1 5864 108 SUPPRESSION OF ELF4 IN ULCERATIVE COLITIS PREDISPOSES HOST TO COLORECTAL CANCER. ULCERATIVE COLITIS (UC) IS A CHRONIC INFLAMMATORY BOWEL DISEASE, CHARACTERIZED BY RELAPSING AND REMITTING COLON MUCOSAL INFLAMMATION. FOR PATIENTS SUFFERING FROM UC, A HIGHER RISK OF COLON CANCER HAS BEEN WIDELY RECOGNIZED. HERE, WE FOUND THAT ELF4 (-/-) MICE DEVELOPED COLON TUMORS WITH 3 CYCLES OF DEXTRAN SULFATE SODIUM SALT (DSS) TREATMENT ALONE. WE FURTHER SHOWED THAT ELF4 SUPPRESSION WAS PREVALENT IN BOTH PATIENTS WITH UC AND DSS-INDUCED MICE MODELS, AND THIS SUPPRESSION WAS CAUSED BY PROMOTER REGION METHYLATION. ELF4, UPON PARYLATION BY PARP1, TRANSCRIPTIONALLY REGULATED MULTIPLE DNA DAMAGE REPAIR MACHINERY COMPONENTS. CONSISTENTLY, ELF4 DEFICIENCY LEADS TO MORE SEVERE DNA DAMAGE BOTH IN VITRO AND IN VIVO. ORAL ADMINISTRATION OF MONTMORILLONITE POWDER CAN PREVENT THE REDUCTION OF ELF4 IN DSS-INDUCED COLITIS MODELS AND LOWER THE RISK OF COLON TUMOR DEVELOPMENT DURING AZOXYMETHANE (AOM) AND DSS INDUCED COLITIS-ASSOCIATED CANCER (CAC). THESE DATA PROVIDED ADDITIONAL MECHANISM OF CAC INITIATION AND SUPPORTED THE "EPIGENETIC PRIMING MODEL OF TUMOR INITIATION". 2021 2 5963 31 TEM STUDY OF CHRONIC ALCOHOLISM EFFECTS ON EARLY CARCINOGENESIS BY PROBING THE NANOSCALE STRUCTURAL ALTERATIONS OF CELL NUCLEI. NANOSCALE STRUCTURAL ALTERATION IN THE NUCLEI OF CELLS WITH THE PROGRESSION OF CARCINOGENESIS IS DUE TO THE REARRANGEMENTS OF THE BASIC BUILDING BLOCKS IN THE CELL SUCH AS DNA, RNA, LIPIDS, ETC. ALTHOUGH EPIGENETIC MODIFICATIONS UNDERLIE THE DEVELOPMENT OF CANCER, EXPOSURE TO CARCINOGENIC CHEMICALS SUCH AS ALCOHOL ALSO ENHANCES THE DEVELOPMENT OF CANCER. WE REPORT THE EFFECTS OF CHRONIC ALCOHOLISM ON EARLY-CARCINOGENESIS BASED ON CHANGES IN THE DEGREE OF NANOSCALE STRUCTURAL ALTERATIONS (L (D)) IN NUCLEI. FOR THIS, TRANSMISSION ELECTRON MICROSCOPY (TEM) IMAGING OF THE NUCLEI OF COLONIC CELLS IS PERFORMED FOR THE FOLLOWING FOUR MOUSE MODELS: CONTROL MICE; CHRONIC ALCOHOLIC MICE TREATED WITH ETHANOL (I.E., ETOH MICE); MICE TREATED WITH COLONIC CARCINOGEN AZOXYMETHANE (AOM) AND DEXTRAN SULFATE SODIUM (DSS) THAT INDUCED COLITIS (I.E., AOM + DSS MICE); AND CHRONIC ALCOHOLIC OR ETOH TREATED MICE, TOGETHER WITH AOM AND DSS TREATMENT (I.E., AOM + DSS + ETOH MICE). THE DISORDERED OPTICAL LATTICES ARE CONSTRUCTED FROM THEIR RESPECTIVE TEM IMAGES OF THIN COLONIC CELL NUCLEI AND THE L (D) VALUES ARE CALCULATED USING THE INVERSE PARTICIPATION RATIO (IPR) TECHNIQUE FROM THE SPATIALLY LOCALIZED EIGENFUNCTIONS OF THESE LATTICES. RESULTS SHOW NO SIGNIFICANT DIFFERENCE IN THE AVERAGE L (D) VALUE OF THE COLON CELL NUCLEI OF ALCOHOL TREATED MICE RELATIVE TO ITS CONTROL [I.E., L (D)(C) APPROXIMATELY L (D)(ETOH)]; HOWEVER, AN INCREASE IN THE L (D) VALUE OF ALCOHOL TREATED PRECANCEROUS CELLS [I.E., L (D)(AOM + DSS + ETOH) > L (D)(AOM + DSS)], INDICATING THAT ALCOHOL ACCELERATES THE EARLY CARCINOGENIC PROCESS. 