1 6145 355 THE EXPANDING PHENOTYPES OF COHESINOPATHIES: ONE RING TO RULE THEM ALL! PRESERVATION AND DEVELOPMENT OF LIFE DEPEND ON THE ADEQUATE SEGREGATION OF SISTER CHROMATIDS DURING MITOSIS AND MEIOSIS. THIS PROCESS IS ENSURED BY THE COHESIN MULTI-SUBUNIT COMPLEX. MUTATIONS IN THIS COMPLEX HAVE BEEN ASSOCIATED WITH AN INCREASING NUMBER OF DISEASES, TERMED COHESINOPATHIES. THE BEST CHARACTERIZED COHESINOPATHY IS CORNELIA DE LANGE SYNDROME (CDLS), IN WHICH INTELLECTUAL AND GROWTH RETARDATIONS ARE THE MAIN PHENOTYPIC MANIFESTATIONS. DESPITE SOME OVERLAP, THE CLINICAL MANIFESTATIONS OF COHESINOPATHIES VARY CONSIDERABLY. NOVEL ROLES OF THE COHESIN COMPLEX HAVE EMERGED DURING THE PAST DECADES, SUGGESTING THAT IMPORTANT CELL CYCLE REGULATORS EXERT IMPORTANT BIOLOGICAL EFFECTS THROUGH NON-COHESION-RELATED FUNCTIONS AND BROADENING THE POTENTIAL PATHOMECHANISMS INVOLVED IN COHESINOPATHIES. THIS REVIEW FOCUSES ON NON-COHESION-RELATED FUNCTIONS OF THE COHESIN COMPLEX, GENE DOSAGE EFFECT, EPIGENETIC REGULATION AND TGF-BETA IN COHESINOPATHY CONTEXT, ESPECIALLY IN COMPARISON TO CHRONIC ATRIAL AND INTESTINAL DYSRHYTHMIA (CAID) SYNDROME, A VERY DISTINCT COHESINOPATHY CAUSED BY A HOMOZYGOUS SHUGOSHIN-1 (SGO1) MUTATION (K23E) AND CHARACTERIZED BY PACEMAKER FAILURE IN BOTH HEART (SICK SINUS SYNDROME FOLLOWED BY ATRIAL FLUTTER) AND GUT (CHRONIC INTESTINAL PSEUDO-OBSTRUCTION) WITH NO INTELLECTUAL OR GROWTH DELAY. WE DISCUSS THE POSSIBLE IMPACT OF SGO1 ALTERATIONS IN HUMAN PATHOLOGIES AND THE POTENTIAL IMPACT OF THE SGO1 K23E MUTATION IN THE SINUS NODE AND GUT DEVELOPMENT AND FUNCTIONS. WE SUGGEST THAT THE HUMAN PHENOTYPES OBSERVED IN CDLS, CAID SYNDROME AND OTHER COHESINOPATHIES CAN INFORM FUTURE STUDIES INTO THE LESS WELL-KNOWN NON-COHESION-RELATED FUNCTIONS OF COHESIN COMPLEX GENES. ABBREVIATIONS: AD: ALZHEIMER DISEASE; AFF4: AF4/FMR2 FAMILY MEMBER 4; ANKRD11: ANKYRIN REPEAT DOMAIN 11; APC: ANAPHASE PROMOTER COMPLEX; ASD: ATRIAL SEPTAL DEFECT; ATRX: ATRX CHROMATIN REMODELER; ATRX: ALPHA THALASSEMIA X-LINKED INTELLECTUAL DISABILITY SYNDROME; BIRC5: BACULOVIRAL IAP REPEAT CONTAINING 5; BMP: BONE MORPHOGENETIC PROTEIN; BRD4: BROMODOMAIN CONTAINING 4; BUB1: BUB1 MITOTIC CHECKPOINT SERINE/THREONINE KINASE; CAID: CHRONIC ATRIAL AND INTESTINAL DYSRHYTHMIA; CDK1: CYCLIN DEPENDENT KINASE 1; CDLS: CORNELIA DE LANGE SYNDROME; CHD: CONGENITAL HEART DISEASE; CHOPS: COGNITIVE IMPAIRMENT, COARSE FACIES, HEART DEFECTS, OBESITY, PULMONARY INVOLVEMENT, SHORT STATURE, AND SKELETAL DYSPLASIA; CIPO: CHRONIC INTESTINAL PSEUDO-OBSTRUCTION; C-KIT: KIT PROTO-ONCOGENE RECEPTOR TYROSINE KINASE; COATS: COHESIN ACETYLTRANSFERASES; CTCF: CCCTC-BINDING FACTOR; DDX11: DEAD/H-BOX HELICASE 11; ERG: TRANSCRIPTIONAL REGULATOR ERG; ESCO2: ESTABLISHMENT OF SISTER CHROMATID COHESION N-ACETYLTRANSFERASE 2; GJC1: GAP JUNCTION PROTEIN GAMMA 1; H2A: HISTONE H2A; H3K4: HISTONE H3 LYSINE 4; H3K9: HISTONE H3 LYSINE 9; HCN4: HYPERPOLARIZATION ACTIVATED CYCLIC NUCLEOTIDE GATED POTASSIUM AND SODIUM CHANNEL 4;P HDAC8: HISTONE DEACETYLASES 8; HP1: HETEROCHROMATIN PROTEIN 1; ICC: INTERSTITIAL CELLS OF CAJAL; ICC-MP: MYENTERIC PLEXUS INTERSTITIAL CELLS OF CAJAL; ICC-DMP: DEEP MUSCULAR PLEXUS INTERSTITIAL CELLS OF CAJAL; I(F): PACEMAKER FUNNY CURRENT; IP3: INOSITOL TRISPHOSPHATE; JNK: C-JUN N-TERMINAL KINASE; LDS: LOEYS-DIETZ SYNDROME; LOAD: LATE-ONSET ALZHEIMER DISEASE; MAPK: MITOGEN-ACTIVATED PROTEIN KINASE; MAU: MAU SISTER CHROMATID COHESION FACTOR; MFS: MARFAN SYNDROME; NIPBL: NIPBL, COHESIN LOADING FACTOR; OCT4: OCTAMER-BINDING PROTEIN 4; P38: P38 MAP KINASE; PDA: PATENT DUCTUS ARTERIOSUS; PDS5: PDS5 COHESIN ASSOCIATED FACTOR; P-H3: PHOSPHO HISTONE H3; PLK1: POLO LIKE KINASE 1; POPDC1: POPEYE DOMAIN CONTAINING 1; POPDC2: POPEYE DOMAIN CONTAINING 2; PP2A: PROTEIN PHOSPHATASE 2; RAD21: RAD21 COHESIN COMPLEX COMPONENT; RBS: ROBERTS SYNDROME; REC8: REC8 MEIOTIC RECOMBINATION PROTEIN; RNAP2: RNA POLYMERASE II; SAN: SINOATRIAL NODE; SCN5A: SODIUM VOLTAGE-GATED CHANNEL ALPHA SUBUNIT 5; SEC: SUPER ELONGATION COMPLEX; SGO1: SHOGOSHIN-1; SMAD: SMAD FAMILY MEMBER; SMC1A: STRUCTURAL MAINTENANCE OF CHROMOSOMES 1A; SMC3: STRUCTURAL MAINTENANCE OF CHROMOSOMES 3; SNV: SINGLE NUCLEOTIDE VARIANT; SOX2: SRY-BOX 2; SOX17: SRY-BOX 17; SSS: SICK SINUS SYNDROME; STAG2: COHESIN SUBUNIT SA-2; TADS: TOPOLOGY ASSOCIATED DOMAINS; TBX: T-BOX TRANSCRIPTION FACTORS; TGF-BETA: TRANSFORMING GROWTH FACTOR BETA; TGFBR: TRANSFORMING GROWTH FACTOR BETA RECEPTOR; TOF: TETRALOGY OF FALLOT; TREK1: TREK-1 K(+) CHANNEL SUBUNIT; VSD: VENTRICULAR SEPTAL DEFECT; WABS: WARSAW BREAKAGE SYNDROME; WAPL: WAPL COHESIN RELEASE FACTOR. 2019 2 4484 53 MOLECULAR SIGNATURE OF CAID SYNDROME: NONCANONICAL ROLES OF SGO1 IN REGULATION OF TGF-BETA SIGNALING AND EPIGENOMICS. BACKGROUND & AIMS: A GENERALIZED HUMAN PACEMAKING SYNDROME, CHRONIC ATRIAL AND INTESTINAL DYSRHYTHMIA (CAID) (OMIM 616201), IS CAUSED BY A HOMOZYGOUS SGO1 MUTATION (K23E), LEADING TO CHRONIC INTESTINAL PSEUDO-OBSTRUCTION AND ARRHYTHMIAS. BECAUSE CAID PATIENTS DO NOT SHOW PHENOTYPES CONSISTENT WITH PERTURBATION OF KNOWN ROLES OF SGO1, WE HYPOTHESIZED THAT NONCANONICAL ROLES OF SGO1 DRIVE THE CLINICAL MANIFESTATIONS OBSERVED. METHODS: TO IDENTIFY A MOLECULAR SIGNATURE FOR CAID SYNDROME, WE ACHIEVED UNBIASED SCREENS IN CELL LINES AND GUT TISSUES FROM CAID PATIENTS VS WILD-TYPE CONTROLS. WE PERFORMED RNA SEQUENCING ALONG WITH STABLE ISOTOPE LABELING WITH AMINO ACIDS IN CELL CULTURE. IN ADDITION, WE DETERMINED THE GENOME-WIDE DNA METHYLATION AND CHROMATIN ACCESSIBILITY SIGNATURES USING REDUCED REPRESENTATIVE BISULFITE SEQUENCING AND ASSAY FOR TRANSPOSASE-ACCESSIBLE CHROMATIN WITH