF4 EXPRESSION AND A DECREASE IN ALBUMINURIA. IN PODOCYTE-SPECIFIC KLF4 KNOCKOUT MICE, THE EFFECT OF ARB ON ALBUMINURIA AND THE NEPHRIN PROMOTER METHYLATION WAS ATTENUATED. IN CULTURED HUMAN PODOCYTES, ANGIOTENSIN II REDUCED KLF4 EXPRESSION AND CAUSED METHYLATION OF THE NEPHRIN PROMOTER WITH DECREASED NEPHRIN EXPRESSION. IN PATIENTS, NEPHRIN PROMOTER METHYLATION WAS INCREASED IN PROTEINURIC KIDNEY DISEASES WITH DECREASED KLF4 AND NEPHRIN EXPRESSION. KLF4 EXPRESSION IN ARB-TREATED PATIENTS WAS HIGHER IN PATIENTS WITH THAN WITHOUT ARB TREATMENT. THUS, ANGIOTENSIN II CAN MODULATE EPIGENETIC REGULATION IN PODOCYTES AND ARB INHIBITS THESE ACTIONS IN PART VIA KLF4 IN PROTEINURIC KIDNEY DISEASES. THIS STUDY PROVIDES A NEW CONCEPT THAT RENIN-ANGIOTENSIN SYSTEM BLOCKADE CAN EXERT THERAPEUTIC EFFECTS THROUGH EPIGENETIC MODULATION OF THE KIDNEY GENE EXPRESSION. 2015 8 4226 9 METHYLATION IN PERICYTES AFTER ACUTE INJURY PROMOTES CHRONIC KIDNEY DISEASE. THE ORIGIN AND FATE OF RENAL MYOFIBROBLASTS IS NOT CLEAR AFTER ACUTE KIDNEY INJURY (AKI). HERE, WE DEMONSTRATE THAT MYOFIBROBLASTS WERE ACTIVATED FROM QUIESCENT PERICYTES (QPERICYTES) AND THE CELL NUMBERS INCREASED AFTER ISCHEMIA/REPERFUSION INJURY-INDUCED AKI (IRI-AKI). MYOFIBROBLASTS UNDERWENT APOPTOSIS DURING RENAL RECOVERY BUT ONE-FIFTH OF THEM SURVIVED IN THE RECOVERED KIDNEYS ON DAY 28 AFTER IRI-AKI AND THEIR CELL NUMBERS INCREASED AGAIN AFTER DAY 56. MICROARRAY DATA SHOWED THE DISTINCTIVE GENE EXPRESSION PATTERNS OF QPERICYTES, ACTIVATED PERICYTES (APERICYTES, MYOFIBROBLASTS), AND INACTIVATED PERICYTES (IPERICYTES) ISOLATED FROM KIDNEYS BEFORE, ON DAY 7, AND ON DAY 28 AFTER IRI-AKI. HYPERMETHYLATION OF THE ACTA2 REPRESSOR YBX2 DURING IRI-AKI RESULTED IN EPIGENETIC MODIFICATION OF IPERICYTES TO PROMOTE THE TRANSITION TO CHRONIC KIDNEY DISEASE (CKD) AND AGGRAVATED FIBROGENESIS INDUCED BY A SECOND AKI INDUCED BY ADENINE. MECHANISTICALLY, TRANSFORMING GROWTH FACTOR-BETA1 DECREASED THE BINDING OF YBX2 TO THE PROMOTER OF ACTA2 AND INDUCED YBX2 HYPERMETHYLATION, THEREBY INCREASING ALPHA-SMOOTH MUSCLE ACTIN EXPRESSION IN APERICYTES. DEMETHYLATION BY 5-AZACYTIDINE RECOVERED THE MICROVASCULAR STABILIZING FUNCTION OF APERICYTES, REVERSED THE PROFIBROTIC PROPERTY OF IPERICYTES, PREVENTED AKI-CKD TRANSITION, AND ATTENUATED FIBROGENESIS INDUCED BY A SECOND ADENINE-AKI. IN CONCLUSION, INTERVENTION TO ERASE HYPERMETHYLATION OF PERICYTES AFTER AKI PROVIDES A STRATEGY TO STOP THE TRANSITION TO CKD. 2020 9 2867 17 FUNCTIONAL AND CANCER GENOMICS OF ASXL FAMILY MEMBERS. ADDITIONAL SEX COMBS-LIKE (ASXL)1, ASXL2 AND ASXL3 ARE HUMAN HOMOLOGUES OF THE DROSOPHILA ASX GENE THAT ARE INVOLVED IN THE REGULATION OR RECRUITMENT OF THE POLYCOMB-GROUP REPRESSOR COMPLEX (PRC) AND TRITHORAX-GROUP (TRXG) ACTIVATOR COMPLEX. ASXL PROTEINS CONSIST OF ASXN, ASXH, ASXM1, ASXM2 AND PHD DOMAINS. ASXL1 DIRECTLY INTERACTS WITH BAP1, KDM1A (LSD1), NCOA1 AND NUCLEAR HORMONE RECEPTORS (NHRS), SUCH AS RETINOIC ACID RECEPTORS, OESTROGEN RECEPTOR AND ANDROGEN RECEPTOR. ASXL FAMILY MEMBERS ARE EPIGENETIC SCAFFOLDING PROTEINS THAT ASSEMBLE EPIGENETIC REGULATORS AND TRANSCRIPTION FACTORS TO SPECIFIC GENOMIC LOCI WITH HISTONE MODIFICATIONS. ASXL1 IS INVOLVED IN TRANSCRIPTIONAL REPRESSION THROUGH AN INTERACTION WITH PRC2 AND ALSO CONTRIBUTES TO TRANSCRIPTIONAL REGULATION THROUGH INTERACTIONS WITH BAP1 AND/OR NHR COMPLEXES. GERM-LINE MUTATIONS OF HUMAN ASXL1 AND ASXL3 OCCUR IN BOHRING-OPITZ AND RELATED SYNDROMES. AMPLIFICATION AND OVEREXPRESSION OF ASXL1 OCCUR IN CERVICAL CANCER. TRUNCATION MUTATIONS OF ASXL1 OCCUR IN COLORECTAL CANCERS WITH MICROSATELLITE INSTABILITY (MSI), MALIGNANT MYELOID DISEASES, CHRONIC LYMPHOCYTIC LEUKAEMIA, HEAD AND NECK SQUAMOUS CELL CARCINOMA, AND LIVER, PROSTATE AND BREAST CANCERS; THOSE OF ASXL2 OCCUR IN PROSTATE CANCER, PANCREATIC CANCER AND BREAST CANCER AND THOSE OF ASXL3 ARE OBSERVED IN MELANOMA. EPC1-ASXL2 GENE FUSION OCCURS IN ADULT T-CELL LEUKAEMIA/LYMPHOMA. THE PROGNOSIS OF MYELOID MALIGNANCIES WITH MISREGULATING TRUNCATION MUTATIONS OF ASXL1 IS POOR. ASXL FAMILY MEMBERS ARE ASSUMED TO BE TUMOUR SUPPRESSIVE OR ONCOGENIC IN A CONTEXT-DEPENDENT MANNER. 2013 10 4143 17 MECHANISMS OF SCARRING IN FOCAL SEGMENTAL GLOMERULOSCLEROSIS. FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS) PRESENTS WITH SCAR IN PARTS OF SOME GLOMERULI AND OFTEN PROGRESSES TO GLOBAL AND DIFFUSE GLOMERULOSCLEROSIS. PODOCYTE INJURY IS THE INITIAL TARGET IN PRIMARY FSGS, INDUCED BY A CIRCULATING FACTOR. SEVERAL GENE VARIANTS, FOR EXAMPLE, APOL1, ARE ASSOCIATED WITH INCREASED SUSCEPTIBILITY TO FSGS. PRIMARY FSGS MAY BE DUE TO GENETIC MUTATION IN KEY PODOCYTE GENES. INCREASED WORK STRESS AFTER LOSS OF NEPHRONS, EPIGENETIC MECHANISMS, AND VARIOUS PROFIBROTIC PATHWAYS CAN CONTRIBUTE TO PROGRESSIVE SCLEROSIS, REGARDLESS OF THE INITIAL INJURY. THE PROGRESSION OF FSGS LESIONS ALSO INVOLVES CROSSTALK BETWEEN PODOCYTES AND OTHER KIDNEY CELLS, SUCH AS PARIETAL EPITHELIAL CELLS, GLOMERULAR ENDOTHELIAL CELLS, AND EVEN TUBULAR EPITHELIAL CELLS. NEW INSIGHTS RELATED TO THESE MECHANISMS COULD POTENTIALLY LEAD TO NEW THERAPEUTIC STRATEGIES TO PREVENT PROGRESSION OF FSGS. 2019 11 4005 11 LOSS OF THE TUMOR SUPPRESSOR BAP1 CAUSES MYELOID TRANSFORMATION. DE-UBIQUITINATING ENZYME BAP1 IS MUTATED IN A HEREDITARY CANCER SYNDROME WITH INCREASED RISK OF MESOTHELIOMA AND UVEAL MELANOMA. SOMATIC BAP1 MUTATIONS OCCUR IN VARIOUS MALIGNANCIES. WE SHOW THAT MOUSE BAP1 GENE DELETION IS LETHAL DURING EMBRYOGENESIS, BUT SYSTEMIC OR