2021 3 5999 27 THE ACETYLOME REGULATORS HDAC1 AND HDAC2 DIFFERENTLY MODULATE INTESTINAL EPITHELIAL CELL DEPENDENT HOMEOSTATIC RESPONSES IN EXPERIMENTAL COLITIS. HISTONE DEACETYLASES (HDAC) REMOVE ACETYL GROUPS FROM PROTEINS, INFLUENCING GLOBAL AND SPECIFIC GENE EXPRESSION. HDACS CONTROL INFLAMMATION, AS SHOWN BY HDAC INHIBITOR-DEPENDENT PROTECTION FROM DEXTRAN SULFATE SODIUM (DSS)-INDUCED MURINE COLITIS. ALTHOUGH TISSUE-SPECIFIC HDAC KNOCKOUTS SHOW REDUNDANT AND SPECIFIC FUNCTIONS, LITTLE IS KNOWN OF THEIR INTESTINAL EPITHELIAL CELL (IEC) ROLE. WE HAVE SHOWN PREVIOUSLY THAT DUAL HDAC1/HDAC2 IEC-SPECIFIC LOSS DISRUPTS CELL PROLIFERATION AND DETERMINATION, WITH DECREASED SECRETORY CELL NUMBERS AND ALTERED BARRIER FUNCTION. WE THUS INVESTIGATED HOW COMPOUND HDAC1/HDAC2 OR HDAC2 IEC-SPECIFIC DEFICIENCY ALTERS THE INFLAMMATORY RESPONSE. FLOXED HDAC1 AND HDAC2 AND VILLIN-CRE MICE WERE INTERBRED. COMPOUND HDAC1/HDAC2 IEC-DEFICIENT MICE SHOWED CHRONIC BASAL INFLAMMATION, WITH INCREASED BASAL DISEASE ACTIVITY INDEX (DAI) AND DEREGULATED REG GENE COLONIC EXPRESSION. DSS-TREATED DUAL HDAC1/HDAC2 IEC-DEFICIENT MICE DISPLAYED INCREASED DAI, HISTOLOGICAL SCORE, INTESTINAL PERMEABILITY, AND INFLAMMATORY GENE EXPRESSION. IN CONTRAST TO DOUBLE KNOCKOUTS, HDAC2 IEC-SPECIFIC LOSS DID NOT AFFECT IEC DETERMINATION AND GROWTH, NOR RESULT IN CHRONIC INFLAMMATION. HOWEVER, HDAC2 DISRUPTION PROTECTED AGAINST DSS COLITIS, AS SHOWN BY DECREASED DAI, INTESTINAL PERMEABILITY AND CASPASE-3 CLEAVAGE. HDAC2 IEC-SPECIFIC DEFICIENT MICE DISPLAYED INCREASED EXPRESSION OF IEC GENE SUBSETS, SUCH AS COLONIC ANTIMICROBIAL REG3B AND REG3G MRNAS, AND DECREASED EXPRESSION OF IMMUNE CELL FUNCTION-RELATED GENES. OUR DATA SHOW THAT HDAC1 AND HDAC2 ARE ESSENTIAL IEC HOMEOSTASIS REGULATORS. IEC-SPECIFIC HDAC1 AND HDAC2 MAY ACT AS EPIGENETIC SENSORS AND TRANSMITTERS OF ENVIRONMENTAL CUES AND REGULATE IEC-MEDIATED MUCOSAL HOMEOSTATIC AND INFLAMMATORY RESPONSES. DIFFERENT LEVELS OF IEC HDAC ACTIVITY MAY LEAD TO POSITIVE OR NEGATIVE OUTCOMES ON INTESTINAL HOMEOSTASIS DURING INFLAMMATION. 2014 4 3867 30 JMJD3/H3K27ME3 EPIGENETIC MODIFICATION REGULATES TH17/TREG CELL DIFFERENTIATION IN ULCERATIVE COLITIS. ULCERATIVE COLITIS (UC) IS A CHRONIC NONSPECIFIC INFLAMMATORY BOWEL DISEASE CHARACTERIZED BY CHRONIC INFLAMMATION AND ULCERATION OF THE COLONIC MUCOSA, FREQUENT RELAPSE, AND CANCERIZATION THAT IS DIFFICULT TO CURE. IN RECENT YEARS, THE INCIDENCE OF UC HAS INCREASED. HOWEVER, ITS ETIOLOGY AND PATHOGENESIS ARE STILL NOT COMPLETELY CLEAR. IN THIS STUDY, DEXTRAN SODIUM SULFATE (DSS) WAS USED TO INDUCE THE MODEL, AND GSK-J1 AND DEXAMETHASONE WERE ADMINISTERED TO THE MICE. A VARIETY OF MOLECULAR BIOLOGY AND IMMUNOLOGICAL TECHNIQUES, SUCH AS IMMUNOFLUORESCENCE, PCR AND CHROMATIN IMMUNOPRECIPITATION (CHIP), WERE USED TO EXAMINE JMJD3/H3K27ME3-MEDIATED REGULATION OF TH17/TREG CELL DIFFERENTIATION IN UC BY TARGETING HISTONE MODIFICATION. THIS STUDY WILL PROVIDE AN IMPORTANT THEORETICAL BASIS FOR UNDERSTANDING THE PATHOGENESIS AND POTENTIAL THERAPEUTIC TARGETS OF UC. 2022 5 4933 