HIGH-THROUGHPUT SEQUENCING. FUNCTIONAL STUDIES INCLUDED PATCH-CLAMP, QUANTITATION OF TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA) SIGNALING, AND IMMUNOHISTOCHEMISTRY IN CAID PATIENT GUT BIOPSY SPECIMENS. RESULTS: PROTEOME AND TRANSCRIPTOME STUDIES CONVERGE ON CELL-CYCLE REGULATION, CARDIAC CONDUCTION, AND SMOOTH MUSCLE REGULATION AS DRIVERS OF CAID SYNDROME. SPECIFICALLY, THE INWARD RECTIFIER CURRENT, AN IMPORTANT REGULATOR OF CELLULAR FUNCTION, WAS DISRUPTED. IMMUNOHISTOCHEMISTRY CONFIRMED OVEREXPRESSION OF BUDDING UNINHIBITED BY BENZIMIDAZOLES 1 (BUB1) IN PATIENTS, IMPLICATING THE TGF-BETA PATHWAY IN CAID PATHOGENESIS. CANONICAL TGF-BETA SIGNALING WAS UP-REGULATED AND UNCOUPLED FROM NONCANONICAL SIGNALING IN CAID PATIENTS. REDUCED REPRESENTATIVE BISULFITE SEQUENCING AND ASSAY FOR TRANSPOSASE-ACCESSIBLE CHROMATIN WITH HIGH-THROUGHPUT SEQUENCING EXPERIMENTS SHOWED SIGNIFICANT CHANGES OF CHROMATIN STATES IN CAID, POINTING TO EPIGENETIC REGULATION AS A POSSIBLE PATHOLOGIC MECHANISM. CONCLUSIONS: OUR FINDINGS POINT TO IMPAIRED INWARD RECTIFIER POTASSIUM CURRENT, DYSREGULATION OF CANONICAL TGF-BETA SIGNALING, AND EPIGENETIC REGULATION AS POTENTIAL DRIVERS OF INTESTINAL AND CARDIAC MANIFESTATIONS OF CAID SYNDROME. TRANSCRIPT PROFILING AND GENOMICS DATA ARE AS FOLLOWS: REPOSITORY URL: HTTPS://WWW.NCBI.NLM.NIH.GOV/GEO; SUPERSERIES GSE110612 WAS COMPOSED OF THE FOLLOWING SUBSERIES: GSE110309, GSE110576, AND GSE110601. 2019 3 1092 45 COHESIN MUTATIONS IN MYELOID MALIGNANCIES. COHESIN IS A MULTISUBUNIT PROTEIN COMPLEX THAT FORMS A RING-LIKE STRUCTURE AROUND DNA. IT IS ESSENTIAL FOR SISTER CHROMATID COHESION, CHROMATIN ORGANIZATION, TRANSCRIPTIONAL REGULATION, AND DNA DAMAGE REPAIR AND PLAYS A MAJOR ROLE IN DYNAMICALLY SHAPING THE GENOME ARCHITECTURE AND MAINTAINING DNA INTEGRITY. THE CORE COMPLEX SUBUNITS STAG2, RAD21, SMC1, AND SMC3, AS WELL AS ITS MODULATORS PDS5A/B, WAPL, AND NIPBL, HAVE BEEN FOUND TO BE RECURRENTLY MUTATED IN HEMATOLOGIC AND SOLID MALIGNANCIES. THESE MUTATIONS ARE FOUND ACROSS THE FULL SPECTRUM OF MYELOID NEOPLASIA, INCLUDING PEDIATRIC DOWN SYNDROME-ASSOCIATED ACUTE MEGAKARYOBLASTIC LEUKEMIA, MYELODYSPLASTIC SYNDROMES, CHRONIC MYELOMONOCYTIC LEUKEMIA, AND DE NOVO AND SECONDARY ACUTE MYELOID LEUKEMIAS. THE MECHANISMS BY WHICH COHESIN MUTATIONS ACT AS DRIVERS OF CLONAL EXPANSION AND DISEASE PROGRESSION ARE STILL POORLY UNDERSTOOD. RECENT STUDIES HAVE DESCRIBED THE IMPACT OF COHESIN ALTERATIONS ON SELF-RENEWAL AND DIFFERENTIATION OF HEMATOPOIETIC STEM AND PROGENITOR CELLS, WHICH ARE ASSOCIATED WITH CHANGES IN CHROMATIN AND EPIGENETIC STATE DIRECTING LINEAGE COMMITMENT, AS WELL AS GENOMIC INTEGRITY. HEREIN, WE REVIEW THE ROLE OF THE COHESIN COMPLEX IN HEALTHY AND MALIGNANT HEMATOPOIESIS. WE DISCUSS CLINICAL IMPLICATIONS OF COHESIN MUTATIONS IN MYELOID MALIGNANCIES AND DISCUSS OPPORTUNITIES FOR THERAPEUTIC TARGETING. 2021 4 6569 40 TRANSPLANTATION OF EPIGENETICALLY MODIFIED ADULT CARDIAC C-KIT+ CELLS RETARDS REMODELING AND IMPROVES CARDIAC FUNCTION IN ISCHEMIC HEART FAILURE MODEL. CARDIAC C-KIT+ CELLS HAVE A MODEST CARDIOGENIC POTENTIAL THAT COULD LIMIT THEIR EFFICACY IN HEART DISEASE TREATMENT. THE PRESENT STUDY WAS DESIGNED TO AUGMENT THE CARDIOGENIC POTENTIAL OF CARDIAC C-KIT+ CELLS THROUGH CLASS I HISTONE DEACETYLASE (HDAC) INHIBITION AND EVALUATE THEIR THERAPEUTIC POTENCY IN THE CHRONIC HEART FAILURE (CHF) ANIMAL MODEL. MYOCARDIAL INFARCTION (MI) WAS CREATED BY CORONARY ARTERY OCCLUSION IN RATS. C-KIT+ CELLS WERE TREATED WITH MOCETINOSTAT (MOCE), A SPECIFIC CLASS I HDAC INHIBITOR. AT 3 WEEKS AFTER MI, CHF ANIMALS WERE RETROGRADELY INFUSED WITH UNTREATED (CONTROL) OR MOCE-TREATED C-KIT+ CELLS (MOCE/C-KIT+ CELLS) AND EVALUATED AT 3 WEEKS AFTER CELL INFUSION. WE FOUND THAT CLASS I HDAC INHIBITION IN C-KIT+ CELLS ELEVATED THE LEVEL OF ACETYLATED HISTONE H3 (ACH3) AND INCREASED ACH3 LEVELS IN THE PROMOTER REGIONS OF PLURIPOTENT AND CARDIAC-SPECIFIC GENES. EPIGENETIC CHANGES WERE ACCOMPANIED BY INCREASED EXPRESSION OF CARDIAC-SPECIFIC MARKERS. TRANSPLANTATION OF CHF RATS WITH EITHER CONTROL OR MOCE/C-KIT+ CELLS RESULTED IN AN IMPROVEMENT IN CARDIAC FUNCTION, RETARDATION OF CHF REMODELING MADE EVIDENT BY INCREASED VASCULARIZATION AND SCAR SIZE, AND CARDIOMYOCYTE HYPERTROPHY REDUCTION. COMPARED WITH CHF INFUSED WITH CONTROL CELLS, INFUSION OF MOCE/C-KIT+ CELLS RESULTED IN A FURTHER REDUCTION IN LEFT VENTRICLE END-DIASTOLIC PRESSURE AND TOTAL COLLAGEN AND AN INCREASE IN INTERLEUKIN-6 EXPRESSION. THE LOW ENGRAFTMENT OF INFUSED CELLS SUGGESTS THAT PARACRINE EFFECTS MIGHT ACCOUNT FOR THE BENEFICIAL EFFECTS OF C-KIT+ CELLS IN CHF. IN CONCLUSION, SELECTIVE INHIBITION OF CLASS I HDACS INDUCED EXPRESSION OF CARDIAC MARKERS IN C-KIT+ CELLS AND PARTIALLY AUGMENTED THE EFFICACY OF THESE CELLS FOR CHF REPAIR. SIGNIFICANCE: THE STUDY HAS SHOWN THAT SELECTIVE CLASS 1 HISTONE DEACETYLASE INHIBITION IS SUFFICIENT TO REDIRECT C-KIT+ CELLS TOWARD A CARDIAC FATE. EPIGENETICALLY MODIFIED C-KIT+ CELLS IMPROVED CONTRACTILE FUNCTION AND RETARDED REMODELING OF THE CONGESTIVE HEART FAILURE HEART. THIS STUDY PROVIDES NEW INSIGHTS INTO THE EFFICACY OF CARDIAC C-KIT+ CELLS IN THE ISCHEMIC HEART FAILURE MODEL. 