1 5949 101 TARGETING THE PRC2-DEPENDENT EPIGENETIC PROGRAM ALLEVIATES URINARY TRACT INFECTIONS. URINARY TRACT INFECTION (UTI) IS A PERVASIVE HEALTH PROBLEM WORLDWIDE. PATIENTS WITH A HISTORY OF UTIS SUFFER INCREASED RISK OF RECURRENT INFECTIONS, A MAJOR RISK OF ANTIBIOTIC RESISTANCE. HERE, WE SHOW THAT BLADDER INFECTIONS INDUCE EXPRESSION OF EZH2 IN BLADDER UROTHELIAL CELLS. EZH2 IS THE METHYLTRANSFERASE OF POLYCOMB REPRESSOR COMPLEX 2 (PRC2)-A POTENT EPIGENETIC REGULATOR. UROTHELIUM-SPECIFIC INACTIVATION OF PRC2 RESULTS IN REDUCED URINE BACTERIAL BURDEN, MUTED INFLAMMATORY RESPONSE, AND DECREASED ACTIVITY OF THE NF-KAPPAB SIGNALING PATHWAY. PRC2 INACTIVATION ALSO FACILITATES PROPER REGENERATION AFTER UROTHELIAL DAMAGE FROM UTIS, BY ATTENUATING BASAL CELL HYPERPLASIA AND INCREASING UROTHELIAL DIFFERENTIATION. IN ADDITION, TREATMENT WITH EZH2-SPECIFIC SMALL-MOLECULE INHIBITORS IMPROVES OUTCOMES OF THE CHRONIC AND SEVERE BLADDER INFECTIONS IN MICE. THESE FINDINGS COLLECTIVELY SUGGEST THAT THE PRC2-DEPENDENT EPIGENETIC REPROGRAMING CONTROLS THE AMPLITUDE OF INFLAMMATION AND SEVERITY OF UTIS AND THAT EZH2 INHIBITORS MAY BE A VIABLE NON-ANTIBIOTIC STRATEGY TO MANAGE CHRONIC AND SEVERE UTIS. 2023 2 6671 33 UROPATHOGENIC ESCHERICHIA COLI INFECTION-INDUCED EPITHELIAL TRAINED IMMUNITY IMPACTS URINARY TRACT DISEASE OUTCOME. PREVIOUS URINARY TRACT INFECTIONS (UTIS) CAN PREDISPOSE ONE TO FUTURE INFECTIONS; HOWEVER, THE UNDERLYING MECHANISMS AFFECTING RECURRENCE ARE POORLY UNDERSTOOD. WE PREVIOUSLY FOUND THAT UTIS IN MICE CAUSE DIFFERENTIAL BLADDER EPITHELIAL (UROTHELIAL) REMODELLING, DEPENDING ON DISEASE OUTCOME, THAT IMPACTS SUSCEPTIBILITY TO RECURRENT UTI. HERE WE COMPARED UROTHELIAL STEM CELL (USC) LINES ISOLATED FROM MICE WITH A HISTORY OF EITHER RESOLVED OR CHRONIC UROPATHOGENIC ESCHERICHIA COLI (UPEC) INFECTION, ELUCIDATING EVIDENCE OF MOLECULAR IMPRINTING THAT INVOLVED EPIGENETIC CHANGES, INCLUDING DIFFERENCES IN CHROMATIN ACCESSIBILITY, DNA METHYLATION AND HISTONE MODIFICATION. EPIGENETIC MARKS IN USCS FROM CHRONICALLY INFECTED MICE ENHANCED CASPASE-1-MEDIATED CELL DEATH UPON UPEC INFECTION, PROMOTING BACTERIAL CLEARANCE. INCREASED PTGS2OS2 EXPRESSION ALSO OCCURRED, POTENTIALLY CONTRIBUTING TO SUSTAINED CYCLOOXYGENASE-2 EXPRESSION, BLADDER INFLAMMATION AND MUCOSAL WOUNDING-RESPONSES ASSOCIATED WITH SEVERE RECURRENT CYSTITIS. THUS, UPEC INFECTION ACTS AS AN EPI-MUTAGEN REPROGRAMMING THE UROTHELIAL EPIGENOME, LEADING TO UROTHELIAL-INTRINSIC REMODELLING AND TRAINING OF THE INNATE RESPONSE TO SUBSEQUENT INFECTION. 2023 3 58 27 A GENOME-WIDE SCAN TO LOCATE REGIONS ASSOCIATED WITH FAMILIAL VESICOURETERAL REFLUX. VESICOURETERAL REFLUX (VUR) IS A CONGENITAL MALFORMATION CARRYING A HIGH RISK OF RECURRENT URINARY TRACT INFECTIONS (UTI) AND, AT WORST, CHRONIC RENAL FAILURE. FAMILIAL CLUSTERING IMPLIES A GENETIC ETIOLOGY, BUT STUDIES DURING THE PAST FEW DECADES HAVE DEMONSTRATED A CAUSAL GENE VARIANT IN <10% OF PATIENTS WITH VUR. THE AIM OF THE PRESENT STUDY WAS TO SEARCH FOR FULLY OR PARTIALLY SHARED ANCESTRAL HAPLOTYPES IN 14 FAMILIES FROM SOUTH-WESTERN SWEDEN WITH AT LEAST THREE AFFECTED MEMBERS. HIGH-DENSITY SINGLE NUCLEOTIDE POLYMORPHISM MICROARRAY WAS USED FOR GENOTYPING PRIOR TO ANALYSIS WITH A COMPATIBILITY MATCHING METHOD DEVELOPED IN-HOUSE, AND THE ANALYSIS OF COPY NUMBER VARIATIONS (CNV). NO SINGLE UNIQUE HAPLOTYPE WAS REVEALED TO BE SHARED BY THE FAMILIES, THEREBY EXCLUDING A COMMON ANCESTRY AND FOUNDER MUTATIONS AS A PROBABLE CAUSE OF VUR. AFTER EVALUATION OF HAPLOTYPES SHARED BY SUBSETS OF FAMILIES, A HAPLOTYPE SHARED BY NINE FAMILIES WAS FOUND TO BE OF PARTICULAR INTEREST. THIS HAPLOTYPE, LOCATED AT CHROMOSOMAL REGION 4Q21.21, HARBOURS TWO TENTATIVE CANDIDATE GENES (BONE MORPHOGENETIC PROTEIN 3 AND FIBROBLAST GROWTH FACTOR 