29 PATERNAL CHRONIC COLITIS CAUSES EPIGENETIC INHERITANCE OF SUSCEPTIBILITY TO COLITIS. INFLAMMATORY BOWEL DISEASE (IBD) ARISES BY UNKNOWN ENVIRONMENTAL TRIGGERS IN GENETICALLY SUSCEPTIBLE INDIVIDUALS. EPIGENETIC REGULATION OF GENE EXPRESSION MAY INTEGRATE INTERNAL AND EXTERNAL INFLUENCES AND MAY THEREBY MODULATE DISEASE SUSCEPTIBILITY. EPIGENETIC MODIFICATION MAY ALSO AFFECT THE GERM-LINE AND IN CERTAIN CONTEXTS CAN BE INHERITED TO OFFSPRING. THIS STUDY INVESTIGATES EPIGENETIC ALTERATIONS CONSEQUENT TO EXPERIMENTAL MURINE COLITIS INDUCED BY DEXTRAN SODIUM SULPHATE (DSS), AND THEIR PATERNAL TRANSMISSION TO OFFSPRING. GENOME-WIDE METHYLOME- AND TRANSCRIPTOME-PROFILING OF INTESTINAL EPITHELIAL CELLS (IECS) AND SPERM CELLS OF MALES OF THE F0 GENERATION, WHICH RECEIVED EITHER DSS AND CONSEQUENTLY DEVELOPED COLITIS (F0(DSS)), OR NON-SUPPLEMENTED TAP WATER (F0(CTRL)) AND HENCE REMAINED HEALTHY, AND OF THEIR F1 OFFSPRING WAS PERFORMED USING REDUCED REPRESENTATION BISULFITE SEQUENCING (RRBS) AND RNA-SEQUENCING (RNA-SEQ), RESPECTIVELY. OFFSPRING OF F0(DSS) MALES EXHIBITED ABERRANT METHYLATION AND EXPRESSION PATTERNS OF MULTIPLE GENES, INCLUDING IGF1R AND NR4A2, WHICH ARE INVOLVED IN ENERGY METABOLISM. IMPORTANTLY, DSS COLITIS IN F0(DSS) MICE WAS ASSOCIATED WITH DECREASED BODY WEIGHT AT BASELINE OF THEIR F1 OFFSPRING, AND THESE F1 MICE EXHIBITED INCREASED SUSCEPTIBILITY TO DSS-INDUCED COLITIS COMPARED TO OFFSPRING FROM F0(CTRL) MALES. THIS STUDY HENCE DEMONSTRATES EPIGENETIC TRANSMISSIBILITY OF METABOLIC AND INFLAMMATORY TRAITS RESULTING FROM EXPERIMENTAL COLITIS. 2016 6 1905 39 ENHANCER OF ZESTE HOMOLOG 2 CONTRIBUTES TO APOPTOSIS BY INACTIVATING JANUS KINASE 2/ SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION SIGNALING IN INFLAMMATORY BOWEL DISEASE. BACKGROUND: INFLAMMATORY BOWEL DISEASE (IBD) IS A PREVALENT WORLDWIDE HEALTH PROBLEM FEATURED BY RELAPSING, CHRONIC GASTROINTESTINAL INFLAMMATION. ENHANCER OF ZESTE HOMOLOG 2 (EZH2) IS A CRITICAL EPIGENETIC REGULATOR IN DIFFERENT PATHOLOGICAL MODELS, SUCH AS CANCER AND INFLAMMATION. HOWEVER, THE ROLE OF EZH2 IN THE IBD DEVELOPMENT IS STILL OBSCURE. AIM: TO EXPLORE THE EFFECT OF EZH2 ON IBD PROGRESSION AND THE UNDERLYING MECHANISM. METHODS: THE IBD MOUSE MODEL WAS CONDUCTED BY ADDING DEXTRAN SODIUM SULFATE (DSS), AND THE EFFECT OF EZH2 ON DSS-INDUCED COLITIS WAS ASSESSED IN THE MODEL. THE FUNCTION OF EZH2 IN REGULATING APOPTOSIS AND PERMEABILITY WAS EVALUATED BY ANNEXIN V-FITC APOPTOSIS DETECTION KIT, TRANSEPITHELIAL ELECTRICAL RESISTANCE ANALYSIS, AND WESTERN BLOT ANALYSIS OF RELATED MARKERS, INCLUDING ZONA OCCLUDENS 1, CLAUDIN-5, AND OCCLUDIN, IN NCM460 AND FETAL HUMAN COLON (FHC) CELLS. THE MECHANICAL INVESTIGATION WAS PERFORMED BY QUANTITATIVE REVERSE TRANSCRIPTION-POLYMERASE CHAIN REACTION, WESTERN BLOT ANALYSIS, AND CHROMATIN IMMUNOPRECIPITATION ASSAYS. RESULTS: THE COLON LENGTH WAS INHIBITED IN THE DSS-TREATED MICE AND WAS ENHANCED BY THE EZH2 DEPLETION IN THE SYSTEM. DSS TREATMENT CAUSED A