HEMATOPOIETIC-RESTRICTED DELETION IN ADULTS RECAPITULATES FEATURES OF HUMAN MYELODYSPLASTIC SYNDROME (MDS). KNOCKIN MICE EXPRESSING BAP1 WITH A 3XFLAG TAG REVEALED THAT BAP1 INTERACTS WITH HOST CELL FACTOR-1 (HCF-1), O-LINKED N-ACETYLGLUCOSAMINE TRANSFERASE (OGT), AND THE POLYCOMB GROUP PROTEINS ASXL1 AND ASXL2 IN VIVO. OGT AND HCF-1 LEVELS WERE DECREASED BY BAP1 DELETION, INDICATING A CRITICAL ROLE FOR BAP1 IN STABILIZING THESE EPIGENETIC REGULATORS. HUMAN ASXL1 IS MUTATED FREQUENTLY IN CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) SO AN ASXL/BAP1 COMPLEX MAY SUPPRESS CMML. A BAP1 CATALYTIC MUTATION FOUND IN A MDS PATIENT IMPLIES THAT BAP1 LOSS OF FUNCTION HAS SIMILAR CONSEQUENCES IN MICE AND HUMANS. 2012 12 5228 17 PRMT7 TARGETS OF FOXM1 CONTROLS ALVEOLAR MYOFIBROBLAST PROLIFERATION AND DIFFERENTIATION DURING ALVEOLOGENESIS. ALTHOUGH ABERRANT ALVEOLAR MYOFIBROBLASTS (AMYFS) PROLIFERATION AND DIFFERENTIATION ARE OFTEN ASSOCIATED WITH ABNORMAL LUNG DEVELOPMENT AND DISEASES, SUCH AS BRONCHOPULMONARY DYSPLASIA (BPD), CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), AND IDIOPATHIC PULMONARY FIBROSIS (IPF), EPIGENETIC MECHANISMS REGULATING PROLIFERATION AND DIFFERENTIATION OF AMYFS REMAIN POORLY UNDERSTOOD. PROTEIN ARGININE METHYLTRANSFERASE 7 (PRMT7) IS THE ONLY REPORTED TYPE III ENZYME RESPONSIBLE FOR MONOMETHYLATION OF ARGININE RESIDUE ON BOTH HISTONE AND NONHISTONE SUBSTRATES. HERE WE PROVIDE EVIDENCE FOR PRMT7'S FUNCTION IN REGULATING AMYFS PROLIFERATION AND DIFFERENTIATION DURING LUNG ALVEOLOGENESIS. IN PRMT7-DEFICIENT MICE, WE FOUND REDUCED AMYFS PROLIFERATION AND DIFFERENTIATION, ABNORMAL ELASTIN DEPOSITION, AND FAILURE OF ALVEOLAR SEPTUM FORMATION. WE FURTHER SHOWN THAT ONCOGENE FORKHEAD BOX M1 (FOXM1) IS A DIRECT TARGET OF PRMT7 AND THAT PRMT7-CATALYZED MONOMETHYLATION AT HISTONE H4 ARGININE 3 (H4R3ME1) DIRECTLY ASSOCIATE WITH CHROMATIN OF FOXM1 TO ACTIVATE ITS TRANSCRIPTION, AND THEREBY REGULATE OF CELL CYCLE-RELATED GENES TO INHIBIT AMYFS PROLIFERATION AND DIFFERENTIATION. OVEREXPRESSION OF FOXM1 IN ISOLATED MYOFIBROBLASTS (MYFS) SIGNIFICANTLY RESCUED PRMT7-DEFICIENCY-INDUCED CELL PROLIFERATION AND DIFFERENTIATION DEFECTS. THUS, OUR RESULTS REVEAL A NOVEL EPIGENETIC MECHANISM THROUGH WHICH PRMT7-MEDIATED HISTONE ARGININE MONOMETHYLATION ACTIVATES FOXM1 TRANSCRIPTIONAL EXPRESSION TO REGULATE AMYFS PROLIFERATION AND DIFFERENTIATION DURING LUNG ALVEOLOGENESIS AND MAY REPRESENT A POTENTIAL TARGET FOR INTERVENTION IN PULMONARY DISEASES. 