5), BOTH EXPRESSED IN METANEPHROS AND WITH KNOWN FUNCTIONS DURING NEPHROGENESIS. AS TO CNV, ONLY ONE FAMILY HAD A SPECIFIC CNV SHARED BY ALL AFFECTED MEMBERS. THIS WAS A FOCAL DELETION AT 5Q31.1 INCLUDING FOLLISTATIN-LIKE 4, A GENE WITHOUT A PREVIOUS KNOWN CONNECTION TO VUR. THESE DATA DEMONSTRATED THE GENETIC HETEROGENEITY OF VUR AND INDICATED THAT AN INTERACTION OF ENVIRONMENTAL AND GENETIC FACTORS, INCLUDING NON-CODING AND EPIGENETIC REGULATORS, ALL CONTRIBUTE TO THE COMPLEXITY OF VUR. 2022 4 866 30 CHRONIC ACTIVATION OF MUC1-C IN WOUND REPAIR PROMOTES PROGRESSION TO CANCER STEM CELLS. THE MUCIN 1 (MUC1) GENE EMERGED IN MAMMALS TO AFFORD PROTECTION OF BARRIER EPITHELIAL TISSUES FROM THE EXTERNAL ENVIRONMENT. MUC1 ENCODES A TRANSMEMBRANE C-TERMINAL (MUC1-C) SUBUNIT THAT IS ACTIVATED BY LOSS OF HOMEOSTASIS AND INDUCES INFLAMMATORY, PROLIFERATIVE, AND REMODELING PATHWAYS ASSOCIATED WITH WOUND REPAIR. AS A CONSEQUENCE, CHRONIC ACTIVATION OF MUC1-C PROMOTES LINEAGE PLASTICITY, EPIGENETIC REPROGRAMMING, AND CARCINOGENESIS. IN DRIVING CANCER PROGRESSION, MUC1-C IS IMPORTED INTO THE NUCLEUS, WHERE IT INDUCES NF-KAPPAB INFLAMMATORY SIGNALING AND THE EPITHELIAL-MESENCHYMAL TRANSITION (EMT). MUC1-C REPRESSES GENE EXPRESSION BY ACTIVATING (I) DNA METHYLTRANSFERASE 1 (DNMT1) AND DNMT3B, (II) POLYCOMB REPRESSIVE COMPLEX 1 (PRC1) AND PRC2, AND (III) THE NUCLEOSOME REMODELING AND DEACETYLASE (NURD) COMPLEX. PRC1/2-MEDIATED GENE REPRESSION IS COUNTERACTED BY THE SWI/SNF CHROMATIN REMODELING COMPLEXES. MUC1-C ACTIVATES THE SWI/SNF BAF AND PBAF COMPLEXES IN CANCER STEM CELL (CSC) MODELS WITH THE INDUCTION OF GENOME-WIDE DIFFERENTIALLY ACCESSIBLE REGIONS AND EXPRESSED GENES. MUC1-C REGULATES CHROMATIN ACCESSIBILITY OF ENHANCER-LIKE SIGNATURES IN ASSOCIATION WITH THE INDUCTION OF THE YAMANAKA PLURIPOTENCY FACTORS AND RECRUITMENT OF JUN AND BAF, WHICH PROMOTE INCREASES IN HISTONE ACTIVATION MARKS AND OPENING OF CHROMATIN. THESE AND OTHER FINDINGS DESCRIBED IN THIS REVIEW HAVE UNCOVERED A PIVOTAL ROLE FOR MUC1-C IN INTEGRATING LINEAGE PLASTICITY AND EPIGENETIC REPROGRAMMING, WHICH ARE TRANSIENT IN WOUND REPAIR AND SUSTAINED IN PROMOTING CSC PROGRESSION. 2022 5 1458 28 DISORDER OF G2-M CHECKPOINT CONTROL IN ANILINE-INDUCED CELL PROLIFERATION IN RAT SPLEEN. ANILINE, A TOXIC AROMATIC AMINE, IS KNOWN TO CAUSE HEMOPOIETIC TOXICITY BOTH IN HUMANS AND ANIMALS. ANILINE EXPOSURE ALSO LEADS TO TOXIC RESPONSE IN SPLEEN WHICH IS CHARACTERIZED BY SPLENOMEGALY, HYPERPLASIA, FIBROSIS AND THE EVENTUAL FORMATION OF TUMORS ON CHRONIC IN VIVO EXPOSURE. PREVIOUSLY, WE HAVE SHOWN THAT ANILINE EXPOSURE LEADS TO IRON OVERLOAD, OXIDATIVE DNA DAMAGE, AND INCREASED CELL PROLIFERATION, WHICH COULD EVENTUALLY CONTRIBUTE TO A TUMORIGENIC RESPONSE IN THE SPLEEN. DESPITE OUR DEMONSTRATION THAT CELL PROLIFERATION WAS ASSOCIATED WITH DEREGULATION OF G1 PHASE CYCLINS AND INCREASED EXPRESSION OF G1 PHASE CYCLIN-DEPENDENT KINASES (CDKS), MOLECULAR MECHANISMS, ESPECIALLY THE REGULATION OF G2 PHASE AND CONTRIBUTION OF EPIGENETIC MECHANISMS IN ANILINE-INDUCED SPLENIC CELLULAR PROLIFERATION REMAIN LARGELY UNCLEAR. THIS STUDY THEREFORE, MAINLY FOCUSED ON THE REGULATION OF G2 PHASE IN AN ANIMAL MODEL PRECEDING A TUMORIGENIC RESPONSE. MALE SPRAGUE-DAWLEY RATS WERE GIVEN ANILINE (0.5 MMOL/KG/DAY) IN DRINKING WATER OR DRINKING WATER ONLY (CONTROLS) FOR 30 DAYS, AND EXPRESSION OF G2 PHASE CYCLINS, CDK1, CDK INHIBITORS AND MIRNAS WERE MEASURED IN THE SPLEEN. ANILINE TREATMENT RESULTED IN SIGNIFICANT INCREASES IN CELL CYCLE REGULATORY PROTEINS, INCLUDING CYCLINS A, B AND CDK1, PARTICULARLY PHOSPHOR-CDK1, AND DECREASES IN CDK INHIBITORS P21 AND P27, WHICH COULD PROMOTE THE SPLENOCYTES TO GO THROUGH G2/M TRANSITION. OUR DATA ALSO SHOWED UPREGULATION OF TUMOR MARKERS TRX-1 AND REF-1 IN RATS TREATED WITH ANILINE. MORE IMPORTANTLY, WE OBSERVED LOWER EXPRESSION OF MIRNAS INCLUDING LET-7A, MIR-15B, MIR24, MIR-100 AND MIR-125, AND GREATER EXPRESSION OF CDK INHIBITOR REGULATORY MIRNAS SUCH AS MIR-181A, MIR-221 AND MIR-222 IN THE SPLEENS OF ANILINE-TREATED ANIMALS. OUR FINDINGS SUGGEST THAT SIGNIFICANT INCREASES IN THE EXPRESSION OF CYCLINS, CDK1 AND ABERRANT REGULATION OF MIRNAS COULD LEAD TO AN ACCELERATED G2/M TRANSITION OF THE SPLENOCYTES, AND POTENTIALLY TO A TUMORIGENIC RESPONSE ON CHRONIC ANILINE EXPOSURE. 