DECREASED HISTOLOGICAL SCORE IN THE MICE, WHICH WAS REVERSED BY EZH2 DEPLETION. THE INFLAMMATORY CYTOKINES, SUCH AS TUMOR NECROSIS FACTOR-ALPHA, INTERLEUKIN-6, AND INTERLEUKIN-1BETA, WERE INDUCED IN THE DSS-TREATED MICE, IN WHICH THE DEPLETION OF EZH2 COULD REVERSE THIS EFFECT. MOREOVER, THE TUMOR NECROSIS FACTOR-ALPHA TREATMENT INDUCED THE APOPTOSIS OF NCM460 AND FHC CELLS, IN WHICH EZH2 DEPLETION COULD REVERSE THIS EFFECT IN THE CELLS. MOREOVER, THE DEPLETION OF EZH2 ATTENUATED PERMEABILITY OF COLONIC EPITHELIAL CELLS. MECHANICALLY, THE DEPLETION OF EZH2 OR EZH2 INHIBITOR GSK343 WAS ABLE TO ENHANCE THE EXPRESSION AND THE PHOSPHORYLATION OF JANUS KINASE 2 (JK2) AND SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION IN THE NCM460 AND FHC CELLS. SPECIFICALLY, EZH2 INACTIVATED JAK2 EXPRESSION BY REGULATING HISTONE H3K27ME3. JAK2 INHIBITOR TG101348 WAS ABLE TO REVERSE EZH2 KNOCKDOWN-MEDIATED COLONIC EPITHELIAL CELL PERMEABILITY AND APOPTOSIS. CONCLUSION: THUS, WE CONCLUDED THAT EZH2 CONTRIBUTED TO APOPTOSIS AND INFLAMMATORY RESPONSE BY INACTIVATING JAK2/ SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION SIGNALING IN IBD. EZH2 MAY BE APPLIED AS A POTENTIAL TARGET FOR IBD THERAPY. 2021 7 6118 37 THE EPIGENETIC EFFECTS OF ASPIRIN: THE MODIFICATION OF HISTONE H3 LYSINE 27 ACETYLATION IN THE PREVENTION OF COLON CARCINOGENESIS IN AZOXYMETHANE- AND DEXTRAN SULFATE SODIUM-TREATED CF-1 MICE. COLORECTAL CANCER (CRC) IS THE THIRD MOST COMMON CANCER WORLDWIDE. CHRONIC INFLAMMATION APPEARS TO ENHANCE THE RISK OF CRC. EMERGING EVIDENCE HAS SUGGESTED THAT EPIGENETIC MECHANISMS PLAY AN IMPORTANT ROLE IN CRC. ASPIRIN [ACETYLSALICYLIC ACID (ASA)] HAS BEEN SHOWN TO PREVENT CRC; HOWEVER, THE EPIGENETIC MECHANISMS OF ITS ACTION REMAIN UNKNOWN. THIS STUDY INVESTIGATED THE PROTECTIVE ROLE OF ASA IN AZOXYMETHANE (AOM)-INITIATED AND DEXTRAN SULFATE SODIUM (DSS)-PROMOTED COLITIS-ASSOCIATED COLON CANCER (CAC) AND EXAMINED THE EPIGENETIC EFFECTS, PARTICULARLY ON HISTONE 3 LYSINE 27 ACETYLATION (H3K27AC), UNDERLYING THE PREVENTIVE EFFECT OF ASA. CF-1 MICE WERE FED WITH AIN-93M DIET WITH OR WITHOUT 0.02% ASA FROM 1 WEEK PRIOR TO AOM INITIATION UNTIL THE MICE WERE KILLED 20 WEEKS AFTER AOM INJECTION. OUR RESULTS SHOWED THAT AOM/DSS + ASA SIGNIFICANTLY SUPPRESSED INFLAMMATORY COLITIS SYMPTOMS AND TUMOR MULTIPLICITY. AOM/DSS + ASA REDUCED AOM/DSS-INDUCED PROTEIN EXPRESSION AND THE ACTIVITY OF HISTONE DEACETYLASES (HDACS) AND GLOBALLY RESTORED H3K27AC. FURTHERMORE, AOM/DSS + ASA INHIBITED AOM/DSS-INDUCED ENRICHMENT OF H3K27AC IN THE PROMOTERS OF INDUCIBLE NITRIC OXIDE SYNTHASE (INOS), TUMOR NECROSIS FACTOR ALPHA (TNF-ALPHA) AND INTERLEUKIN 6 (IL-6) THAT CORRESPONDED TO THE DRAMATIC SUPPRESSION OF THE MESSENGER RNA (MRNA) AND PROTEIN LEVELS. SURPRISINGLY, NO SIGNIFICANT CHANGES IN THE H3K27AC ABUNDANCE IN THE PROSTAGLANDIN-ENDOPEROXIDE SYNTHASE 2 (COX-2) PROMOTERS OR IN THE COX-2 MRNA AND PROTEIN EXPRESSION WERE OBSERVED. COLLECTIVELY, OUR RESULTS SUGGEST THAT A POTENTIAL NOVEL EPIGENETIC MECHANISM UNDERLIES THE CHEMOPREVENTIVE EFFECTS OF ASA, AND THIS MECHANISM ATTENUATES CAC IN AOM/DSS-INDUCED CF-1 MICE VIA THE INHIBITION OF HDACS AND THE MODIFICATION OF H3K27AC MARKS THAT SUPPRESS INOS, TNF-ALPHA AND IL-6. 