2021 13 370 18 AN APICOMPLEXAN BROMODOMAIN PROTEIN, TGBDP1, ASSOCIATES WITH DIVERSE EPIGENETIC FACTORS TO REGULATE ESSENTIAL TRANSCRIPTIONAL PROCESSES IN TOXOPLASMA GONDII. THE PROTOZOAN PATHOGEN TOXOPLASMA GONDII RELIES ON TIGHT REGULATION OF GENE EXPRESSION TO INVADE AND ESTABLISH INFECTION IN ITS HOST. THE DIVERGENT GENE REGULATORY MECHANISMS OF TOXOPLASMA AND RELATED APICOMPLEXAN PATHOGENS RELY HEAVILY ON REGULATORS OF CHROMATIN STRUCTURE AND HISTONE MODIFICATIONS. THE IMPORTANT CONTRIBUTION OF HISTONE ACETYLATION FOR TOXOPLASMA IN BOTH ACUTE AND CHRONIC INFECTION HAS BEEN DEMONSTRATED, WHERE HISTONE ACETYLATION INCREASES AT ACTIVE GENE LOCI. HOWEVER, THE DIRECT CONSEQUENCES OF SPECIFIC HISTONE ACETYLATION MARKS AND THE CHROMATIN PATHWAY THAT INFLUENCES TRANSCRIPTIONAL REGULATION IN RESPONSE TO THE MODIFICATION ARE UNCLEAR. AS A READER OF LYSINE ACETYLATION, THE BROMODOMAIN SERVES AS A MEDIATOR BETWEEN THE ACETYLATED HISTONE AND TRANSCRIPTIONAL REGULATORS. HERE WE SHOW THAT THE BROMODOMAIN PROTEIN, TGBDP1, WHICH IS CONSERVED AMONG APICOMPLEXA AND WITHIN THE ALVEOLATA SUPERPHYLUM, IS ESSENTIAL FOR TOXOPLASMA ASEXUAL PROLIFERATION. USING CLEAVAGE UNDER TARGETS AND TAGMENTATION, WE DEMONSTRATE THAT TGBDP1 IS RECRUITED TO TRANSCRIPTIONAL START SITES OF A LARGE PROPORTION OF PARASITE GENES. TRANSCRIPTIONAL PROFILING DURING TGBDP1 KNOCKDOWN REVEALED THAT LOSS OF TGBDP1 LEADS TO MAJOR DYSREGULATION OF GENE EXPRESSION, IMPLYING MULTIPLE ROLES FOR TGBDP1 IN BOTH GENE ACTIVATION AND REPRESSION. THIS IS SUPPORTED BY INTERACTOME ANALYSIS OF TGBDP1 DEMONSTRATING THAT TGBDP1 FORMS A CORE COMPLEX WITH TWO OTHER BROMODOMAIN PROTEINS AND AN APIAP2 FACTOR. THIS CORE COMPLEX APPEARS TO INTERACT WITH OTHER EPIGENETIC FACTORS SUCH AS NUCLEOSOME REMODELING COMPLEXES. WE CONCLUDE THAT TGBDP1 INTERACTS WITH DIVERSE EPIGENETIC REGULATORS TO EXERT OPPOSING INFLUENCES ON GENE EXPRESSION IN THE TOXOPLASMA TACHYZOITE. IMPORTANCE HISTONE ACETYLATION IS CRITICAL FOR PROPER REGULATION OF GENE EXPRESSION IN THE SINGLE-CELLED EUKARYOTIC PATHOGEN TOXOPLASMA GONDII. BROMODOMAIN PROTEINS ARE "READERS" OF HISTONE ACETYLATION AND MAY LINK THE MODIFIED CHROMATIN TO TRANSCRIPTION FACTORS. HERE, WE SHOW THAT THE BROMODOMAIN PROTEIN TGBDP1 IS ESSENTIAL FOR PARASITE SURVIVAL AND THAT LOSS OF TGBDP1 RESULTS IN GLOBAL DYSREGULATION OF GENE EXPRESSION. TGBDP1 IS RECRUITED TO THE PROMOTER REGION OF A LARGE PROPORTION OF PARASITE GENES, FORMS A CORE COMPLEX WITH TWO OTHER BROMODOMAIN PROTEINS, AND INTERACTS WITH DIFFERENT TRANSCRIPTIONAL REGULATORY COMPLEXES. WE CONCLUDE THAT TGBDP1 IS A KEY FACTOR FOR SENSING SPECIFIC HISTONE MODIFICATIONS TO INFLUENCE MULTIPLE FACETS OF TRANSCRIPTIONAL REGULATION IN TOXOPLASMA GONDII. 