2015 6 2403 32 EPIGENETIC REPROGRAMMING: A POSSIBLE ETIOLOGICAL FACTOR IN BLADDER PAIN SYNDROME/INTERSTITIAL CYSTITIS? PURPOSE: THE ETIOLOGY OF BLADDER PAIN SYNDROME/INTERSTITIAL CYSTITIS IS POORLY UNDERSTOOD. THE POSSIBILITY THAT EPIGENETIC REPROGRAMMING MAY HAVE A ROLE IS DISCUSSED. MATERIALS AND METHODS: A LITERATURE SEARCH WAS PERFORMED WITH THE ENTREZ-PUBMED(R) DATABASE USING THE KEY WORDS URINARY BLADDER, EPIGENETICS, EPIGENETIC MECHANISMS, INTERSTITIAL CYSTITIS, DIAGNOSIS, ETIOLOGY, UROTHELIAL CELLS, MAST CELLS, NERVE FIBERS, NERVES, NERVE GROWTH FACTOR, RECURRENT INJURY, STEM CELLS, INFLAMMATORY MEDIATORS AND DEMETHYLASES. RESULTS: THE UROEPITHELIUM IS INTIMATELY ASSOCIATED WITH THE NERVOUS SYSTEM. SENSORY INPUT AT THE APICAL SURFACE OF UMBRELLA CELLS REGULATES BLADDER FUNCTION VIA A TRANSMURAL SIGNALING PATHWAY. WHEN UMBRELLA CELLS ARE SHED IN RESPONSE TO NOXIOUS STIMULI, STEM CELLS IN THE BASAL LAYER BECOME EXPOSED. THE POLYCOMB GROUP GENES ARE KEY IN THE MAINTENANCE OF ADULT STEM CELLS. THE POLYCOMB GROUP GENES MEDIATE GENE SILENCING AND REPRESS TRANSDIFFERENTIATION BY METHYLATING LYSINE 27 OF HISTONE H3 (H3K27ME3). JMJD3, AN ENZYME DEMETHYLATING H3K27ME3, ANTAGONIZES POLYCOMB GROUP GENES MEDIATED SILENCING. INFLAMMATORY STIMULI ARE STRONG INDUCERS OF JMJD3 AND MAY REVERSE GENE SILENCING IN STEM CELLS, MODIFYING THE DIFFERENTIATION PATTERN. EPIGENETIC PROCESSES INVOLVING H3K27 METHYLATION ARE MULTISTABLE PROCESSES. TRANSIENT SIGNALING, EG BY LIPOPOLYSACCHARIDE, TRIGGERS EPIGENETIC REPROGRAMMING AND ESTABLISHES ONE OF THE ALTERNATIVE REGULATORY STATES. ONCE ESTABLISHED SUCH STATES CAN BE MAINTAINED AND PROPAGATED EVEN IN THE ABSENCE OF THE INITIAL SIGNAL. CONCLUSIONS: WE POSTULATE THAT SIMILAR EPIGENETIC REPROGRAMMING MECHANISMS IN THE BLADDER MAY PROVIDE AN EXPLANATION FOR UROEPITHELIAL, MAST CELLS AND NERVE CELL ABNORMALITIES IN BLADDER PAIN SYNDROME/INTERSTITIAL CYSTITIS, AS WELL AS PROPAGATION OF THIS ALTERED STATE IN THE ABSENCE OF THE SIGNAL THAT MAY HAVE TRIGGERED IT. IT ALSO PROVIDES A NEW EXPERIMENTAL PARADIGM FOR EXPLORING THE ETIOLOGY OF BLADDER PAIN SYNDROME/INTERSTITIAL CYSTITIS. DATA SUPPORTING THIS HYPOTHESIS WOULD PROVIDE A RATIONALE FOR NEW DIAGNOSTIC AS WELL AS TREATMENT OPTIONS FOR BLADDER PAIN SYNDROME/INTERSTITIAL CYSTITIS. 2009 7 545 20 ATTENUATED EPIGENETIC SUPPRESSION OF MUSCLE STEM CELL NECROPTOSIS IS REQUIRED FOR EFFICIENT REGENERATION OF DYSTROPHIC MUSCLES. SOMATIC STEM CELLS EXPAND MASSIVELY DURING TISSUE REGENERATION, WHICH MIGHT REQUIRE CONTROL OF CELL FITNESS, ALLOWING ELIMINATION OF NON-COMPETITIVE, POTENTIALLY HARMFUL CELLS. HOW OR IF SUCH CELLS ARE REMOVED TO RESTORE ORGAN FUNCTION IS NOT FULLY UNDERSTOOD. HERE, WE SHOW THAT A SUBSTANTIAL FRACTION OF MUSCLE STEM CELLS (MUSCS) UNDERGO NECROPTOSIS BECAUSE OF EPIGENETIC REWIRING DURING CHRONIC SKELETAL MUSCLE REGENERATION, WHICH IS REQUIRED FOR EFFICIENT REGENERATION OF DYSTROPHIC MUSCLES. INHIBITION OF NECROPTOSIS STRONGLY ENHANCES SUPPRESSION OF MUSC EXPANSION IN A NON-CELL-AUTONOMOUS MANNER. PREVENTION OF NECROPTOSIS IN MUSCS OF HEALTHY MUSCLES IS MEDIATED BY THE CHROMATIN REMODELER CHD4, WHICH DIRECTLY REPRESSES THE NECROPTOTIC EFFECTOR RIPK3, WHILE CHD4-DEPENDENT RIPK3 REPRESSION IS DRAMATICALLY ATTENUATED IN DYSTROPHIC MUSCLES. LOSS OF RIPK3 REPRESSION BY INACTIVATION OF CHD4 CAUSES MASSIVE NECROPTOSIS OF MUSCS, ABOLISHING REGENERATION. OUR STUDY DEMONSTRATES HOW PROGRAMMED CELL DEATH IN MUSCS IS TIGHTLY CONTROLLED TO ACHIEVE OPTIMAL TISSUE REGENERATION. 