2016 8 2957 36 GENETIC AND EPIGENETIC IMPACT OF CHRONIC INFLAMMATION ON COLON MUCOSA CELLS. CHRONIC INFLAMMATION INCREASES CANCER RISK, AND CANCER DEVELOPMENT IS CHARACTERIZED BY STEPWISE ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS. DURING CHRONIC INFLAMMATION, INFECTIOUS AGENTS AND INTRINSIC MEDIATORS OF INFLAMMATORY RESPONSES CAN INDUCE GENETIC AND EPIGENETIC CHANGES. THIS STUDY TRIED TO EVALUATE BOTH THE GENETIC AND EPIGENETIC INFLUENCE OF CHRONIC INFLAMMATION ON COLON MUCOSA CELLS. REPETITIVE DEXTRAN SULFATE SODIUM (DSS) TREATMENT INDUCED CHRONIC COLITIS MODEL. WHOLE-EXOME SEQUENCING (WES) (200X COVERAGE) WAS PERFORMED TO DETECT SOMATIC VARIATIONS IN COLON MUCOSA CELLS. WITH THE USE OF WHOLE-GENOME BISULFITE SEQUENCING (BS) AT 34-FOLD COVERAGE (17-FOLD PER STRAND), THE METHYLOME OF BOTH THE COLITIS AND CONTROL TISSUE WAS COMPARATIVELY ANALYZED. BIOINFORMATICS ASSAY SHOWED THAT THERE WAS NO SIGNIFICANT SINGLE-NUCLEOTIDE POLYMORPHISM/INSERTION OR DELETION (SNP/INDEL) MUTATION ACCUMULATION IN COLITIS TISSUE, WHILE IT ACCUMULATED IN AGED MICE. FORTY-EIGHT GENES WITH SNP/INDEL MUTATION WERE OVERLAPPED IN THE THREE COLITIS TISSUES, TWO (WNT3A AND LAMA2) OF WHICH ARE IN THE CANCER DEVELOPMENT-RELATED SIGNALING PATHWAY. DIFFERENTIALLY METHYLATED REGION (DMR) ASSAY SHOWED THAT MANY GENES IN THE COLITIS TISSUE ARE ENRICHED IN THE CANCER DEVELOPMENT-RELATED SIGNALING PATHWAY, SUCH AS PI3K-AKT, RAS, WNT, TGF-BETA, AND MAPK SIGNALING PATHWAY. TOGETHER, THESE DATA SUGGESTED THAT EVEN THOUGH CHRONIC INFLAMMATION DID NOT OBVIOUSLY INCREASE GENETIC MUTATION ACCUMULATION, IT COULD BOTH GENETICALLY AND EPIGENETICALLY ALTER SOME GENES RELATED TO CANCER DEVELOPMENT. 2021 9 3658 35 INDUCTION OF ABERRANT TRIMETHYLATION OF HISTONE H3 LYSINE 27 BY INFLAMMATION IN MOUSE COLONIC EPITHELIAL CELLS. A FIELD FOR CANCERIZATION (FIELD DEFECT), WHERE GENETIC AND EPIGENETIC ALTERATIONS ARE ACCUMULATED IN NORMAL-APPEARING TISSUES, IS INVOLVED IN HUMAN CARCINOGENESIS, ESPECIALLY CANCERS ASSOCIATED WITH CHRONIC INFLAMMATION. ALTHOUGH ABERRANT DNA METHYLATION IS INVOLVED IN THE FIELD DEFECT AND INDUCED BY CHRONIC INFLAMMATION, IT IS STILL UNCLEAR FOR TRIMETHYLATION OF HISTONE H3 LYSINE 27 (H3K27ME3), WHICH IS INVOLVED IN GENE REPRESSION INDEPENDENT OF DNA METHYLATION AND FUNCTIONS AS A PRE-MARK FOR ABERRANT DNA METHYLATION. IN THIS STUDY, USING A MOUSE COLITIS MODEL INDUCED BY DEXTRAN SULFATE SODIUM (DSS), WE AIMED TO CLARIFY WHETHER ABERRANT H3K27ME3 IS INDUCED BY INFLAMMATION AND INVOLVED IN A FIELD DEFECT. CHIP-ON-CHIP ANALYSIS OF COLONIC EPITHELIAL CELLS REVEALED THAT H3K27ME3 LEVELS WERE INCREASED OR DECREASED FOR 266 GENOMIC REGIONS BY AGING, AND MORE EXTENSIVELY (23 INCREASED AND 3574 DECREASED REGIONS) BY COLITIS. SUCH