2015 5 5822 24 STRESS IN THE ONSET AND AGGRAVATION OF LEARNING DISABILITIES. DESPITE SUBSTANTIAL GROUNDS FOR SUCH RESEARCH, THE ROLE OF CHRONIC EXPOSURE TO STRESSORS IN THE ONSET AND AGGRAVATION OF LEARNING DISABILITIES (LDS) IS LARGELY UNEXPLORED. IN THIS REVIEW, WE FIRST CONSIDER THE HORMONAL, (EPI)GENETIC, AND NEUROBIOLOGICAL MECHANISMS THAT MIGHT UNDERLIE THE IMPACT OF ADVERSE CHILDHOOD EXPERIENCES, A FORM OF CHRONIC STRESSORS, ON THE ONSET OF LDS. WE THEN FOUND THAT STRESS FACTORS COMBINED WITH FEELINGS OF INFERIORITY, LOW SELF-ESTEEM, AND PEER VICTIMIZATION COULD POTENTIALLY FURTHER AGGRAVATE ACADEMIC FAILURES IN CHILDREN WITH LDS. SINCE EFFECTIVE EVIDENCE-BASED INTERVENTIONS FOR REDUCING CHRONIC STRESS IN CHILDREN WITH LDS COULD IMPROVE THEIR ACADEMIC PERFORMANCE, CONSIDERATION OF THE ROLE OF EXPOSURE TO STRESSORS IN CHILDREN WITH LDS HAS BOTH THEORETICAL AND PRACTICAL IMPORTANCE, ESPECIALLY WHEN DELIVERED IN COMBINATION WITH ACADEMIC INTERVENTIONS. 2021 6 2969 90 GENETIC AND EPIGENETIC REGULATION OF THE INNATE IMMUNE RESPONSE TO GOUT. GOUT IS A DISEASE CAUSED BY URIC ACID (UA) ACCUMULATION IN THE JOINTS, CAUSING INFLAMMATION. TWO UA FORMS - MONOSODIUM URATE (MSU) AND SOLUBLE URIC ACID (SUA) HAVE BEEN SHOWN TO INTERACT PHYSICALLY WITH INFLAMMASOMES, ESPECIALLY WITH THE NOD-LIKE RECEPTOR (NLR) FAMILY PYRIN DOMAIN CONTAINING 3 (NLRP3), ALBEIT THE ROLE OF THE IMMUNE RESPONSE TO UA IS POORLY UNDERSTOOD, GIVEN THAT ASYMPTOMATIC HYPERURICEMIA DOES ALSO EXIST. MACROPHAGE PHAGOCYTOSIS OF UA ACTIVATE NLRP3, LEAD TO CYTOKINES RELEASE, AND ULTIMATELY, LEAD TO CHEMOATTRACT NEUTROPHILS AND LYMPHOCYTES TO THE GOUT FLARE JOINT SPOT. GENETIC VARIANTS OF INFLAMMASOME GENES AND OF GENES ENCODING THEIR MOLECULAR PARTNERS MAY INFLUENCE HYPERURICEMIA AND GOUT SUSCEPTIBILITY, WHILE ALSO INFLUENCING OTHER COMORBIDITIES SUCH AS METABOLIC SYNDROME AND CARDIOVASCULAR DISEASES. IN THIS REVIEW, WE SUMMARIZE THE INFLAMMATORY RESPONSES IN ACUTE AND CHRONIC GOUT, SPECIFICALLY FOCUSING ON INNATE IMMUNE CELL MECHANISMS AND GENETIC AND EPIGENETIC CHARACTERISTICS OF PARTICIPATING MOLECULES. UNPRECEDENTLY, A NOVEL UA BINDING PROTEIN - THE NEURONAL APOPTOSIS INHIBITOR PROTEIN (NAIP) - IS SUGGESTED AS RESPONSIBLE FOR THE ASYMPTOMATIC HYPERURICEMIA PARADOX.ABBREVIATION: BETA2-INTEGRINS: LEUKOCYTE-SPECIFIC ADHESION MOLECULES; ABCG2: ATP-BINDING CASSETE FAMILY/BREAST CANCER-RESISTANT PROTEIN; ACR: AMERICAN COLLEGE OF RHEUMATOLOGY; AIM2: ABSENT IN MELANOMA 2, TYPE OF PATTERN RECOGNITION RECEPTOR; ALPK1: ALPHA-PROTEIN KINASE 1; ANGPTL2: ANGIOPOIETIN-LIKE PROTEIN 2; ASC: APOPTOSIS-ASSOCIATED SPECK-LIKE PROTEIN; BIR: BACULOVIRUS INHIBITOR OF APOPTOSIS PROTEIN REPEAT; BIRC1: BACULOVIRUS IAP REPEAT-CONTAINING PROTEIN 1; BIRC2: BACULOVIRAL IAP REPEAT-CONTAINING PROTEIN 2; C5A: COMPLEMENT ANAPHYLATOXIN; CAMP: CYCLIC ADENOSINE MONOPHOSPHATE; CARD: CASPASE ACTIVATION AND RECRUITMENT DOMAINS; CARD8: CASPASE RECRUITMENT DOMAIN-CONTAINING PROTEIN 8; CASP1: CASPASE 1; CCL3: CHEMOKINE (C-C MOTIF) LIGAND 3; CD14: CLUSTER OF DIFFERENTIATION 14; CD44: CLUSTER OF DIFFERENTIATION 44; CG05102552: DNA-METHYLATION SITE, USUALLY CYTOSINE FOLLOWED BY GUANINE NUCLEOTIDES; CONTAINS ARBITRARY IDENTIFICATION CODE; CIDEC: CELL DEATH-INDUCING DNA FRAGMENTATION FACTOR-LIKE EFFECTOR FAMILY; CKD: CHRONIC KIDNEY DISEASE; CNV: COPY NUMBER VARIATION; CPT1A: CARNITINE PALMITOYL TRANSFERASE - TYPE 1A; CXCL1: CHEMOKINE (CXC MOTIF) LIGAND 1; DAMPS: DAMAGE ASSOCIATED MOLECULAR PATTERNS; DC: DENDRITIC CELLS; DNMT(1): MAINTENANCE DNA METHYLTRANSFERASE; EQTL: EXPRESSION QUANTITATIVE TRAIT LOCI; ERK1: EXTRACELLULAR SIGNAL-REGULATED KINASE 1; ERK2: EXTRACELLULAR SIGNAL-REGULATED KINASE 2; EULAR: EUROPEAN LEAGUE AGAINST RHEUMATISM; GMCSF: GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR; GWAS: GLOBAL WIDE ASSOCIATION STUDIES; H3K27ME3: TRI-METHYLATION AT THE 27TH LYSINE RESIDUE OF THE HISTONE H3 PROTEIN; H3K4ME1: MONO-METHYLATION AT THE 4TH LYSINE RESIDUE OF THE HISTONE H3 PROTEIN; H3K4ME3: TRI-METHYLATION AT THE 4TH LYSINE RESIDUE OF THE HISTONE H3 PROTEIN; HOTAIR: HUMAN GENE LOCATED BETWEEN HOXC11 AND HOXC12 ON CHROMOSOME 12; IKAPPABALPHA: CYTOPLASMATIC PROTEIN/NF-KAPPAB TRANSCRIPTION INHIBITOR; IAP: INHIBITORY APOPTOSIS PROTEIN; IFNGAMMA: INTERFERON GAMMA; IL-1BETA: INTERLEUKIN 1 BETA; IL-12: INTERLEUKIN 12; IL-17: INTERLEUKIN 17; IL18: INTERLEUKIN 18; IL1R1: INTERLEUKIN-1 RECEPTOR; IL-1RA: INTERLEUKIN-1 RECEPTOR ANTAGONIST; IL-22: INTERLEUKIN 22; IL-23: INTERLEUKIN 23; IL23R: INTERLEUKIN 23 RECEPTOR; IL-33: INTERLEUKIN 33; IL-6: INTERLEUKIN 6; IMP: INOSINE MONOPHOSPHATE; INSIG1: INSULIN-INDUCED GENE 1; JNK1: C-JUN N-TERMINAL KINASE 1; LNCRNA: LONG NON-CODING RIBONUCLEIC ACID; LRR: LEUCINE-RICH REPEATS; MIR: MATURE NON-CODING MICRORNAS MEASURING FROM 20 TO 24 NUCLEOTIDES, ANIMAL ORIGIN; MIR-1: MIR FOLLOWED BY ARBITRARY IDENTIFICATION CODE; MIR-145: MIR FOLLOWED BY ARBITRARY IDENTIFICATION CODE; MIR-146A: MIR FOLLOWED BY ARBITRARY IDENTIFICATION CODE, "A" STANDS FOR MIR FAMILY; "A" FAMILY PRESENTS SIMILAR MIR SEQUENCE TO "B" FAMILY, BUT DIFFERENT PRECURSORS; MIR-20B: MIR FOLLOWED BY ARBITRARY IDENTIFICATION CODE; "B" STANDS FOR MIR FAMILY; "B" FAMILY PRESENTS SIMILAR MIR SEQUENCE TO "A" FAMILY, BUT DIFFERENT PRECURSORS; MIR-221: MIR - FOLLOWED BY ARBITRARY IDENTIFICATION CODE; MIR-221-5P: MIR FOLLOWED BY ARBITRARY IDENTIFICATION CODE; "5P" INDICATES DIFFERENT MATURE MIRNAS GENERATED FROM THE 5' ARM OF THE PRE-MIRNA HAIRPIN; MIR-223: MIR FOLLOWED BY ARBITRARY IDENTIFICATION CODE; MIR-223-3P: MIR FOLLOWED BY ARBITRARY IDENTIFICATION CODE; "3P" INDICATES DIFFERENT MATURE MIRNAS GENERATED FROM THE 3' ARM OF THE PRE-MIRNA HAIRPIN; MIR-22-3P: MIR FOLLOWED BY ARBITRARY IDENTIFICATION CODE, "3P" INDICATES DIFFERENT MATURE MIRNAS GENERATED FROM THE 3' ARM OF THE PRE-MIRNA HAIRPIN; MLKL: MIXED LINEAGE KINASE DOMAIN-LIKE PSEUDO KINASE; MM2P: INDUCTOR OF M2-MACROPHAGE POLARIZATION; MSU: MONOSODIUM URATE; MTOR: MAMMALIAN TARGET OF RAPAMYCIN; MYD88: MYELOID DIFFERENTIATION PRIMARY RESPONSE 88; N-3-PUFAS: N-3-POLYUNSATURATED