2020 8 3924 18 LIPOSOMAL UHRF1 SIRNA SHOWS LUNG FIBROSIS TREATMENT POTENTIAL THROUGH REGULATION OF FIBROBLAST ACTIVATION. PULMONARY FIBROSIS IS A CHRONIC AND PROGRESSIVE INTERSTITIAL LUNG DISEASE ASSOCIATED WITH THE DECAY OF PULMONARY FUNCTION, WHICH LEADS TO A FATAL OUTCOME. AS AN ESSENTIAL EPIGENETIC REGULATOR OF DNA METHYLATION, THE INVOLVEMENT OF UBIQUITIN-LIKE CONTAINING PHD AND RING FINGER DOMAINS 1 (UHRF1) IN FIBROBLAST ACTIVATION REMAINS LARGELY UNDEFINED IN PULMONARY FIBROSIS. IN THE PRESENT STUDY, WE FOUND THAT TGF-BETA1-MEDIATED UPREGULATION OF UHRF1 REPRESSED BECLIN 1 VIA METHYLATED INDUCTION OF ITS PROMOTER, WHICH FINALLY RESULTED IN FIBROBLAST ACTIVATION AND LUNG FIBROSIS BOTH IN VITRO AND IN VIVO. MOREOVER, KNOCKDOWN OF UHRF1 SIGNIFICANTLY ARRESTED FIBROBLAST PROLIFERATION AND REACTIVATED BECLIN 1 IN LUNG FIBROBLASTS. THUS, INTRAVENOUS ADMINISTRATION OF UHRF1 SIRNA-LOADED LIPOSOMES SIGNIFICANTLY PROTECTED MICE AGAINST EXPERIMENTAL PULMONARY FIBROSIS. ACCORDINGLY, OUR DATA SUGGEST THAT UHRF1 MIGHT BE A NOVEL POTENTIAL THERAPEUTIC TARGET IN THE PATHOGENESIS OF PULMONARY FIBROSIS. 2022 9 3804 18 INTESTINAL MICROBIOTA, CHRONIC INFLAMMATION, AND COLORECTAL CANCER. IN ADDITION TO GENETIC AND EPIGENETIC FACTORS, VARIOUS ENVIRONMENTAL FACTORS, INCLUDING DIET, PLAY IMPORTANT ROLES IN THE DEVELOPMENT OF COLORECTAL CANCER (CRC). RECENTLY, THERE IS INCREASING INTEREST IN THE INTESTINAL MICROBIOTA AS AN ENVIRONMENTAL RISK FACTOR FOR CRC, BECAUSE DIET ALSO INFLUENCES THE COMPOSITION OF THE INTESTINAL MICROBIOTA. THE HUMAN INTESTINAL MICROBIOTA COMPRISES ABOUT 100 TRILLION MICROBES. THIS MICROBIOME THRIVES ON UNDIGESTED DIETARY RESIDUES IN THE INTESTINAL LUMEN AND PRODUCES VARIOUS METABOLITES. IT IS WELL KNOWN THAT THE DIETARY RISK FACTORS FOR CRC ARE MEDIATED BY DYSBIOSIS OF THE INTESTINAL MICROBIOTA AND THEIR METABOLITES. IN THIS REVIEW, WE DESCRIBE THE BACTERIAL TAXA ASSOCIATED WITH CRC, INCLUDING FUSOBACTERIUM NUCLEATUM, ENTEROTOXIGENIC BACTEROIDES FRAGILIS, ESCHERICHIA COLI, AND BUTYRATE-PRODUCING BACTERIA. WE ALSO DISCUSS THE HOST-DIET INTERACTION IN COLORECTAL CARCINOGENESIS. 2018 10 5049 23 PHARMACOLOGICAL INHIBITION OF RORC2 ENHANCES HUMAN TH17-TREG STABILITY AND FUNCTION. INFLAMMATORY BOWEL DISEASES (IBD) ARE CHRONIC CONDITIONS THAT RESULT FROM UNCONTROLLED INTESTINAL INFLAMMATION. PATHOGENIC TH17 CELLS, CHARACTERIZED BY PRODUCTION OF IL-17A IN THE ABSENCE OF IL-10, ARE THOUGHT TO CONTRIBUTE TO THIS INFLAMMATION, BUT IN HUMANS, ANTIBODY-MEDIATED BLOCKADE OF IL-17A IS AN INEFFECTIVE IBD THERAPY WHEREAS IL-23 BLOCKADE IS EFFECTIVE. HERE, WE INVESTIGATED THE EFFECTS OF PHARMACOLOGICAL INHIBITION OF RORC2, THE TH17 CELL LINEAGE-DEFINING TRANSCRIPTION FACTOR, ON IN VIVO-DIFFERENTIATED HUMAN TH17 CELLS AND TH17-LIKE TREGS (TH17-TREGS). BMS-336, A SMALL MOLECULE RORC2 INVERSE AGONIST, INHIBITED EXPRESSION OF RORC2-REGULATED GENES IN PERIPHERAL TH17 CELLS (CD4(+) CD25(-) CD127(+) CXCR3(-) CCR4(+) CCR6(+) ) IN A DOSE-DEPENDENT MANNER, WITH SIMILAR INHIBITORY EFFECTS ON LAMINAR PROPRIA MONONUCLEAR CELLS FROM IBD AND NON-IBD SUBJECTS. EXPOSURE OF PERIPHERAL TH17-TREGS (CD4(+) CD25(HI) CD127(LO) CXCR3(-) CCR4(+) CCR6(+) ) TO BMS-336 ALSO INHIBITED IL-17A PRODUCTION AND PREVENTED INFLAMMATORY CYTOKINE-INDUCED DESTABILIZATION, AS EVIDENCED BY PRESERVED FOXP3 EXPRESSION AND EPIGENETIC STATUS OF THE TREG-SPECIFIC DEMETHYLATION REGION. IN PARALLEL, RORC2 INHIBITION INCREASED THE PRODUCTION OF IL-10 IN TH17-TREGS, RESULTING IN ENHANCED SUPPRESSION OF INFLAMMATORY CYTOKINES FROM