INCREASE OR DECREASE OF H3K27ME3 WAS INDUCED AS EARLY AS 2 WEEKS AFTER THE INITIATION OF DSS TREATMENT, AND PERSISTED AT LEAST FOR 16 WEEKS EVEN AFTER THE INFLAMMATION DISAPPEARED. SOME OF THE ABERRANT H3K27ME3 IN COLONIC EPITHELIAL CELLS WAS CARRIED OVER INTO COLON TUMORS. FURTHERMORE, H3K27ME3 ACQUIRED AT DAPK1 BY COLITIS WAS FOLLOWED BY INCREASED DNA METHYLATION, SUPPORTING ITS FUNCTION AS A PRE-MARK FOR ABERRANT DNA METHYLATION. THESE RESULTS DEMONSTRATED THAT ABERRANT H3K27ME3 CAN BE INDUCED BY EXPOSURE TO A SPECIFIC ENVIRONMENT, SUCH AS COLITIS, AND SUGGESTED THAT ABERRANT HISTONE MODIFICATION, IN ADDITION TO ABERRANT DNA METHYLATION, IS INVOLVED IN THE FORMATION OF A FIELD DEFECT. 2012 10 5601 31 RORALPHA IS CRUCIAL FOR ATTENUATED INFLAMMATORY RESPONSE TO MAINTAIN INTESTINAL HOMEOSTASIS. RETINOIC ACID-RELATED ORPHAN RECEPTOR ALPHA (RORALPHA) FUNCTIONS AS A TRANSCRIPTION FACTOR FOR VARIOUS BIOLOGICAL PROCESSES, INCLUDING CIRCADIAN RHYTHM, CANCER, AND METABOLISM. HERE, WE GENERATE INTESTINAL EPITHELIAL CELL (IEC)-SPECIFIC RORALPHA-DEFICIENT (RORALPHA(DELTAIEC)) MICE AND FIND THAT RORALPHA IS CRUCIAL FOR MAINTAINING INTESTINAL HOMEOSTASIS BY ATTENUATING NUCLEAR FACTOR KAPPAB (NF-KAPPAB) TRANSCRIPTIONAL ACTIVITY. RORALPHA(DELTAIEC) MICE EXHIBIT EXCESSIVE INTESTINAL INFLAMMATION AND HIGHLY ACTIVATED INFLAMMATORY RESPONSES IN THE DEXTRAN SULFATE SODIUM (DSS) MOUSE COLITIS MODEL. TRANSCRIPTOME ANALYSIS REVEALS THAT DELETION OF RORALPHA LEADS TO UP-REGULATION OF NF-KAPPAB TARGET GENES IN IECS. CHROMATIN IMMUNOPRECIPITATION ANALYSIS REVEALS CORECRUITMENT OF RORALPHA AND HISTONE DEACETYLASE 3 (HDAC3) ON NF-KAPPAB TARGET PROMOTERS AND SUBSEQUENT DISMISSAL OF CREB BINDING PROTEIN (CBP) AND BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) FOR TRANSCRIPTIONAL REPRESSION. TOGETHER, WE DEMONSTRATE THAT RORALPHA/HDAC3-MEDIATED ATTENUATION OF NF-KAPPAB SIGNALING CONTROLS THE BALANCE OF INFLAMMATORY RESPONSES, AND THERAPEUTIC STRATEGIES TARGETING THIS EPIGENETIC REGULATION COULD BE BENEFICIAL TO THE TREATMENT OF CHRONIC INFLAMMATORY DISEASES, INCLUDING INFLAMMATORY BOWEL DISEASE (IBD). 2019 11 5794 26 STAT1 EPIGENETICALLY REGULATES LCP2 AND TNFAIP2 BY RECRUITING EP300 TO CONTRIBUTE TO THE PATHOGENESIS OF INFLAMMATORY BOWEL DISEASE. BACKGROUND: THE AETIOLOGY OF INFLAMMATORY BOWEL DISEASE (IBD) IS RELATED TO GENETICS AND EPIGENETICS. EPIGENETIC REGULATION OF THE PATHOGENESIS OF IBD HAS NOT BEEN WELL DEFINED. HERE, WE INVESTIGATED THE ROLE OF H3K27AC EVENTS IN THE PATHOGENESIS OF IBD. BASED ON PREVIOUS CHIP-SEQ AND RNA-SEQ ASSAYS, WE STUDIED SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 1 (STAT1) AS A TRANSCRIPTION FACTOR (TF) AND INVESTIGATED WHETHER THE STAT1-EP300-H3K27AC AXIS CONTRIBUTES TO THE DEVELOPMENT OF IBD. WE PERFORMED CHIP-PCR TO INVESTIGATE THE INTERACTION BETWEEN STAT1 AND H3K27AC, AND CO-IP ASSAYS WERE PERFORMED TO INVESTIGATE THE CROSSTALK BETWEEN STAT1 AND EP300. RESULTS: LYMPHOCYTE CYTOSOLIC PROTEIN 2 (LCP2) AND TNF-ALPHA-INDUCIBLE