FATTY-ACIDS; NACHT: ACRONYM FOR NAIP (NEURONAL APOPTOSIS INHIBITOR PROTEIN), C2TA (MHC CLASS 2 TRANSCRIPTION ACTIVATOR), HET-E (INCOMPATIBILITY LOCUS PROTEIN FROM PODOSPORA ANSERINA) AND TP1 (TELOMERASE-ASSOCIATED PROTEIN); NAIP: NEURONAL APOPTOSIS INHIBITORY PROTEIN (HUMAN); NAIP1: NEURONAL APOPTOSIS INHIBITORY PROTEIN TYPE 1 (MURINE); NAIP5: NEURONAL APOPTOSIS INHIBITORY PROTEIN TYPE 5 (MURINE); NAIP6: NEURONAL APOPTOSIS INHIBITORY PROTEIN TYPE 6 (MURINE); NBD: NUCLEOTIDE-BINDING DOMAIN; NEK7: SMALLEST NIMA-RELATED KINASE; NET: NEUTROPHIL EXTRACELLULAR TRAPS; NF-KAPPAB: NUCLEAR FACTOR KAPPA-LIGHT-CHAIN-ENHANCER OF ACTIVATED B CELLS; NFIL3: NUCLEAR-FACTOR, INTERLEUKIN 3 REGULATED PROTEIN; NIIMA: NETWORK OF IMMUNITY IN INFECTION, MALIGNANCY, AND AUTOIMMUNITY; NLR: NOD-LIKE RECEPTOR; NLRA: NOD-LIKE RECEPTOR NLRA CONTAINING ACIDIC DOMAIN; NLRB: NOD-LIKE RECEPTOR NLRA CONTAINING BIR DOMAIN; NLRC: NOD-LIKE RECEPTOR NLRA CONTAINING CARD DOMAIN; NLRC4: NOD-LIKE RECEPTOR FAMILY CARD DOMAIN CONTAINING 4; NLRP: NOD-LIKE RECEPTOR NLRA CONTAINING PYD DOMAIN; NLRP1: NUCLEOTIDE-BINDING OLIGOMERIZATION DOMAIN, LEUCINE-RICH REPEAT, AND PYRIN DOMAIN CONTAINING 1; NLRP12: NUCLEOTIDE-BINDING OLIGOMERIZATION DOMAIN, LEUCINE-RICH REPEAT, AND PYRIN DOMAIN CONTAINING 12; NLRP3: NOD-LIKE RECEPTOR FAMILY PYRIN DOMAIN CONTAINING 3; NOD2: NUCLEOTIDE-BINDING OLIGOMERIZATION DOMAIN; NRBP1: NUCLEAR RECEPTOR-BINDING PROTEIN; NRF2: NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2; OR: ODDS RATIO; P2X: GROUP OF MEMBRANE ION CHANNELS ACTIVATED BY THE BINDING OF EXTRACELLULAR; P2X7: P2X PURINOCEPTOR 7 GENE; P38: MEMBER OF THE MITOGEN-ACTIVATED PROTEIN KINASE FAMILY; PAMPS: PATHOGEN ASSOCIATED MOLECULAR PATTERS; PBMC: PERIPHERAL BLOOD MONONUCLEAR CELLS; PGGT1B: GERANYLGERANYL TRANSFERASE TYPE-1 SUBUNIT BETA; PHGDH: PHOSPHOGLYCERATE DEHYDROGENASE; PI3-K: PHOSPHO-INOSITOL; PPARGAMMA: PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA; PPARGC1B: PEROXISOME PROLIFERATIVE ACTIVATED RECEPTOR, GAMMA, COACTIVATOR 1 BETA; PR3: PROTEINASE 3 ANTIGEN; PRO-CASP1: INACTIVE PRECURSOR OF CASPASE 1; PRO-IL1BETA: INACTIVE PRECURSOR OF INTERLEUKIN 1 BETA; PRR: PATTERN RECOGNITION RECEPTORS; PYD: PYRIN DOMAIN; RAPTOR: REGULATORY ASSOCIATED PROTEIN OF MTOR COMPLEX 1; RAS: RENIN-ANGIOTENSIN SYSTEM; REDD1: REGULATED IN DNA DAMAGE AND DEVELOPMENT 1; ROS: REACTIVE OXYGEN SPECIES; RS000*G: SINGLE NUCLEAR POLYMORPHISM, "*G" IS RELATED TO SNP WHERE REPLACED NUCLEOTIDE IS GUANINE, USUALLY PRECEDED BY AN ID NUMBER; SLC2A9: SOLUTE CARRIER FAMILY 2, MEMBER 9; SLC7A11: SOLUTE CARRIER FAMILY 7, MEMBER 11; SMA: SMOOTH MUSCULAR ATROPHY; SMAC: SECOND MITOCHONDRIAL-DERIVED ACTIVATOR OF CASPASES; SNP: SINGLE NUCLEAR POLYMORPHISM; SP3: SPECIFICITY PROTEIN 3; ST2: SERUM STIMULATION-2; STK11: SERINE/THREONINE KINASE 11; SUA: SOLUBLE URIC ACID; SYK: SPLEEN TYROSINE KINASE; TAK1: TRANSFORMING GROWTH FACTOR BETA ACTIVATED KINASE; TH1: TYPE 1 HELPER T CELLS; TH17: TYPE 17 HELPER T CELLS; TH2: TYPE 2 HELPER T CELLS; TH22: TYPE 22 HELPER T CELLS; TLR: TOOL-LIKE RECEPTOR; TLR2: TOLL-LIKE RECEPTOR 2; TLR4: TOLL-LIKE RECEPTOR 4; TNFALPHA: TUMOR NECROSIS FACTOR ALPHA; TNFR1: TUMOR NECROSIS FACTOR RECEPTOR 1; TNFR2: TUMOR NECROSIS FACTOR RECEPTOR 2; UA: URIC ACID; UBAP1: UBIQUITIN ASSOCIATED PROTEIN; ULT: URATE-LOWERING THERAPY; URAT1: URATE TRANSPORTER 1; VDAC1: VOLTAGE-DEPENDENT ANION-SELECTIVE CHANNEL 1. 2023 7 3857 36 ISCHEMIA- REPERFUSION INJURY AND ITS INFLUENCE ON THE EPIGENETIC MODIFICATION OF THE DONOR KIDNEY GENOME. BACKGROUND: IN CLINICAL TRANSPLANTATION, ISCHEMIA-REPERFUSION INJURY (I/RI) CAUSES DAMAGE TO DNA. WE HYPOTHESIZE THAT ONE FORM OF DAMAGE IS THE DEMETHYLATION OF METHYLATED CYTOSINES IN THE DONOR GENOME CAUSED BY THE OXIDATIVE ENVIRONMENT CREATED FIRST BY ISCHEMIA, AND SUBSEQUENTLY BY REPERFUSION ON TRANSPLANTATION. THIS STUDY CONTRIBUTES TO THE UNDERSTANDING OF HOW THE SHORT-LIVED AND TRANSIENT ISCHEMIC INSULT MAY INFLUENCE CHRONIC PATHOLOGICAL CHANGES THAT OCCUR IN CLINICAL TRANSPLANTATION IN THE LONG TERM. METHODS: A MODEL OF I/RI AND CHRONIC REJECTION; FISHER TO FISHER KIDNEY TRANSPLANT RENDERED COLD-ISCHEMIC FOR 4 HR BEFORE TRANSPLANTATION, TO INDUCE ANTIGEN-INDEPENDENT CHRONIC NEPHROPATHY OVER A 6-MONTH PERIOD, WAS USED. TISSUE WAS ASSESSED BY HISTOPATHOLOGY AND METHYLATION BY PYROSEQUENCING ANALYSIS. RESULTS: AN EPIGENETIC MAP OF THE RAT RENAL C3 PROMOTER WAS PRODUCED, WHICH IDENTIFIED METHYLATED CYTOSINE PHOSPHO GUANINE (CPG) SITES COINCIDENT TO CYTOKINE RESPONSE ELEMENTS AND NUCLEAR FACTOR KAPPA-LIGHT-CHAIN-ENHANCER OF ACTIVATED B CELLS (NF-KAPPAB) BINDING SITES. PYROSEQUENCING ANALYSIS SHOWED THAT THE TISSUE THAT HAD UNDERGONE 4 HR ISCHEMIA AND REPERFUSION DEVELOPED ABERRANT DEMETHYLATION OF CYTOSINES IN PUTATIVE REGULATORY SITES WITHIN THE C3 PROMOTER. CONCLUSION: THESE FINDINGS MAY DESCRIBE A NEWLY RECOGNIZED PHENOMENA IN THE FIELD OF TRANSPLANTATION. ABERRANT DEMETHYLATION HAS LONG BEEN LINKED TO THE DEVELOPMENT OF TUMORS, AND OUR DATA SUGGEST A SIMILAR MECHANISM OF GENE DYSREGULATION THAT MAY BE INITIATED BY I/RI WITH ACUTE AND CHRONIC EFFECTS. THESE DATA MAY CONTRIBUTE TO A FURTHER UNDERSTANDING OF HOW THE SHORT LIVED AND TRANSIENT ISCHEMIC INSULT INFLUENCES CHRONIC PATHOLOGICAL CHANGES THAT OCCUR EVEN IN THE ABSENCE OF MAJOR HISTOCOMPATIBILITY COMPLEX DISPARITY IN TRANSPLANTATION. 2008 8 1093 21 COHESIN RAD21 GENE PROMOTER METHYLATION IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS THE MOST COMMON TYPE OF LEUKEMIA IN ADULTS AND IS CHARACTERIZED BY THE PRESENCE OF SPECIFIC CYTOGENETIC ABNORMALITIES. CLL RESEARCH HAS BEEN FOCUSED ON EPIGENETIC PROCESSES LIKE GENE PROMOTER METHYLATION OF CPG ISLANDS. IN THE PRESENT STUDY, THE METHYLATION STATUS OF THE RAD21 GENE IS STUDIED AND ASSOCIATED WITH CYTOGENETIC FINDINGS IN CLL PATIENTS IN ORDER TO INVESTIGATE ITS POSSIBLE IMPLICATION IN CLL PATHOGENESIS AND THE FORMATION OF CLL CHROMOSOMAL ABNORMALITIES. 