MYELOID CELLS. THUS, VIA ITS ABILITY TO SIMULTANEOUSLY INHIBIT TH17 CELLS AND ENHANCE THE STABILITY AND FUNCTION OF TH17-TREGS, PHARMACOLOGICAL INHIBITION OF RORC2 IS A PROMISING APPROACH TO SUPPRESS INFLAMMATION AND PROMOTE IMMUNE REGULATION IN IBD. 2020 11 1863 24 EMERGENCE OF MUC1 IN MAMMALS FOR ADAPTATION OF BARRIER EPITHELIA. THE MUCIN 1 (MUC1) GENE WAS DISCOVERED BASED ON ITS OVEREXPRESSION IN HUMAN BREAST CANCERS. SUBSEQUENT WORK DEMONSTRATED THAT MUC1 IS ABERRANTLY EXPRESSED IN CANCERS ORIGINATING FROM OTHER DIVERSE ORGANS, INCLUDING SKIN AND IMMUNE CELLS. THESE FINDINGS SUPPORTED A ROLE FOR MUC1 IN THE ADAPTATION OF BARRIER TISSUES TO INFECTION AND ENVIRONMENTAL STRESS. OF FUNDAMENTAL IMPORTANCE FOR THIS EVOLUTIONARY ADAPTATION WAS INCLUSION OF A SEA DOMAIN, WHICH CATALYZES AUTOPROTEOLYSIS OF THE MUC1 PROTEIN AND FORMATION OF A NON-COVALENT HETERODIMERIC COMPLEX. THE RESULTING MUC1 HETERODIMER IS POISED AT THE APICAL CELL MEMBRANE TO RESPOND TO LOSS OF HOMEOSTASIS. DISRUPTION OF THE COMPLEX RELEASES THE MUC1 N-TERMINAL (MUC1-N) SUBUNIT INTO A PROTECTIVE MUCOUS GEL. CONVERSELY, THE TRANSMEMBRANE C-TERMINAL (MUC1-C) SUBUNIT ACTIVATES A PROGRAM OF LINEAGE PLASTICITY, EPIGENETIC REPROGRAMMING AND REPAIR. THIS MUC1-C-ACTIVATED PROGRAM APPARENTLY EVOLVED FOR BARRIER TISSUES TO MOUNT SELF-REGULATING PROLIFERATIVE, INFLAMMATORY AND REMODELING RESPONSES ASSOCIATED WITH WOUND HEALING. EMERGING EVIDENCE INDICATES THAT MUC1-C UNDERPINS INFLAMMATORY ADAPTATION OF TISSUE STEM CELLS AND IMMUNE CELLS IN THE BARRIER NICHE. THIS REVIEW FOCUSES ON HOW PROLONGED ACTIVATION OF MUC1-C BY CHRONIC INFLAMMATION IN THESE NICHES PROMOTES THE CANCER STEM CELL (CSC) STATE BY ESTABLISHING AUTO-INDUCTIVE NODES THAT DRIVE SELF-RENEWAL AND TUMORIGENICITY. 2022 12 6160 22 THE GENETICS AND PATHOGENESIS OF CAKUT. CONGENITAL ANOMALIES OF THE KIDNEY AND URINARY TRACT (CAKUT) COMPRISE A LARGE VARIETY OF MALFORMATIONS THAT ARISE FROM DEFECTIVE KIDNEY OR URINARY TRACT DEVELOPMENT AND FREQUENTLY LEAD TO KIDNEY FAILURE. THE CLINICAL SPECTRUM RANGES FROM SEVERE MALFORMATIONS, SUCH AS RENAL AGENESIS, TO POTENTIALLY MILDER MANIFESTATIONS, SUCH AS VESICOURETERAL REFLUX. ALMOST 50% OF CASES OF CHRONIC KIDNEY DISEASE THAT MANIFEST WITHIN THE FIRST THREE DECADES OF LIFE ARE CAUSED BY CAKUT. EVIDENCE SUGGESTS THAT A LARGE NUMBER OF CAKUT ARE GENETIC IN ORIGIN. TO DATE, MUTATIONS IN ~54 GENES HAVE BEEN IDENTIFIED AS MONOGENIC CAUSES OF CAKUT, CONTRIBUTING TO 12-20% OF THE AETIOLOGY OF THE DISEASE. PATHOGENIC COPY NUMBER VARIANTS HAVE ALSO BEEN SHOWN TO CAUSE CAKUT AND CAN BE DETECTED IN 4-11% OF PATIENTS. FURTHERMORE, ENVIRONMENTAL AND EPIGENETIC FACTORS CAN INCREASE THE RISK OF CAKUT. THE DISCOVERY OF NOVEL CAKUT-CAUSING GENES IS CHALLENGING OWING TO VARIABLE EXPRESSIVITY, INCOMPLETE PENETRANCE AND VARIABLE GENOTYPE-PHENOTYPE CORRELATION. HOWEVER, SUCH A DISCOVERY COULD ULTIMATELY LEAD TO IMPROVEMENTS IN THE ACCURATE MOLECULAR GENETIC DIAGNOSIS, ASSESSMENT OF PROGNOSIS AND MULTIDISCIPLINARY CLINICAL MANAGEMENT OF PATIENTS WITH CAKUT, POTENTIALLY INCLUDING PERSONALIZED THERAPEUTIC APPROACHES. 2023 13 1262 23 CUTTING EDGE: PROLONGED EXPOSURE TO HIV REINFORCES A POISED EPIGENETIC PROGRAM FOR PD-1 EXPRESSION IN VIRUS-SPECIFIC CD8 T CELLS. AG-SPECIFIC CD8 T CELLS PLAY A CRITICAL ROLE IN CONTROLLING HIV INFECTION BUT EVENTUALLY LOSE ANTIVIRAL FUNCTIONS IN PART BECAUSE OF EXPRESSION AND SIGNALING THROUGH THE INHIBITORY PROGRAMMED DEATH-1 (PD-1) RECEPTOR. TO BETTER UNDERSTAND THE IMPACT OF PROLONGED TCR LIGATION ON REGULATION OF PD-1 EXPRESSION IN HIV-SPECIFIC CD8 T CELLS, WE INVESTIGATED THE CAPACITY OF VIRUS-SPECIFIC CD8 T CELLS TO MODIFY THE PD-1 EPIGENETIC PROGRAM AFTER REDUCTION IN VIRAL LOAD. WE OBSERVED THAT THE TRANSCRIPTIONAL REGULATORY REGION WAS UNMETHYLATED IN THE PD-1(HI) HIV-SPECIFIC CD8 T CELLS, WHEREAS IT REMAINED METHYLATED IN DONOR-MATCHED NAIVE CELLS AT ACUTE AND CHRONIC STAGES OF INFECTION. SURPRISINGLY, THE PD-1 PROMOTER REMAINED UNMETHYLATED IN HIV-SPECIFIC CD8 T CELLS FROM SUBJECTS WITH A VIRAL LOAD CONTROLLED BY ANTIVIRAL THERAPY FOR >2 Y OR FROM ELITE CONTROLLERS. TOGETHER, THESE DATA DEMONSTRATE THAT THE EPIGENETIC PROGRAM AT THE PD-1 LOCUS BECOMES FIXED AFTER PROLONGED EXPOSURE TO HIV VIRUS. 