PROTEIN 2 (TNFAIP2) ARE TARGET GENES OF STAT1. P-STAT1 BINDS TO THE ENHANCER LOCI OF THE TWO GENES WHERE H3K27AC IS ENRICHED, AND EP300 SUBSEQUENTLY BINDS TO REGULATE THEIR EXPRESSION. IN MICE WITH DEXTRAN SULFATE SODIUM (DSS)-INDUCED ACUTE COLITIS, AN EP300 INHIBITOR SIGNIFICANTLY INHIBITED COLITIS. CONCLUSIONS: P-STAT1 AND EP300 PROMOTE TNFAIP2 AND LCP2 EXPRESSION THROUGH AN INCREASE IN H3K27AC ENRICHMENT ON THEIR ENHANCERS AND CONTRIBUTE TO THE PATHOGENESIS OF CHRONIC INFLAMMATION. 2021 12 5602 35 RORGAMMAT(+) HEMATOPOIETIC CELLS ARE NECESSARY FOR TUMOR CELL PROLIFERATION DURING COLITIS-ASSOCIATED TUMORIGENESIS IN MICE. COLORECTAL CANCER (CRC) IS ONE OF THE MOST COMMON TUMOR ENTITIES. IN PATIENTS WITH INFLAMMATORY BOWEL DISEASES, THE DEVELOPMENT OF COLITIS-ASSOCIATED COLON CANCER IS CONSIDERED A DANGEROUS LONG-TERM COMPLICATION. IL-17A AND THE TRANSCRIPTION FACTOR RETINOIC ACID RECEPTOR-RELATED ORPHAN RECEPTOR GAMMAT (RORGAMMAT) PLAY FUNDAMENTAL ROLES IN THE PATHOGENESIS OF INFLAMMATORY BOWEL DISEASES; IN HUMAN STUDIES, WE DETECTED A DENSE INFILTRATION OF RORGAMMAT-DEPENDENT CD4(+) IL17A(+) T HELPER (TH)17 CELLS IN SPECIMENS OF CRC, ULCERATIVE COLITIS, AND ULCERATIVE COLITIS-ASSOCIATED COLORECTAL CANCER. HOWEVER, THE MECHANISTIC ROLE OF RORGAMMAT(+) HEMATOPOIETIC CELLS IN COLITIS-ASSOCIATED TUMORIGENESIS REMAINS UNCLEAR. TO INVESTIGATE COLITIS-ASSOCIATED COLON TUMORIGENESIS, WE CONDUCTED STUDIES IN THE AOM+DSS MOUSE MODEL THAT REVEALED THE IMPORTANCE OF RORGAMMAT FOR COLON TUMOR PROGRESSION. IN THE ABSENCE OF RORGAMMAT-DEPENDENT TH17 LYMPHOCYTES, MICE SHOWED SIGNS OF INTENSE CHRONIC COLITIS, BUT DEVELOPED SIGNIFICANTLY FEWER MACROSCOPIC TUMOR NODULES. THE REDUCTION OF TUMOR DEVELOPMENT IN RORGAMMAT(-/-) MICE WAS NOT DUE TO REDUCED COLON TUMOR INITIATION. HOWEVER, THE PROLIFERATION RATE OF TUMOR CELLS WAS REDUCED IN THE ABSENCE OF RORGAMMAT-DEPENDENT TH17 CELLS AND TUMOR CELLS SHOWED PRONOUNCED SIGNS OF SENESCENCE-ASSOCIATED EPIGENETIC AND LYSOSOMAL CHANGES. THESE RESULTS INDICATE AN IMPORTANT ROLE FOR THE IMMUNOLOGICAL MILIEU IN COLITIS-ASSOCIATED CANCER, WHICH IS SHAPED IN-PART BY RORGAMMAT-DEPENDENT TH17 LYMPHOCYTES THAT SUPPORT CRC GROWTH. 2015 13 4099 33 MBD2 ENABLES TUMOURIGENESIS WITHIN THE INTESTINE WHILE PREVENTING TUMOUR-PROMOTING INFLAMMATION. EPIGENETIC REGULATION PLAYS A KEY ROLE IN THE LINK BETWEEN INFLAMMATION AND CANCER. HERE WE EXAMINE MBD2, WHICH MEDIATES EPIGENETIC TRANSCRIPTIONAL SILENCING BY BINDING TO METHYLATED DNA. IN SEPARATE STUDIES THE MBD2(-/-) MOUSE HAS BEEN SHOWN (1) TO BE RESISTANT TO INTESTINAL TUMOURIGENESIS AND (2) TO HAVE AN ENHANCED INFLAMMATORY/IMMUNE RESPONSE, OBSERVATIONS THAT ARE INCONSISTENT WITH THE LINKS BETWEEN INFLAMMATION AND CANCER. TO CLARIFY ITS ROLE IN TUMOURIGENESIS AND INFLAMMATION, WE USED CONSTITUTIVE AND CONDITIONAL MODELS OF MBD2 DELETION TO EXPLORE ITS EPITHELIAL AND NON-EPITHELIAL ROLES IN THE INTESTINE. USING A CONDITIONAL MODEL, WE FOUND THAT SUPPRESSION OF INTESTINAL TUMOURIGENESIS