2018 9 3064 39 GENOME-WIDE DNA METHYLATION ENCODES CARDIAC TRANSCRIPTIONAL REPROGRAMMING IN HUMAN ISCHEMIC HEART FAILURE. ISCHEMIC CARDIOMYOPATHY (ICM) IS THE CLINICAL ENDPOINT OF CORONARY HEART DISEASE AND A LEADING CAUSE OF HEART FAILURE. DESPITE GROWING DEMANDS TO DEVELOP PERSONALIZED APPROACHES TO TREAT ICM, PROGRESS IS LIMITED BY INADEQUATE KNOWLEDGE OF ITS PATHOGENESIS. SINCE EPIGENETICS HAS BEEN IMPLICATED IN THE DEVELOPMENT OF OTHER CHRONIC DISEASES, THE CURRENT STUDY WAS DESIGNED TO DETERMINE WHETHER TRANSCRIPTIONAL AND/OR EPIGENETIC CHANGES ARE SUFFICIENT TO DISTINGUISH ICM FROM OTHER ETIOLOGIES OF HEART FAILURE. SPECIFICALLY, WE HYPOTHESIZE THAT GENOME-WIDE DNA METHYLATION ENCODES TRANSCRIPTIONAL REPROGRAMMING IN ICM. RNA-SEQUENCING ANALYSIS WAS PERFORMED ON HUMAN ISCHEMIC LEFT VENTRICULAR TISSUE OBTAINED FROM PATIENTS WITH END-STAGE HEART FAILURE, WHICH ENRICHED KNOWN TARGETS OF THE POLYCOMB METHYLTRANSFERASE EZH2 COMPARED TO NON-ISCHEMIC HEARTS. COMBINED RNA SEQUENCING AND GENOME-WIDE DNA METHYLATION ANALYSIS REVEALED A ROBUST GENE EXPRESSION PATTERN CONSISTENT WITH SUPPRESSION OF OXIDATIVE METABOLISM, INDUCED ANAEROBIC GLYCOLYSIS, AND ALTERED CELLULAR REMODELING. LASTLY, KLF15 WAS IDENTIFIED AS A PUTATIVE UPSTREAM REGULATOR OF METABOLIC GENE EXPRESSION THAT WAS ITSELF REGULATED BY EZH2 IN A SET DOMAIN-DEPENDENT MANNER. OUR OBSERVATIONS THEREFORE DEFINE A NOVEL ROLE OF DNA METHYLATION IN THE METABOLIC REPROGRAMMING OF ICM. FURTHERMORE, WE IDENTIFY EZH2 AS AN EPIGENETIC REGULATOR OF KLF15 ALONG WITH DNA HYPERMETHYLATION, AND WE PROPOSE A NOVEL MECHANISM THROUGH WHICH CORONARY HEART DISEASE REPROGRAMS THE EXPRESSION OF BOTH INTERMEDIATE ENZYMES AND UPSTREAM REGULATORS OF CARDIAC METABOLISM SUCH AS KLF15. 2019 10 5760 31 SOLUBLE URIC ACID PRIMES TLR-INDUCED PROINFLAMMATORY CYTOKINE PRODUCTION BY HUMAN PRIMARY CELLS VIA INHIBITION OF IL-1RA. OBJECTIVES: THE STUDY OF THE PROINFLAMMATORY ROLE OF URIC ACID HAS FOCUSED ON THE EFFECTS OF ITS CRYSTALS OF MONOSODIUM URATE (MSU). HOWEVER, LITTLE IS KNOWN WHETHER URIC ACID ITSELF CAN DIRECTLY HAVE PROINFLAMMATORY EFFECTS. IN THIS STUDY, WE INVESTIGATE THE PRIMING EFFECTS OF URIC ACID EXPOSURE ON THE CYTOKINE PRODUCTION OF PRIMARY HUMAN CELLS UPON STIMULATION WITH GOUT-RELATED STIMULI. METHODS: PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) WERE HARVESTED FROM PATIENTS WITH GOUT AND HEALTHY VOLUNTEERS. CELLS WERE PRETREATED WITH OR WITHOUT URIC ACID IN SOLUBLE FORM FOR 24 H AND THEN STIMULATED FOR 24 H WITH TOLL-LIKE RECEPTOR (TLR)2 OR TLR4 LIGANDS IN THE PRESENCE OR ABSENCE OF MSU CRYSTALS. CYTOKINE PRODUCTION WAS MEASURED BY ELISA; MRNA LEVELS WERE ASSESSED USING QPCR. RESULTS: THE PRODUCTION OF INTERLEUKIN (IL)-1BETA AND IL-6 WAS HIGHER IN PATIENTS COMPARED WITH CONTROLS AND THIS CORRELATED WITH SERUM URATE LEVELS. PROINFLAMMATORY CYTOKINE PRODUCTION WAS SIGNIFICANTLY POTENTIATED WHEN CELLS FROM HEALTHY SUBJECTS WERE PRETREATED WITH URIC ACID. SURPRISINGLY, THIS WAS ASSOCIATED WITH A SIGNIFICANT DOWNREGULATION OF THE ANTI-INFLAMMATORY CYTOKINE IL-1 RECEPTOR ANTAGONIST (IL-1RA). THIS EFFECT WAS SPECIFIC TO STIMULATION BY URIC ACID AND WAS EXERTED AT THE LEVEL OF GENE TRANSCRIPTION. EPIGENETIC REPROGRAMMING AT THE LEVEL OF HISTONE METHYLATION BY URIC ACID WAS INVOLVED IN THIS EFFECT. CONCLUSIONS: IN THIS STUDY WE DEMONSTRATE A MECHANISM THROUGH WHICH HIGH CONCENTRATIONS OF URIC ACID (UP TO 50 MG/DL) INFLUENCE INFLAMMATORY RESPONSES BY FACILITATING IL-1BETA PRODUCTION IN PBMCS. WE SHOW THAT A MECHANISM FOR THE AMPLIFICATION OF IL-1BETA CONSISTS IN THE DOWNREGULATION OF IL-1RA AND THAT THIS EFFECT COULD BE EXERTED VIA EPIGENETIC MECHANISMS SUCH AS HISTONE METHYLATION. HYPERURICAEMIA CAUSES A SHIFT IN THE IL-1BETA/IL-1RA BALANCE PRODUCED BY PBMCS AFTER EXPOSURE TO MSU CRYSTALS AND TLR-MEDIATED STIMULI, AND THIS PHENOMENON IS LIKELY TO REINFORCE THE ENHANCED STATE OF CHRONIC INFLAMMATION. 2016 11 6540 33 TRANSCRIPTIONAL, EPIGENETIC, AND FUNCTIONAL REPROGRAMMING OF MONOCYTES FROM NON-HUMAN PRIMATES FOLLOWING CHRONIC ALCOHOL DRINKING. CHRONIC HEAVY DRINKING (CHD) OF ALCOHOL IS A KNOWN RISK FACTOR FOR INCREASED SUSCEPTIBILITY TO BACTERIAL AND VIRAL INFECTION AS WELL AS IMPAIRED WOUND HEALING. EVIDENCE SUGGESTS THAT THESE DEFECTS ARE MEDIATED BY A DYSREGULATED INFLAMMATORY RESPONSE ORIGINATING FROM MYELOID CELLS, NOTABLY MONOCYTES AND MACROPHAGES, BUT THE MECHANISMS REMAIN POORLY UNDERSTOOD. OUR ABILITY TO STUDY CHD IS IMPACTED BY THE COMPLEXITIES OF HUMAN DRINKING PATTERNS AND BEHAVIOR AS WELL AS COMORBIDITIES AND CONFOUNDING RISK FACTORS FOR PATIENTS WITH ALCOHOL USE DISORDERS. TO OVERCOME THESE CHALLENGES, WE UTILIZED A TRANSLATIONAL RHESUS MACAQUE MODEL OF VOLUNTARY ETHANOL SELF-ADMINISTRATION THAT CLOSELY RECAPITULATES HUMAN DRINKING PATTERNS AND CHRONICITY. IN THIS STUDY, WE EXAMINED THE EFFECTS OF CHD ON BLOOD MONOCYTES IN CONTROL AND CHD FEMALE MACAQUES AFTER 12 MONTHS OF DAILY ETHANOL CONSUMPTION. WHILE MONOCYTES FROM CHD FEMALE MACAQUES GENERATED A HYPER-INFLAMMATORY RESPONSE TO EX VIVO LPS STIMULATION, THEIR RESPONSE TO E. COLI WAS DAMPENED. IN DEPTH SCRNA-SEQ ANALYSIS OF PURIFIED MONOCYTES REVEALED SIGNIFICANT SHIFTS IN CLASSICAL MONOCYTE SUBSETS WITH ACCUMULATION OF CELLS EXPRESSING MARKERS OF HYPOXIA (HIF1A) AND INFLAMMATION (NFKB SIGNALING PATHWAY) IN CHD MACAQUES. THE INCREASED PRESENCE OF MONOCYTE SUBSETS SKEWED TOWARDS INFLAMMATORY PHENOTYPES WAS COMPLEMENTED BY EPIGENETIC ANALYSIS, WHICH REVEALED HIGHER ACCESSIBILITY OF PROMOTER REGIONS THAT REGULATE GENES INVOLVED IN CYTOKINE SIGNALING PATHWAYS. COLLECTIVELY, DATA PRESENTED IN THIS MANUSCRIPT DEMONSTRATE THAT CHD SHIFTS CLASSICAL MONOCYTE SUBSET COMPOSITION AND PRIMES THE MONOCYTES TOWARDS A MORE HYPER-INFLAMMATORY RESPONSE TO LPS, BUT COMPROMISED PATHOGEN RESPONSE. 