2023 14 385 13 AN IMMORTALIZED CELL LINE DERIVED FROM RENAL ERYTHROPOIETIN-PRODUCING (REP) CELLS DEMONSTRATES THEIR POTENTIAL TO TRANSFORM INTO MYOFIBROBLASTS. THE ERYTHROID GROWTH FACTOR ERYTHROPOIETIN (EPO) IS PRODUCED BY RENAL INTERSTITIAL FIBROBLASTS, CALLED REP (RENAL EPO-PRODUCING) CELLS, IN A HYPOXIA-INDUCIBLE MANNER. IN CHRONIC KIDNEY DISEASE (CKD), REP CELLS LOSE THEIR EPO-PRODUCTION ABILITY, LEADING TO RENAL ANAEMIA. CONCURRENTLY, REP CELLS ARE SUGGESTED TO BE TRANSFORMED INTO MYOFIBROBLASTS, WHICH ARE THE MAJOR PLAYER OF RENAL FIBROSIS. ALTHOUGH ESTABLISHMENT OF CULTURED CELL LINES DERIVED FROM REP CELLS HAS BEEN A LONG-TERM CHALLENGE, WE HERE SUCCESSFULLY ESTABLISHED A REP-CELL-DERIVED IMMORTALIZED AND CULTIVABLE CELL LINE (REPLIC CELLS) BY USING A GENETICALLY MODIFIED MOUSE LINE. REPLIC CELLS EXHIBITED MYOFIBROBLASTIC PHENOTYPES AND LOST THEIR EPO-PRODUCTION ABILITY, REFLECTING THE SITUATION IN RENAL FIBROSIS. ADDITIONALLY, WE FOUND THAT CELL-AUTONOMOUS TGFBETA SIGNALLING CONTRIBUTES TO MAINTENANCE OF THE MYOFIBROBLASTIC FEATURES OF REPLIC CELLS. FURTHERMORE, THE PROMOTERS OF GENES FOR EPO AND HIF2ALPHA, A MAJOR ACTIVATOR OF EPO GENE EXPRESSION, WERE HIGHLY METHYLATED IN REPLIC CELLS. THUS, THESE RESULTS STRONGLY SUPPORT OUR CONTENTION THAT REP CELLS ARE THE ORIGIN OF MYOFIBROBLASTS IN FIBROTIC KIDNEYS AND DEMONSTRATE THAT CELL-AUTONOMOUS TGFBETA SIGNALLING AND EPIGENETIC SILENCING ARE INVOLVED IN RENAL FIBROSIS AND RENAL ANAEMIA, RESPECTIVELY, IN CKD. THE REPLIC CELL LINE IS A USEFUL TOOL TO FURTHER INVESTIGATE THE MOLECULAR MECHANISMS UNDERLYING RENAL FIBROSIS. 2019 15 4867 12 OSSIFYING FIBROMA TUMOR STEM CELLS ARE MAINTAINED BY EPIGENETIC REGULATION OF A TSP1/TGF-BETA/SMAD3 AUTOCRINE LOOP. ABNORMAL STEM CELL FUNCTION MAKES A KNOWN CONTRIBUTION TO MANY MALIGNANT TUMORS, BUT THE ROLE OF STEM CELLS IN BENIGN TUMORS IS NOT WELL UNDERSTOOD. HERE, WE SHOW THAT OSSIFYING FIBROMA (OF) CONTAINS A STEM CELL POPULATION THAT RESEMBLES MESENCHYMAL STEM CELLS (OFMSCS) AND IS CAPABLE OF GENERATING OF-LIKE TUMOR XENOGRAFTS. MECHANISTICALLY, OFMSCS SHOW ENHANCED TGF-BETA SIGNALING THAT INDUCES ABERRANT PROLIFERATION AND DEFICIENT OSTEOGENESIS VIA NOTCH AND BMP SIGNALING PATHWAYS, RESPECTIVELY. THE ELEVATED TGF-BETA ACTIVITY IS TIGHTLY REGULATED BY JHDM1D-MEDIATED EPIGENETIC REGULATION OF THROMBOSPONDIN-1 (TSP1), FORMING A JHDM1D/TSP1/TGF-BETA/SMAD3 AUTOCRINE LOOP. INHIBITION OF TGF-BETA SIGNALING IN OFMSCS CAN RESCUE THEIR ABNORMAL OSTEOGENIC DIFFERENTIATION AND ELEVATED PROLIFERATION RATE. FURTHERMORE, CHRONIC ACTIVATION OF TGF-BETA CAN CONVERT NORMAL MSCS INTO OF-LIKE MSCS VIA ESTABLISHMENT OF THIS JHDM1D/TSP1/TGF-BETA/SMAD3 AUTOCRINE LOOP. THESE RESULTS REVEAL THAT EPIGENETIC REGULATION OF TGF-BETA SIGNALING IN MSCS GOVERNS THE BENIGN TUMOR PHENOTYPE IN OF AND HIGHLIGHT TGF-BETA SIGNALING AS A CANDIDATE THERAPEUTIC TARGET. 