2013 14 1470 26 DISTINCT GENE EXPRESSION PROFILES IN IMMORTALIZED HUMAN UROTHELIAL CELLS EXPOSED TO INORGANIC ARSENITE AND ITS METHYLATED TRIVALENT METABOLITES. INORGANIC ARSENIC IS AN ENVIRONMENTAL CARCINOGEN. THE GENERATION OF TOXIC TRIVALENT METHYLATED METABOLITES COMPLICATES THE STUDY OF ARSENIC-MEDIATED CARCINOGENESIS. THIS STUDY SYSTEMATICALLY EVALUATED THE EFFECT OF CHRONIC TREATMENT WITH SODIUM ARSENITE (IAS(III)), MONOMETHYLARSONOUS ACID (MMA(III)), AND DIMETHYLARSINOUS ACID (DMA(III)) ON IMMORTALIZED HUMAN UROEPITHELIAL CELLS (SV-HUC-1 CELLS) USING CDNA MICROARRAY. AFTER EXPOSURE FOR 25 PASSAGES TO IAS(III) (0.5 MICROM), MMA(III) (0.05, 0.1, OR 0.2 MICROM), OR DMA(III) (0.2 OR 0.5 MICROM), SIGNIFICANT COMPOUND-SPECIFIC MORPHOLOGIC CHANGES WERE OBSERVED. A SET OF 114 GENES (5.7% OF THE EXAMINED GENES) WAS DIFFERENTIALLY EXPRESSED IN ONE OR MORE SETS OF ARSENICAL-TREATED CELLS COMPARED WITH UNTREATED CONTROLS. EXPRESSION ANALYSIS SHOWED THAT EXPOSURE OF CELLS TO DMA(III) RESULTED IN A GENE PROFILE DIFFERENT FROM THAT IN CELLS EXPOSED TO IAS(III) OR MMA(III), AND THAT THE IAS(III)-INDUCED GENE PROFILE WAS CLOSEST TO THAT IN THE TUMORIGENIC HUC-1-DERIVED 3-METHYLCHOLANTHRENE-INDUCED TUMORIGENIC CELL LINE MC-SV-HUC T2, WHICH WAS DERIVED FROM SV-HUC-1 CELLS BY METHYLCHOLANTHRENE TREATMENT. OF THE GENES AFFECTED BY ALL THREE ARSENICALS, ONLY ONE, THAT CODING FOR INTERLEUKIN-1 RECEPTOR, TYPE II, SHOWED ENHANCED EXPRESSION, A FINDING CONFIRMED BY THE REDUCED INCREASE IN NF-KAPPAB (NUCLEAR FACTOR KAPPA B) ACTIVITY SEEN IN RESPONSE TO INTERLEUKIN-1BETA IN IAS(III)-EXPOSED CELLS. THE EXPRESSION OF 11 GENES WAS SUPPRESSED BY ALL THREE ARSENICALS. 5-AZA-DEOXYCYTIDINE PARTIALLY RESTORED THE TRANSCRIPTION OF SEVERAL SUPPRESSED GENES, SHOWING THAT EPIGENETIC DNA METHYLATION WAS PROBABLY INVOLVED IN ARSENICAL-INDUCED GENE REPRESSION. OUR DATA DEMONSTRATE THAT CHRONIC EXPOSURE TO IAS(III), MMA(III), OR DMA(III) HAS DIFFERENT EPIGENETIC EFFECTS ON UROTHELIAL CELLS AND REPRESSES NF-KAPPAB ACTIVITY. 2006 15 6052 27 THE CROHN'S DISEASE ASSOCIATED SNP RS6651252 IMPACTS MYC GENE EXPRESSION IN HUMAN COLONIC EPITHELIAL CELLS. CROHN'S DISEASE (CD) IS A DEBILITATING INFLAMMATORY BOWEL DISEASE (IBD) THAT ARISES FROM CHRONIC INFLAMMATION IN THE GASTROINTESTINAL TRACT. GENOME-WIDE ASSOCIATION STUDIES (GWAS) HAVE IDENTIFIED OVER 200 SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) THAT ARE ASSOCIATED WITH A PREDISPOSITION FOR DEVELOPING IBD. FOR THE MAJORITY, THE CAUSAL VARIANT AND TARGET GENES AFFECTED ARE UNKNOWN. HERE, WE INVESTIGATED THE CD-ASSOCIATED SNP RS6651252 THAT MAPS TO A GENE DESERT REGION ON CHROMOSOME 8. WE DEMONSTRATE THAT RS6651252 RESIDES WITHIN A WNT RESPONSIVE DNA ENHANCER ELEMENT (WRE) AND THAT THE DISEASE ASSOCIATED ALLELE AUGMENTS BINDING OF THE TCF7L2 TRANSCRIPTION FACTOR TO THIS REGION. USING CRISPR/CAS9 DIRECTED GENE EDITING AND EPIGENETIC MODULATION, WE FIND THAT THE RS6651252 ENHANCER REGULATES EXPRESSION OF THE C-MYC PROTO-ONCOGENE (MYC). FURTHERMORE, WE FOUND MYC TRANSCRIPT LEVELS ARE ELEVATED IN PATIENT-DERIVED COLONIC SEGMENTS HARBORING THE DISEASE-ASSOCIATED ALLELE IN COMPARISON TO THOSE CONTAINING THE ANCESTRAL ALLELE. THESE RESULTS SUGGEST THAT WNT/MYC SIGNALING CONTRIBUTES TO CD PATHOGENESIS AND THAT PATIENTS HARBORING THE DISEASE-ASSOCIATED ALLELE MAY BENEFIT FROM THERAPIES THAT TARGET MYC OR MYC-REGULATED GENES. 