2021 12 5227 30 PRMT6 MEDIATES INFLAMMATION VIA ACTIVATION OF THE NF-KAPPAB/P65 PATHWAY ON A CIGARETTE SMOKE EXTRACT-INDUCED MURINE EMPHYSEMA MODEL. INTRODUCTION: SMOKE-DRIVEN LUNG INFLAMMATION IS CONSIDERED TO BE THE MAJOR PATHOPHYSIOLOGY MECHANISM OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)/EMPHYSEMA. PROTEIN ARGININE METHYLTRANSFERASE 6 (PRMT6) IS A KEY EPIGENETIC ENZYME, WHICH IS RELATED TO PROTECTING THE TRI-METHYLATION OF H3K4 (H3K4ME3). WE HYPOTHESIZED THAT PTMT6 PROTECTS LUNG INFLAMMATION THROUGH THE NUCLEAR FACTOR KAPPA B (NF-KAPPAB) PATHWAY. METHODS: MICE WERE INJECTED WITH CIGARETTE SMOKE EXTRACT (CSE) OR PBS TO ESTABLISH A MICE MODEL, INTRATRACHEALLY INSTILLED WITH OVEREXPRESSED PRMT6 OR NEGATIVE CONTROL VECTOR. MORPHOMETRY OF LUNG SLIDES AND LUNG FUNCTION WERE MEASURED. WE DETERMINED THE PROTEIN EXPRESSION OF PRMT6 AND ITS RELATED HISTONE TARGETS, THE ACTIVATION OF NF-KAPPAB PATHWAY, THE LEVEL OF TUMOR NECROSIS FACTOR ALPHA (TNFALPHA) AND INTERLEUKIN-1BETA (IL-1BETA). RESULTS: AFTER PRMT6 OVEREXPRESSION, THE MORPHOMETRY INDEXES AND LUNG FUNCTION WERE IMPROVED. ALSO, THE EXPRESSION OF H3K4ME3 WAS DECREASED. OVEREXPRESSED PRMT6 COULD SUPPRESS CSE-INDUCED NF-KAPPAB ACTIVATION AND PRO-INFLAMMATION GENES EXPRESSION. CONCLUSIONS: THE OVEREXPRESSED PRMT6 COULD SERVE AS AN INFLAMMATION INHIBITOR, POTENTIALLY THROUGH BLOCKING THE NF-KAPPAB/P65 PATHWAY IN THE MURINE EMPHYSEMA MODEL. 2020 13 1141 32 CONCERTED CELL AND IN VIVO SCREEN FOR PANCREATIC DUCTAL ADENOCARCINOMA (PDA) CHEMOTHERAPEUTICS. PDA IS A MAJOR CAUSE OF US CANCER-RELATED DEATHS. ONCOGENIC KRAS PRESENTS IN 90% OF HUMAN PDAS. KRAS MUTATIONS OCCUR EARLY IN PRE-NEOPLASTIC LESIONS BUT ARE INSUFFICIENT TO CAUSE PDA. OTHER CONTRIBUTING FACTORS EARLY IN DISEASE PROGRESSION INCLUDE CHRONIC PANCREATITIS, ALTERATIONS IN EPIGENETIC REGULATORS, AND TUMOR SUPPRESSOR GENE MUTATION. GPCRS ACTIVATE HETEROTRIMERIC G-PROTEINS THAT STIMULATE INTRACELLULAR CALCIUM AND ONCOGENIC KRAS SIGNALING, THEREBY PROMOTING PANCREATITIS AND PROGRESSION TO PDA. BY CONTRAST, RGS PROTEINS INHIBIT GI/Q-COUPLED GPCRS TO NEGATIVELY REGULATE PDA PROGRESSION. RGS16::GFP IS EXPRESSED IN RESPONSE TO CAERULEIN-INDUCED ACINAR CELL DEDIFFERENTIATION, EARLY NEOPLASIA, AND THROUGHOUT PDA PROGRESSION. IN GENETICALLY ENGINEERED MOUSE MODELS OF PDA, RGS16::GFP IS USEFUL FOR PRE-CLINICAL RAPID IN VIVO VALIDATION OF NOVEL CHEMOTHERAPEUTICS TARGETING EARLY LESIONS IN PATIENTS FOLLOWING SUCCESSFUL RESECTION OR AT HIGH RISK FOR PROGRESSING TO PDA. CULTURED PRIMARY PDA CELLS EXPRESS RGS16::GFP IN RESPONSE TO CYTOTOXIC DRUGS. A HISTONE DEACETYLASE INHIBITOR, TSA, STIMULATED RGS16::GFP EXPRESSION IN PDA PRIMARY CELLS, POTENTIATED GEMCITABINE AND JQ1 CYTOTOXICITY IN CELL CULTURE, AND GEM + TSA + JQ1 INHIBITED TUMOR INITIATION AND PROGRESSION IN VIVO. HERE WE ESTABLISH THE USE OF RGS16::GFP EXPRESSION FOR TESTING DRUG COMBINATIONS IN CELL CULTURE AND VALIDATION OF BEST CANDIDATES IN OUR RAPID IN VIVO SCREEN. 2020 14 5651 27 SEX DIFFERENCES IN THE EPIGENETIC REGULATION OF CHRONIC VISCERAL PAIN FOLLOWING UNPREDICTABLE EARLY LIFE STRESS. BACKGROUND: WE PREVIOUSLY REPORTED THAT EARLY LIFE STRESS (ELS) DYSREGULATED GLUCOCORTICOID RECEPTOR (GR) AND CORTICOTROPHIN-RELEASING HORMONE (CRH) EXPRESSION IN THE CENTRAL NUCLEUS OF THE AMYGDALA (CEA). EPIGENETIC MODIFICATIONS SERVE AS MEMORIES OF ADVERSE EVENTS THAT OCCURRED DURING EARLY LIFE. THEREFORE, WE HYPOTHESIZED THAT EPIGENETIC MECHANISMS ALTER GR AND CRH EXPRESSION IN THE CEA AND UNDERLIE CHRONIC VISCERAL PAIN AFTER ELS. METHODS: NEONATAL RATS WERE EXPOSED TO UNPREDICTABLE, PREDICTABLE ELS, OR ODOR ONLY (NO STRESS CONTROL) FROM POSTNATAL DAYS 8 TO 12. IN ADULTHOOD, VISCERAL SENSITIVITY WAS ASSESSED OR THE CEA WAS ISOLATED FOR WESTERN BLOT OR CHIP-QPCR TO STUDY HISTONE MODIFICATIONS AT THE GR AND CRH PROMOTERS. FEMALE ADULT RATS UNDERWENT STEREOTAXIC IMPLANTATION OF INDWELLING CANNULAS FOR MICROINJECTIONS OF GARCINOL (HAT INHIBITOR) INTO THE CEA. AFTER 7 DAYS OF MICROINJECTIONS, VISCERAL SENSITIVITY WAS ASSESSED OR THE CEA WAS ISOLATED FOR CHIP-QPCR ASSAYS. RESULTS: UNPREDICTABLE ELS INCREASED VISCERAL SENSITIVITY IN ADULT FEMALE RATS, BUT NOT IN MALE COUNTERPARTS. ELS INCREASED HISTONE 3 LYSINE 9 (H3K9) ACETYLATION IN THE CEA AND H3K9 ACETYLATION LEVELS AT THE GR PROMOTER IN THE CEA OF ADULT FEMALE RATS. AFTER UNPREDICTABLE ELS, H3K9 ACETYLATION WAS INCREASED AND GR BINDING WAS DECREASED AT THE CRH PROMOTER. ADMINISTRATION OF GARCINOL IN THE CEA OF ADULT FEMALES, THAT UNDERWENT UNPREDICTABLE ELS, NORMALIZED H3K9 ACETYLATION AND RESTORED GR BINDING AT THE CRH PROMOTER. CONCLUSION: DYSREGULATED HISTONE ACETYLATION AND GR BINDING AT THE CRH PROMOTER IN THE CEA ARE AN IMPORTANT MECHANISM FOR "MEMORIZING" ELS EVENTS MEDIATING VISCERAL PAIN IN ADULTHOOD. 