2013 16 5504 19 RHEIN REVERSAL OF DNA HYPERMETHYLATION-ASSOCIATED KLOTHO SUPPRESSION AMELIORATES RENAL FIBROSIS IN MICE. RENAL FIBROSIS IS THE HALLMARK OF CHRONIC KIDNEY DISEASES (CKD) AND ITS DEVELOPMENT AND PROGRESSION ARE SIGNIFICANTLY AFFECTED BY EPIGENETIC MODIFICATIONS. RHEIN, A PLANT-DERIVED ANTHRAQUINONE, DISPLAYS STRONG ANTI-FIBROSIS PROPERTIES, BUT ITS PROTECTIVE MODE OF ACTION REMAINS INCOMPLETELY UNDERSTOOD. HERE WE EXPLORE THE MECHANISM OF RHEIN ANTI-RENAL FIBROSIS BY INVESTIGATING ITS REGULATION OF KLOTHO, A KNOWN RENAL ANTI-FIBROTIC PROTEIN WHOSE SUPPRESSION AFTER RENAL INJURY REPORTEDLY INVOLVES ABERRANT DNA METHYLATION. WE REPORT THAT RHEIN IS AN IMPRESSIVE UP-REGULATOR OF KLOTHO AND IT MARKEDLY REVERSED KLOTHO DOWN-REGULATION IN UNILATERAL URETERAL OCCLUSION-INDUCED FIBROTIC KIDNEY. FURTHER EXAMINATIONS REVEALED THAT KLOTHO LOSS IN FIBROTIC KIDNEY IS ASSOCIATED WITH KLOTHO PROMOTER HYPERMETHYLATION DUE TO ABERRANT METHYLTRANSFERASE 1 AND 3A EXPRESSIONS. HOWEVER, RHEIN SIGNIFICANTLY CORRECTED ALL THESE EPIGENETIC ALTERATIONS AND SUBSEQUENTLY ALLEVIATED PRO-FIBROTIC PROTEIN EXPRESSION AND RENAL FIBROSIS, WHEREAS KLOTHO KNOCKDOWN VIA RNA INTERFERENCES LARGELY ABROGATED THE ANTI-RENAL FIBROTIC EFFECTS OF RHEIN, SUGGESTING THAT RHEIN EPIGENETIC REVERSAL OF KLOTHO LOSS REPRESENTS A CRITICAL MODE OF ACTION THAT CONFERS RHEIN'S ANTI- RENAL FIBROTIC FUNCTIONS. ALTOGETHER OUR STUDIES UNCOVER A NOVEL HYPOMETHYLATING CHARACTER OF RHEIN IN PREVENTING KLOTHO LOSS AND RENAL FIBROSIS, AND DEMONSTRATE THE EFFICACY OF KLOTHO-TARGETED EPIGENETIC INTERVENTION IN POTENTIAL TREATMENT OF RENAL FIBROSIS-ASSOCIATED KIDNEY DISEASES. 2016 17 1305 13 DEFICIENT H2A.Z DEPOSITION IS ASSOCIATED WITH GENESIS OF UTERINE LEIOMYOMA. ONE IN FOUR WOMEN SUFFERS FROM UTERINE LEIOMYOMAS (ULS)-BENIGN TUMOURS OF THE UTERINE WALL, ALSO KNOWN AS UTERINE FIBROIDS-AT SOME POINT IN PREMENOPAUSAL LIFE. ULS CAN CAUSE EXCESSIVE BLEEDING, PAIN AND INFERTILITY(1), AND ARE A COMMON CAUSE OF HYSTERECTOMY(2). THEY EMERGE THROUGH AT LEAST THREE DISTINCT GENETIC DRIVERS: MUTATIONS IN MED12 OR FH, OR GENOMIC REARRANGEMENT OF HMGA2(3). HERE WE CREATED GENOME-WIDE DATASETS, USING DNA, RNA, ASSAY FOR TRANSPOSASE-ACCESSIBLE CHROMATIN (ATAC), CHROMATIN IMMUNOPRECIPITATION (CHIP) AND HIC CHROMATIN IMMUNOPRECIPITATION (HICHIP) SEQUENCING OF PRIMARY TISSUES TO PROFOUNDLY UNDERSTAND THE GENESIS OF UL. WE IDENTIFIED SOMATIC MUTATIONS IN GENES ENCODING SIX MEMBERS OF THE SRCAP HISTONE-LOADING COMPLEX(4), AND FOUND THAT GERMLINE MUTATIONS IN THE SRCAP MEMBERS YEATS4 AND ZNHIT1 PREDISPOSE WOMEN TO UL. TUMOURS BEARING THESE MUTATIONS SHOWED DEFECTIVE DEPOSITION OF THE HISTONE VARIANT H2A.Z. IN ULS, H2A.Z OCCUPANCY CORRELATED POSITIVELY WITH CHROMATIN ACCESSIBILITY AND GENE EXPRESSION, AND NEGATIVELY WITH DNA METHYLATION, BUT THESE CORRELATIONS WERE WEAK IN TUMOURS BEARING SRCAP COMPLEX MUTATIONS. IN THESE TUMOURS, OPEN