2019 16 2425 25 EPIGENETIC SILENCING OF IRF1 DYSREGULATES TYPE III INTERFERON RESPONSES TO RESPIRATORY VIRUS INFECTION IN EPITHELIAL TO MESENCHYMAL TRANSITION. CHRONIC OXIDATIVE INJURY PRODUCED BY AIRWAY DISEASE TRIGGERS A TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA)-MEDIATED EPIGENETIC REPROGRAMMING KNOWN AS THE EPITHELIAL-MESENCHYMAL TRANSITION (EMT). WE OBSERVE THAT EMT SILENCES PROTECTIVE MUCOSAL INTERFERON (IFN)-I AND III PRODUCTION ASSOCIATED WITH ENHANCED RHINOVIRUS (RV) AND RESPIRATORY SYNCYTIAL VIRUS (RSV) REPLICATION. MESENCHYMAL TRANSITIONED CELLS ARE DEFECTIVE IN INDUCIBLE INTERFERON REGULATORY FACTOR 1 (IRF1) EXPRESSION BY OCCLUDING RELA AND IRF3 ACCESS TO THE PROMOTER. IRF1 IS NECESSARY FOR THE EXPRESSION OF TYPE III IFNS (IFNLS 1 AND 2/3). INDUCED BY THE EMT, ZINC FINGER E-BOX BINDING HOMEOBOX 1 (ZEB1) BINDS AND SILENCES IRF1. ECTOPIC ZEB1 IS SUFFICIENT FOR IRF1 SILENCING, WHEREAS ZEB1 KNOCKDOWN PARTIALLY RESTORES IRF1-IFNL UPREGULATION. ZEB1 SILENCES IRF1 THROUGH THE CATALYTIC ACTIVITY OF THE ENHANCER OF ZESTE 2 POLYCOMB REPRESSIVE COMPLEX 2 SUBUNIT (EZH2), FORMING REPRESSIVE H3K27(ME3) MARKS. WE OBSERVE THAT IRF1 EXPRESSION IS MEDIATED BY ZEB1 DE-REPRESSION, AND OUR STUDY DEMONSTRATES HOW AIRWAY REMODELLING/FIBROSIS IS ASSOCIATED WITH A DEFECTIVE MUCOSAL ANTIVIRAL RESPONSE THROUGH ZEB1-INITIATED EPIGENETIC SILENCING. 2017 17 5292 26 PROSTATIC INFLAMMATION ENHANCES BASAL-TO-LUMINAL DIFFERENTIATION AND ACCELERATES INITIATION OF PROSTATE CANCER WITH A BASAL CELL ORIGIN. CHRONIC INFLAMMATION HAS BEEN SHOWN TO PROMOTE THE INITIATION AND PROGRESSION OF DIVERSE MALIGNANCIES BY INDUCING GENETIC AND EPIGENETIC ALTERATIONS. IN THIS STUDY, WE INVESTIGATE AN ALTERNATIVE MECHANISM THROUGH WHICH INFLAMMATION PROMOTES THE INITIATION OF PROSTATE CANCER. ADULT MURINE PROSTATE EPITHELIA ARE COMPOSED PREDOMINANTLY OF BASAL AND LUMINAL CELLS. PREVIOUS STUDIES REVEALED THAT THE TWO LINEAGES ARE LARGELY SELF-SUSTAINED WHEN RESIDING IN THEIR NATIVE MICROENVIRONMENT. TO INTERROGATE WHETHER TISSUE INFLAMMATION ALTERS THE DIFFERENTIATION PROGRAM OF BASAL CELLS, WE CONDUCTED LINEAGE TRACING OF BASAL CELLS USING A K14-CREER;MTMG MODEL IN CONCERT WITH A MURINE MODEL OF PROSTATITIS INDUCED BY INFECTION FROM THE UROPATHOGENIC BACTERIA CP9. WE SHOW THAT ACUTE PROSTATITIS CAUSES TISSUE DAMAGE AND CREATES A TISSUE MICROENVIRONMENT THAT INDUCES THE DIFFERENTIATION OF BASAL CELLS INTO LUMINAL CELLS, AN ALTERATION THAT RARELY OCCURS UNDER NORMAL PHYSIOLOGICAL CONDITIONS. PREVIOUSLY WE SHOWED THAT A MOUSE MODEL WITH PROSTATE BASAL CELL-SPECIFIC DELETION OF PHOSPHATASE AND TENSIN HOMOLOG (K14-CREER;PTEN(FL/FL)) DEVELOPS PROSTATE CANCER WITH A LONG LATENCY, BECAUSE DISEASE INITIATION IN THIS MODEL REQUIRES AND IS LIMITED BY THE DIFFERENTIATION OF TRANSFORMATION-RESISTANT BASAL CELLS INTO TRANSFORMATION-COMPETENT LUMINAL CELLS. HERE, WE SHOW THAT CP9-INDUCED PROSTATITIS SIGNIFICANTLY ACCELERATES THE INITIATION OF PROSTATIC INTRAEPITHELIAL NEOPLASIA IN THIS MODEL. OUR RESULTS DEMONSTRATE THAT INFLAMMATION RESULTS IN A TISSUE MICROENVIRONMENT THAT ALTERS THE NORMAL PROSTATE EPITHELIAL CELL DIFFERENTIATION PROGRAM AND THAT THROUGH THIS CELLULAR PROCESS INFLAMMATION ACCELERATES THE INITIATION OF PROSTATE CANCER WITH A BASAL CELL ORIGIN. 