2020 15 775 41 CELL TYPE-SPECIFIC WHOLE-GENOME LANDSCAPE OF DELTAFOSB BINDING IN THE NUCLEUS ACCUMBENS AFTER CHRONIC COCAINE EXPOSURE. BACKGROUND: THE ABILITY OF NEURONS TO RESPOND TO EXTERNAL STIMULI INVOLVES ADAPTATIONS OF GENE EXPRESSION. INDUCTION OF THE TRANSCRIPTION FACTOR DELTAFOSB IN THE NUCLEUS ACCUMBENS, A KEY BRAIN REWARD REGION, IS IMPORTANT FOR THE DEVELOPMENT OF DRUG ADDICTION. HOWEVER, A COMPREHENSIVE MAP OF DELTAFOSB'S GENE TARGETS HAS NOT YET BEEN GENERATED. METHODS: WE USED CUT&RUN (CLEAVAGE UNDER TARGETS AND RELEASE USING NUCLEASE) TO MAP THE GENOME-WIDE CHANGES IN DELTAFOSB BINDING IN THE 2 MAIN TYPES OF NUCLEUS ACCUMBENS NEURONS-D1 OR D2 MEDIUM SPINY NEURONS-AFTER CHRONIC COCAINE EXPOSURE. TO ANNOTATE GENOMIC REGIONS OF DELTAFOSB BINDING SITES, WE ALSO EXAMINED THE DISTRIBUTIONS OF SEVERAL HISTONE MODIFICATIONS. RESULTING DATASETS WERE LEVERAGED FOR MULTIPLE BIOINFORMATIC ANALYSES. RESULTS: THE MAJORITY OF DELTAFOSB PEAKS OCCUR OUTSIDE PROMOTER REGIONS, INCLUDING INTERGENIC REGIONS, AND ARE SURROUNDED BY EPIGENETIC MARKS INDICATIVE OF ACTIVE ENHANCERS. BRG1, THE CORE SUBUNIT OF THE SWI/SNF CHROMATIN REMODELING COMPLEX, OVERLAPS WITH DELTAFOSB PEAKS, A FINDING CONSISTENT WITH EARLIER STUDIES OF DELTAFOSB'S INTERACTING PROTEINS. CHRONIC COCAINE USE INDUCES BROAD CHANGES IN DELTAFOSB BINDING IN BOTH D1 AND D2 NUCLEUS ACCUMBENS MEDIUM SPINY NEURONS OF MALE AND FEMALE MICE. IN ADDITION, IN SILICO ANALYSES PREDICT THAT DELTAFOSB COOPERATIVELY REGULATES GENE EXPRESSION WITH HOMEOBOX AND T-BOX TRANSCRIPTION FACTORS. CONCLUSIONS: THESE NOVEL FINDINGS UNCOVER KEY ELEMENTS OF DELTAFOSB'S MOLECULAR MECHANISMS IN TRANSCRIPTIONAL REGULATION AT BASELINE AND IN RESPONSE TO CHRONIC COCAINE EXPOSURE. FURTHER CHARACTERIZATION OF DELTAFOSB'S COLLABORATIVE TRANSCRIPTIONAL AND CHROMATIN PARTNERS SPECIFICALLY IN D1 AND D2 MEDIUM SPINY NEURONS WILL REVEAL A BROADER PICTURE OF THE FUNCTION OF DELTAFOSB AND THE MOLECULAR BASIS OF DRUG ADDICTION. 2023 16 1709 29 DYSFUNCTIONAL ERG SIGNALING DRIVES PULMONARY VASCULAR AGING AND PERSISTENT FIBROSIS. VASCULAR DYSFUNCTION IS A HALLMARK OF CHRONIC DISEASES IN ELDERLY. THE CONTRIBUTION OF THE VASCULATURE TO LUNG REPAIR AND FIBROSIS IS NOT FULLY UNDERSTOOD. HERE, WE PERFORMED AN EPIGENETIC AND TRANSCRIPTIONAL ANALYSIS OF LUNG ENDOTHELIAL CELLS (ECS) FROM YOUNG AND AGED MICE DURING THE RESOLUTION OR PROGRESSION OF BLEOMYCIN-INDUCED LUNG FIBROSIS. WE IDENTIFIED THE TRANSCRIPTION FACTOR ETS-RELATED GENE (ERG) AS PUTATIVE ORCHESTRATOR OF LUNG CAPILLARY HOMEOSTASIS AND REPAIR, AND WHOSE FUNCTION IS DYSREGULATED IN AGING. ERG DYSREGULATION IS ASSOCIATED WITH REDUCED CHROMATIN ACCESSIBILITY AND MALADAPTIVE TRANSCRIPTIONAL RESPONSES TO INJURY. LOSS OF ENDOTHELIAL ERG ENHANCES PARACRINE FIBROBLAST ACTIVATION IN VITRO, AND IMPAIRS LUNG FIBROSIS RESOLUTION IN YOUNG MICE IN VIVO. SCRNA-SEQ OF ERG DEFICIENT MOUSE LUNGS REVEALES TRANSCRIPTIONAL AND FIBROGENIC ABNORMALITIES RESEMBLING THOSE ASSOCIATED WITH AGING AND HUMAN LUNG FIBROSIS, INCLUDING REDUCED NUMBER OF GENERAL CAPILLARY (GCAP) ECS. OUR FINDINGS DEMONSTRATE THAT LUNG ENDOTHELIAL CHROMATIN REMODELING DETERIORATES WITH AGING LEADING TO ABNORMAL TRANSCRIPTION, VASCULAR DYSREPAIR, AND PERSISTENT FIBROSIS FOLLOWING INJURY. 2022 17 3086 31 GENOME-WIDE TRANSCRIPTOMICS OF THE AMYGDALA REVEALS SIMILAR OLIGODENDROCYTE-RELATED RESPONSES TO ACUTE AND CHRONIC ALCOHOL DRINKING IN FEMALE MICE. REPEATED EXCESSIVE ALCOHOL CONSUMPTION IS A RISK FACTOR FOR ALCOHOL USE DISORDER (AUD). ALTHOUGH AUD HAS BEEN MORE COMMON IN MEN THAN WOMEN, WOMEN DEVELOP MORE SEVERE BEHAVIORAL AND PHYSICAL IMPAIRMENTS. HOWEVER, RELATIVELY FEW NEW THERAPEUTICS TARGETING DEVELOPMENT OF AUD, PARTICULARLY IN WOMEN, HAVE BEEN VALIDATED. TO GAIN A BETTER UNDERSTANDING OF MOLECULAR MECHANISMS UNDERLYING ALCOHOL INTAKE, WE CONDUCTED A GENOME-WIDE RNA-SEQUENCING ANALYSIS IN FEMALE MICE EXPOSED TO DIFFERENT MODES (ACUTE VS CHRONIC) OF ETHANOL DRINKING. WE FOCUSED ON TRANSCRIPTIONAL PROFILES IN THE AMYGDALA INCLUDING THE CENTRAL AND BASOLATERAL SUBNUCLEI, BRAIN AREAS PREVIOUSLY IMPLICATED IN ALCOHOL DRINKING AND SEEKING. SURPRISINGLY, WE FOUND THAT BOTH DRINKING MODES TRIGGERED SIMILAR CHANGES IN GENE EXPRESSION AND CANONICAL PATHWAYS, INCLUDING UPREGULATION OF RIBOSOME-RELATED/TRANSLATIONAL PATHWAYS AND MYELINATION PATHWAYS, AND DOWNREGULATION OF CHROMATIN BINDING AND HISTONE MODIFICATION. IN ADDITION, ANALYSES OF HUB GENES AND UPSTREAM REGULATORY PATHWAYS REVEALED THAT VOLUNTARY ETHANOL CONSUMPTION AFFECTS EPIGENETIC CHANGES VIA HISTONE DEACETYLATION PATHWAYS, OLIGODENDROCYTE AND MYELIN FUNCTION, AND THE OLIGODENDROCYTE-RELATED TRANSCRIPTION FACTOR, SOX17. FURTHERMORE, A VIRAL VECTOR-ASSISTED KNOCKDOWN OF SOX17 GENE EXPRESSION IN THE AMYGDALA PREVENTED A GRADUAL INCREASE IN ALCOHOL CONSUMPTION DURING REPEATED ACCESSES. OVERALL, THESE RESULTS SUGGEST THAT THE EXPRESSION OF OLIGODENDROCYTE-RELATED GENES IN THE AMYGDALA IS SENSITIVE TO VOLUNTARY ALCOHOL DRINKING IN FEMALE MICE. THESE FINDINGS SUGGEST POTENTIAL MOLECULAR TARGETS FOR FUTURE THERAPEUTIC APPROACHES TO PREVENT THE DEVELOPMENT OF AUD, DUE TO REPEATED EXCESSIVE ALCOHOL CONSUMPTION, PARTICULARLY IN WOMEN. 