CHROMATIN EMERGED AT TRANSCRIPTION START SITES WHERE H2A.Z WAS LOST, WHICH WAS ASSOCIATED WITH UPREGULATION OF GENES. FURTHERMORE, YEATS4 DEFECTS WERE ASSOCIATED WITH ABNORMAL UPREGULATION OF BIVALENT EMBRYONIC STEM CELL GENES, AS PREVIOUSLY SHOWN IN MICE(5). OUR WORK DESCRIBES A POTENTIAL MECHANISM OF TUMORIGENESIS-EPIGENETIC INSTABILITY CAUSED BY DEFICIENT H2A.Z DEPOSITION-AND SUGGESTS THAT ULS ARISE THROUGH AN ABERRANT DIFFERENTIATION PROGRAM DRIVEN BY DERANGED CHROMATIN, EMANATING FROM A SMALL NUMBER OF MUTUALLY EXCLUSIVE DRIVER MUTATIONS. 2021 18 3157 13 GLYCEMIC MEMORY. PURPOSE OF REVIEW: THE MISTAKE OF PREDICTING THE FUTURE IS PERHAPS NOT TENDING TO REPRESSED OR PAST MEMORIES. HAMLET'S 17TH-CENTURY SOLILOQUY 'THE HEARTACHE AND THE THOUSAND NATURAL SHOCKS, THAT FLESH IS HEIR TO', (3.1. 7-8) IS A TALE THAT LOOKS BEYOND THE PRESENT BY LINKING THE PAST WITH THE FUTURE. THE PRESENT ARTICLE EXAMINES THE RESURGENCE IN THE FIELD TO UNDERSTAND GENE-REGULATING EPIGENETIC CHANGES CONFERRING GLYCEMIC MEMORY. RECENT FINDINGS: CHROMATIN MODIFICATIONS ARE CRITICAL IN REGULATING GENOME STRUCTURE AND FUNCTION AND DESPITE THE SIGNIFICANT ADVANCES OF RECENT YEARS IN IDENTIFYING THE ENZYMES-MEDIATING CHEMICAL CHANGES TO HISTONE TAILS AND THE DNA TEMPLATE, THE PRECISE REGULATION OF GENE EXPRESSION REMAINS INCOMPLETE IN MODELS OF HEALTH AND DIABETIC COMPLICATIONS. SUMMARY: DISPELLING THE MYTH THAT ALL GENOMES ARE DRIVEN AND RESPOND EQUALLY, EXPERIMENTAL RESEARCH IS NOW UNCOVERING THE FUNCTION OF ENZYMES CONFERRING CHROMATIN MODIFICATIONS. WHATEVER THE ROLE OF THE EPIGENOME, SHOWING ITS INVOLVEMENT IN GLYCEMIC SIGNALING IS THE FIRST STEP TO NEW STRATEGIES AND TARGETS TO DEVELOP THERAPIES THAT PREVENT, RETARD OR REVERSE THE LONG-TERM DELETERIOUS END-ORGAN EFFECTS OF CHRONIC, INTERMITTENT AND PRIOR HYPERGLYCEMIA. 2012 19 5675 12 SHIFTS IN PODOCYTE HISTONE H3K27ME3 REGULATE MOUSE AND HUMAN GLOMERULAR DISEASE. HISTONE PROTEIN MODIFICATIONS CONTROL FATE DETERMINATION DURING NORMAL DEVELOPMENT AND DEDIFFERENTIATION DURING DISEASE. HERE, WE SET OUT TO DETERMINE THE EXTENT TO WHICH DYNAMIC CHANGES TO HISTONES AFFECT THE DIFFERENTIATED PHENOTYPE OF ORDINARILY QUIESCENT ADULT GLOMERULAR PODOCYTES. TO DO THIS, WE EXAMINED THE CONSEQUENCES OF SHIFTING THE BALANCE OF THE REPRESSIVE HISTONE H3 LYSINE 27 TRIMETHYLATION (H3K27ME3) MARK IN PODOCYTES. ADRIAMYCIN NEPHROTOXICITY AND SUBTOTAL NEPHRECTOMY (SNX) STUDIES INDICATED THAT DELETION OF THE HISTONE METHYLATING ENZYME EZH2 FROM PODOCYTES DECREASED H3K27ME3 LEVELS AND SENSITIZED MICE TO GLOMERULAR DISEASE. H3K27ME3 WAS ENRICHED AT THE PROMOTER REGION OF THE NOTCH LIGAND JAG1 IN PODOCYTES, AND DEREPRESSION OF JAG1 BY EZH2 INHIBITION OR KNOCKDOWN FACILITATED PODOCYTE