2014 18 6417 25 THE SWI/SNF CHROMATIN REMODELING COMPLEXES BAF AND PBAF DIFFERENTIALLY REGULATE EPIGENETIC TRANSITIONS IN EXHAUSTED CD8(+) T CELLS. CD8(+) T CELL EXHAUSTION (TEX) LIMITS DISEASE CONTROL DURING CHRONIC VIRAL INFECTIONS AND CANCER. HERE, WE INVESTIGATED THE EPIGENETIC FACTORS MEDIATING MAJOR CHROMATIN-REMODELING EVENTS IN TEX-CELL DEVELOPMENT. A PROTEIN-DOMAIN-FOCUSED IN VIVO CRISPR SCREEN IDENTIFIED DISTINCT FUNCTIONS FOR TWO VERSIONS OF THE SWI/SNF CHROMATIN-REMODELING COMPLEX IN TEX-CELL DIFFERENTIATION. DEPLETION OF THE CANONICAL SWI/SNF FORM, BAF, IMPAIRED INITIAL CD8(+) T CELL RESPONSES IN ACUTE AND CHRONIC INFECTION. IN CONTRAST, DISRUPTION OF PBAF ENHANCED TEX-CELL PROLIFERATION AND SURVIVAL. MECHANISTICALLY, PBAF REGULATED THE EPIGENETIC AND TRANSCRIPTIONAL TRANSITION FROM TCF-1(+) PROGENITOR TEX CELLS TO MORE DIFFERENTIATED TCF-1(-) TEX SUBSETS. WHEREAS PBAF ACTED TO PRESERVE TEX PROGENITOR BIOLOGY, BAF WAS REQUIRED TO GENERATE EFFECTOR-LIKE TEX CELLS, SUGGESTING THAT THE BALANCE OF THESE FACTORS COORDINATES TEX-CELL SUBSET DIFFERENTIATION. TARGETING PBAF IMPROVED TUMOR CONTROL BOTH ALONE AND IN COMBINATION WITH ANTI-PD-L1 IMMUNOTHERAPY. THUS, PBAF MAY PRESENT A THERAPEUTIC TARGET IN CANCER IMMUNOTHERAPY. 2023 19 2065 27 EPIGENETIC CONTROL OF INTESTINAL BARRIER FUNCTION AND INFLAMMATION IN ZEBRAFISH. THE INTESTINAL EPITHELIUM FORMS A BARRIER PROTECTING THE ORGANISM FROM MICROBES AND OTHER PROINFLAMMATORY STIMULI. THE INTEGRITY OF THIS BARRIER AND THE PROPER RESPONSE TO INFECTION REQUIRES PRECISE REGULATION OF POWERFUL IMMUNE HOMING SIGNALS SUCH AS TUMOR NECROSIS FACTOR (TNF). DYSREGULATION OF TNF LEADS TO INFLAMMATORY BOWEL DISEASES (IBD), BUT THE MECHANISM CONTROLLING THE EXPRESSION OF THIS POTENT CYTOKINE AND THE EVENTS THAT TRIGGER THE ONSET OF CHRONIC INFLAMMATION ARE UNKNOWN. HERE, WE SHOW THAT LOSS OF FUNCTION OF THE EPIGENETIC REGULATOR UBIQUITIN-LIKE PROTEIN CONTAINING PHD AND RING FINGER DOMAINS 1 (UHRF1) IN ZEBRAFISH LEADS TO A REDUCTION IN TNFA PROMOTER METHYLATION AND THE INDUCTION OF TNFA EXPRESSION IN INTESTINAL EPITHELIAL CELLS (IECS). THE INCREASE IN IEC TNFA LEVELS IS MICROBE-DEPENDENT AND RESULTS IN IEC SHEDDING AND APOPTOSIS, IMMUNE CELL RECRUITMENT, AND BARRIER DYSFUNCTION, CONSISTENT WITH CHRONIC INFLAMMATION. IMPORTANTLY, TNFA KNOCKDOWN IN UHRF1 MUTANTS RESTORES IEC MORPHOLOGY, REDUCES CELL SHEDDING, AND IMPROVES BARRIER FUNCTION. WE PROPOSE THAT LOSS OF EPIGENETIC REPRESSION AND TNF INDUCTION IN THE INTESTINAL EPITHELIUM CAN LEAD TO IBD ONSET. 2015 20 473 25 ARSENIC AND URINARY BLADDER CELL PROLIFERATION. EPIDEMIOLOGIC STUDIES HAVE DEMONSTRATED THAT A CLOSE ASSOCIATION EXISTS BETWEEN THE ELEVATED LEVELS OF ARSENIC IN DRINKING WATER AND THE INCIDENCE OF CERTAIN CANCERS, INCLUDING TRANSITIONAL CELL CARCINOMAS OF THE URINARY BLADDER. WE HAVE EMPLOYED IN VITRO AND IN VIVO MODELS TO EXAMINE THE EFFECTS OF SODIUM ARSENITE ON THE URINARY BLADDER EPITHELIUM. MICE EXPOSED TO 0.01% SODIUM ARSENITE IN DRINKING WATER DEMONSTRATED HYPERPROLIFERATION OF THE BLADDER UROEPITHELIUM WITHIN 4 WEEKS AFTER INITIATING TREATMENT. THIS OCCURRED IN THE ABSENCE OF AMORPHOUS PRECIPITATES AND WAS ACCOMPANIED BY THE ACCUMULATION OF TRIVALENT ARSENITE (IAS(3+)), AND TO A LESSER EXTENT DIMETHYLARSENIC (DMA), ARSENATE (IAS(5+)), AND MONOMETHYLARSENIC (MMA) IN BLADDER TISSUE. IN CONTRAST TO THE BLADDER, URINARY SECRETION WAS PRIMARILY IN THE FORM OF DMA AND MMA. ARSENIC-INDUCED CELL PROLIFERATION IN THE BLADDER EPITHELIUM WAS CORRELATED WITH ACTIVATION OF THE MAP KINASE PATHWAY, LEADING TO EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK) KINASE ACTIVITY, AP-1 ACTIVATION, AND EXPRESSION OF AP-1-ASSOCIATED GENES INVOLVED IN CELL PROLIFERATION. ACTIVATION OF THE MAP KINASE PATHWAY INVOLVED BOTH EPIDERMAL GROWTH FACTOR (EGF) RECEPTOR-DEPENDENT AND -INDEPENDENT EVENTS, THE LATTER INVOLVING SRC ACTIVATION. STUDIES SUMMARIZED IN THIS REVIEW SUGGEST THAT ARSENIC ACCUMULATES IN URINARY BLADDER EPITHELIUM CAUSING ACTIVATION OF SPECIFIC SIGNALING PATHWAYS THAT LEAD TO CHRONIC INCREASED CELL PROLIFERATION. THIS MAY PLAY A NON-EPIGENETIC ROLE IN CARCINOGENESIS BY INCREASING THE PROLIFERATION OF INITIATED CELLS OR INCREASING THE MUTATIONAL RATE. 2004