2022 18 1556 42 DNA METHYLATION MODIFICATIONS ASSOCIATED WITH CHRONIC FATIGUE SYNDROME. CHRONIC FATIGUE SYNDROME (CFS), ALSO KNOWN AS MYALGIC ENCEPHALOMYELITIS, IS A COMPLEX MULTIFACTORIAL DISEASE THAT IS CHARACTERIZED BY THE PERSISTENT PRESENCE OF FATIGUE AND OTHER PARTICULAR SYMPTOMS FOR A MINIMUM OF 6 MONTHS. SYMPTOMS FAIL TO DISSIPATE AFTER SUFFICIENT REST AND HAVE MAJOR EFFECTS ON THE DAILY FUNCTIONING OF CFS SUFFERERS. CFS IS A MULTI-SYSTEM DISEASE WITH A HETEROGENEOUS PATIENT POPULATION SHOWING A WIDE VARIETY OF FUNCTIONAL DISABILITIES AND ITS BIOLOGICAL BASIS REMAINS POORLY UNDERSTOOD. STABLE ALTERATIONS IN GENE FUNCTION IN THE IMMUNE SYSTEM HAVE BEEN REPORTED IN SEVERAL STUDIES OF CFS. EPIGENETIC MODIFICATIONS HAVE BEEN IMPLICATED IN LONG-TERM EFFECTS ON GENE FUNCTION, HOWEVER, TO OUR KNOWLEDGE, GENOME-WIDE EPIGENETIC MODIFICATIONS ASSOCIATED WITH CFS HAVE NOT BEEN EXPLORED. WE EXAMINED THE DNA METHYLOME IN PERIPHERAL BLOOD MONONUCLEAR CELLS ISOLATED FROM CFS PATIENTS AND HEALTHY CONTROLS USING THE ILLUMINA HUMANMETHYLATION450 BEADCHIP ARRAY, CONTROLLING FOR INVARIANT PROBES AND PROBES OVERLAPPING POLYMORPHIC SEQUENCES. GENE ONTOLOGY (GO) AND NETWORK ANALYSIS OF DIFFERENTIALLY METHYLATED GENES WAS PERFORMED TO DETERMINE POTENTIAL BIOLOGICAL PATHWAYS SHOWING CHANGES IN DNA METHYLATION IN CFS. WE FOUND AN INCREASED ABUNDANCE OF DIFFERENTIALLY METHYLATED GENES RELATED TO THE IMMUNE RESPONSE, CELLULAR METABOLISM, AND KINASE ACTIVITY. GENES ASSOCIATED WITH IMMUNE CELL REGULATION, THE LARGEST COORDINATED ENRICHMENT OF DIFFERENTIALLY METHYLATED PATHWAYS, SHOWED HYPOMETHYLATION WITHIN PROMOTERS AND OTHER GENE REGULATORY ELEMENTS IN CFS. THESE DATA ARE CONSISTENT WITH EVIDENCE OF MULTISYSTEM DYSREGULATION IN CFS AND IMPLICATE THE INVOLVEMENT OF DNA MODIFICATIONS IN CFS PATHOLOGY. 2014 19 6108 36 THE ENRICHED ENVIRONMENT AMELIORATES CHRONIC UNPREDICTABLE MILD STRESS-INDUCED DEPRESSIVE-LIKE BEHAVIORS AND COGNITIVE IMPAIRMENT BY ACTIVATING THE SIRT1/MIR-134 SIGNALING PATHWAY IN HIPPOCAMPUS. BACKGROUND: CHRONIC UNPREDICTABLE MILD STRESS (CUMS) IS AN IMPORTANT RISK FACTOR FOR DEPRESSION AND COGNITIVE DEFICITS IN HUMANS. ENRICHED ENVIRONMENT (EE) SHOWED A BENEFICIAL EFFECT ON DEPRESSION AND COGNITION BY ENHANCING BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION AND SYNAPTIC PLASTICITY. HOWEVER, IT IS STILL NOT CLEARLY UNDERSTOOD WHETHER AN EPIGENETIC MECHANISM IS INVOLVED IN THE BDNF MODULATION AND SYNAPTIC PLASTICITY THAT OCCURS AFTER EE TREATMENT FOR THE DEPRESSIVE-LIKE BEHAVIORS AND COGNITIVE DEFICITS ELICITED BY CUMS. IN THIS STUDY, WE INVESTIGATED THE POSSIBLE MECHANISM OF THE NEUROPROTECTIVE EFFECT OF EE. METHODS: ALL RATS WERE EXPOSED TO THE 5-WEEK CUMS PROCEDURE EXCEPT THE CONTROL GROUP. AFTER CUMS PROCEDURE, SOME RATS WERE STEREOTAXICALLY INJECTED WITH SIRT1 PHARMACOLOGIC INHIBITOR EX527 OR SIRT1 KNOCKING DOWN LENTIVIRUS (SH-SIRT1) IN THE HIPPOCAMPUS FOLLOWED BY EE TREATMENT FOR 3 WEEKS. OTHER RATS WERE DIRECTLY SUBJECTED TO EE TREATMENT WITHOUT STEREOTAXIC INJECTION. BEHAVIORAL TESTS WERE USED TO APPRAISE DEPRESSION AND COGNITION AFTER EE TREATMENT. THEN EPIGENETIC MOLECULES, SYNAPTIC PROTEINS, DENDRITIC SPINE DENSITY AND BRANCHES, AND SYNAPTIC MORPHOLOGY OF THE DORSAL HIPPOCAMPUS WERE DETERMINED. RESULTS: WE FOUND THAT CUMS INDUCED DEPRESSIVE-LIKE BEHAVIORS INCLUDING DECREASED SUCROSE PREFERENCE RATIO, PROLONGED IMMOBILITY AND REDUCED LOCOMOTOR AND EXPLORATORY ACTIVITY; COGNITIVE DEFICITS INCLUDING SPATIAL LEARNING AND MEMORY IMPAIRMENT; REDUCED DENDRITIC SPINE DENSITY AND NUMBER OF BRANCHES; THINNED POSTSYNAPTIC DENSITY; DOWNREGULATED SIRT1/MICRORNA-134 PATHWAY, DECREASED BDNF AND SYNAPTIC PROTEINS INCLUDING SYNAPTOPHYSIN (SYN) AND POSTSYNAPTIC DENSITY PROTEIN 95 (PSD95) EXPRESSION IN THE HIPPOCAMPUS. HOWEVER, THE CUMS-INDUCED DEPRESSIVE-LIKE BEHAVIORS, COGNITIVE DEFICITS, DENDRITIC SPINE DENSITY AND BRANCH NUMBER REDUCTION, POSTSYNAPTIC DENSITY THINNING, SIRT1/MICRORNA-134 PATHWAY DOWNREGULATION, BDNF AND SYNAPTIC PROTEINS REDUCTION, INCLUDING SYNAPTOPHYSIN (SYN) AND POSTSYNAPTIC DENSITY PROTEIN 95 (PSD95), WERE REVERSED BY EE TREATMENT. HOWEVER, DEPRESSIVE-LIKE BEHAVIORS AND COGNITIVE DEFICITS WERE OBSERVED AGAIN IN RATS SUBJECTED TO STEREOTAXIC INJECTION WITH EX527 OR SH-SIRT1. FURTHERMORE, THIS STUDY ALSO FOUND THAT SIRT1/MICRORNA-134 REGULATES THE DOWNSTREAM MOLECULES BDNF, AND THE SYNAPTIC PROTEINS SYN AND PSD95 IN PRIMARY CULTURED HIPPOCAMPAL NEURONS. CONCLUSIONS: THIS STUDY PROVIDES EVIDENCE FOR THE NEUROPROTECTIVE ROLE OF EE ON DEPRESSION AND COGNITIVE DEFICITS BY ACTIVATING THE SIRT1/MICRORNA-134 PATHWAY, WHICH ACCOUNTS FOR THE REGULATION OF SYNAPTIC PROTEINS, INCLUDING BDNF, PSD95 AND SYN, DENDRITIC REMODELING AND ULTRASTRUCTURE CHANGES OF SYNAPSES IN THE HIPPOCAMPUS. 2019 20 537 27 ASYMPTOMATIC HYPERURICEMIA: IS IT REALLY ASYMPTOMATIC? PURPOSE OF REVIEW: HYPERURICEMIA IS HIGHLY PREVALENT, AFFECTING APPROXIMATELY 38 MILLION INDIVIDUALS IN THE UNITED STATES. HOWEVER, THE SIGNIFICANCE OF ASYMPTOMATIC HYPERURICEMIA - HYPERURICEMIA IN THE ABSENCE OF GOUT - CONTINUES TO BE DEBATED. RECENT FINDINGS: ASYMPTOMATIC HYPERURICEMIA RESULTS IN MONOSODIUM URATE CRYSTAL DEPOSITION IN TISSUES, WHICH MAY PROMOTE CHRONIC INFLAMMATION. INTRACELLULARLY, HYPERURICEMIA INHIBITS THE MASTER REGULATOR ADENOSINE MONOPHOSPHATE (AMP)-ASSOCIATED PROTEIN KINASE AND MAY CONDITION INNATE IMMUNE RESPONSES THROUGH DURABLE EPIGENETIC MODIFICATIONS. AT THE POPULATION LEVEL, ASYMPTOMATIC HYPERURICEMIA IS ASSOCIATED WITH MULTIPLE COMORBIDITIES, INCLUDING HYPERTENSION, CHRONIC KIDNEY DISEASE, CORONARY ARTERY DISEASE, AND DIABETES; LIMITATIONS OF THESE STUDIES INCLUDE THAT MOST ARE RETROSPECTIVE AND SOME DO NOT RIGOROUSLY DISTINGUISH BETWEEN ASYMPTOMATIC HYPERURICEMIA AND GOUT. TREATMENT STUDIES SUGGEST THAT URATE LOWERING MAY REDUCE THE RISK OF INCIDENCE OR PROGRESSION OF SOME OF THESE COMORBIDITIES; UNFORTUNATELY, MANY OF THESE TREATMENT STUDIES ARE SMALL OR FLAWED, AND NOT ALL STUDY RESULTS ARE CONSISTENT. SUMMARY: ACCUMULATING EVIDENCE SUGGESTS THAT ASYMPTOMATIC HYPERURICEMIA CONTRIBUTES TO THE COMORBIDITIES WITH WHICH IT ASSOCIATES AND THAT PROPER ASYMPTOMATIC HYPERURICEMIA TREATMENT MAY REDUCE FUTURE RISK. ADDITIONAL PROSPECTIVE TRIALS ARE NEEDED TO DEFINITELY ESTABLISH CAUSALITY AND SUPPORT DECISION-MAKING AS TO WHETHER, AND WHICH PATIENTS WITH ASYMPTOMATIC HYPERURICEMIA WOULD WARRANT URATE-LOWERING TREATMENT. 2020