DEDIFFERENTIATION. CONVERSELY, INHIBITION OF THE JUMONJI C DOMAIN-CONTAINING DEMETHYLASES JMJD3 AND UTX INCREASED THE H3K27ME3 CONTENT OF PODOCYTES AND ATTENUATED GLOMERULAR DISEASE IN ADRIAMYCIN NEPHROTOXICITY, SNX, AND DIABETES. PODOCYTES IN GLOMERULI FROM HUMANS WITH FOCAL SEGMENTAL GLOMERULOSCLEROSIS OR DIABETIC NEPHROPATHY EXHIBITED DIMINISHED H3K27ME3 AND HEIGHTENED UTX CONTENT. ANALOGOUS TO HUMAN DISEASE, INHIBITION OF JMJD3 AND UTX ABATED NEPHROPATHY PROGRESSION IN MICE WITH ESTABLISHED GLOMERULAR INJURY AND REDUCED H3K27ME3 LEVELS. TOGETHER, THESE FINDINGS INDICATE THAT OSTENSIBLY STABLE CHROMATIN MODIFICATIONS CAN BE DYNAMICALLY REGULATED IN QUIESCENT CELLS AND THAT EPIGENETIC REPROGRAMMING CAN IMPROVE OUTCOMES IN GLOMERULAR DISEASE BY REPRESSING THE REACTIVATION OF DEVELOPMENTAL PATHWAYS. 2018 20 216 14 ACUTE BETA-ADRENERGIC ACTIVATION TRIGGERS NUCLEAR IMPORT OF HISTONE DEACETYLASE 5 AND DELAYS G(Q)-INDUCED TRANSCRIPTIONAL ACTIVATION. DURING HEMODYNAMIC STRESS, CATECHOLAMINES AND NEUROHUMORAL STIMULI MAY INDUCE CO-ACTIVATION OF G(Q)-COUPLED RECEPTORS AND BETA-ADRENERGIC RECEPTORS (BETA-AR), LEADING TO CARDIAC REMODELING. DYNAMIC REGULATION OF HISTONE DEACETYLASE 5 (HDAC5), A TRANSCRIPTIONAL REPRESSOR, IS CRUCIAL DURING STRESS SIGNALING DUE TO ITS ROLE IN EPIGENETIC CONTROL OF FETAL GENE MARKERS. LITTLE IS KNOWN ABOUT ITS REGULATION DURING ACUTE AND CHRONIC BETA-AR STIMULATION AND ITS CROSS-INTERACTION WITH G(Q) SIGNALING IN ADULT CARDIAC MYOCYTES. HERE, WE EVALUATE THE POTENTIAL CROSS-TALK BETWEEN G(Q)-DRIVEN AND BETA-AR MEDIATED SIGNALING AT THE LEVEL OF NUCLEOCYTOPLASMIC SHUTTLING OF HDAC5. WE SHOW THE TRANSLOCATION OF GFP-TAGGED WILD TYPE HDAC5 OR MUTANTS (S279A AND S279D) IN RESPONSE TO BETA-AR OR G(Q) AGONISTS. ISOPROTERENOL (ISO) OR PKA ACTIVATION RESULTS IN STRONG NUCLEAR ACCUMULATION OF HDAC5 IN CONTRAST TO NUCLEAR EXPORT DRIVEN BY CA(2+)-CALMODULIN PROTEIN KINASE II AND PROTEIN KINASE D. MOREOVER, NUCLEAR ACCUMULATION OF HDAC5 UNDER ACUTE ISO/PKA SIGNALING IS DEPENDENT ON PHOSPHORYLATION OF SER-279 AND CAN BLOCK SUBSEQUENT G(Q)-MEDIATED NUCLEAR HDAC5 EXPORT. INTRIGUINGLY, THE ATTENUATION OF G(Q)-INDUCED EXPORT IS ABOLISHED AFTER CHRONIC PKA ACTIVATION, YET NUCLEAR HDAC5 REMAINS ELEVATED. LAST, THE EFFECT OF CHRONIC BETA-AR SIGNALING ON HDAC5 TRANSLOCATION WAS EXAMINED IN ADULT MYOCYTES FROM A RABBIT MODEL OF HEART FAILURE, WHERE ISO-INDUCED NUCLEAR IMPORT IS ABLATED, BUT G(Q)-AGONIST MEDIATED EXPORT IS PRESERVED. ACUTE BETA-AR/PKA ACTIVATION PROTECTS AGAINST HYPERTROPHIC SIGNALING BY DELAYING G(Q)-MEDIATED TRANSCRIPTIONAL ACTIVATION. THIS SERVES AS A KEY PHYSIOLOGICAL CONTROL SWITCH BEFORE ALLOWING GENETIC REPROGRAMMING VIA HDAC5 NUCLEAR EXPORT DURING MORE SEVERE STRESS, SUCH AS HEART FAILURE. 2013