IS DUE PRIMARILY TO THE ABSENCE OF MBD2 WITHIN THE EPITHELIA. NEXT, WE DEMONSTRATED, USING THE DSS COLITIS MODEL, THAT NON-EPITHELIAL ROLES OF MBD2 ARE KEY IN PREVENTING THE TRANSITION FROM ACUTE TO TUMOUR-PROMOTING CHRONIC INFLAMMATION. COMBINING MODELS REVEALED THAT PRIOR TO INFLAMMATION THE ALTERED MBD2(-/-) IMMUNE RESPONSE PLAYS A ROLE IN INTESTINAL TUMOUR SUPPRESSION. HOWEVER, FOLLOWING INFLAMMATION THE INTESTINE CONVERTS FROM TUMOUR SUPPRESSIVE TO TUMOUR PROMOTING. TO SUMMARISE, IN THE INTESTINE THE NORMAL FUNCTION OF MBD2 IS EXPLOITED BY CANCER CELLS TO ENABLE TUMOURIGENESIS, WHILE IN THE IMMUNE SYSTEM IT PLAYS A KEY ROLE IN PREVENTING TUMOUR-ENABLING INFLAMMATION. WHICH ROLE IS DOMINANT DEPENDS ON THE INFLAMMATION STATUS OF THE INTESTINE. AS ENVIRONMENTAL INTERACTIONS WITHIN THE INTESTINE CAN ALTER DNA METHYLATION PATTERNS, WE PROPOSE THAT MBD2 PLAYS A KEY ROLE IN DETERMINING WHETHER THESE INTERACTIONS ARE ANTI- OR PRO-TUMOURIGENIC AND THIS MAKES IT A USEFUL NEW EPIGENETIC MODEL FOR INFLAMMATION-ASSOCIATED CARCINOGENESIS. (C) 2018 THE AUTHORS. THE JOURNAL OF PATHOLOGY PUBLISHED BY JOHN WILEY & SONS LTD ON BEHALF OF PATHOLOGICAL SOCIETY OF GREAT BRITAIN AND IRELAND. 2018 14 2065 26 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 15 4174 31 MELATONIN MEDIATED INHIBITION OF EZH2-NOS2 CROSSTALK ATTENUATES INFLAMMATORY BOWEL DISEASE IN PRECLINICAL IN VITRO AND IN VIVO MODELS. AIMS: INFLAMMATORY BOWEL DISEASE IS CHARACTERISED BY ABDOMINAL PAIN, DIARRHOEA, RECTAL BLEEDING AND WEIGHT LOSS. SOMETIMES IT MAY LEADS TO SEVERE HEALTH COMPLICATIONS RESULTING IN DEATH OF AN INDIVIDUAL. CURRENT RESEARCH EFFORTS TO HIGHLIGHT THE ROLE OF MELATONIN IN REGULATING EZH2, A MASTER EPIGENETIC REGULATOR AND ITS BENEFICIARY EFFECT IN CASE OF IBD MANAGEMENT. MATERIAL METHODS: MURINE MACROPHAGES (RAW 264.7) WERE TREATED WITH LIPOPOLYSACCHARIDES (LPS) TO ACTIVATE THEM FOR GENERATING INFLAMMATORY RESPONSE TO INVESTIGATE EFFICACY OF MELATONIN IN-VITRO MODELS. SIMILARLY, FOR DEVELOPING IN VIVO MODELS, DEXTRAN SODIUM SULPHATE (36-50 KDA) WAS USED. EVALUATIONS OF ANTI-INFLAMMATORY ACTIVITIES WERE CARRIED OUT BY NITRITE ASSAY, WESTERN BLOTTING, Q-PCR, IMMUNOFLUORESCENCE, AND HISTOLOGICAL STUDIES. KEY FINDINGS: REDUCTION OF EPIGENETIC TARGET, EZH2 BY MELATONIN SIGNIFICANTLY IMPROVES THE CLINICAL SYMPTOMS OF DEXTRAN SODIUM SULPHATE INDUCED COLITIS AND MAY BE IMPLICATED AS A POTENTIAL THERAPEUTIC TARGET IN IBD MANAGEMENT. THE PRESENT STUDY EVALUATES THE EFFICACY OF MELATONIN BY EPIGENETIC REGULATION IN IBD MODELS. DOWN REGULATION OF EZH2 BY MELATONIN REDUCED THE CHEMICAL INDUCED INFLAMMATORY INSULTS IN IN VITRO AND IN VIVO MODELS. EXPLORATION OF MOLECULAR PATHWAYS HAS REVEALED INTERLINK OF EZH2 AND NOS2, A HALLMARK OF INFLAMMATION. MOLECULAR MECHANISTIC ACTION OF MELATONIN IS ATTRIBUTED TO INHIBITION OF THE EXPRESSION AND PHYSICAL INTERACTION OF EZH2 AND NOS2. SIGNIFICANCE: OUR STUDY HIGHLIGHTS MELATONIN THERAPEUTIC EFFECT VIA ATTENUATING INTERACTION BETWEEN EZH2 AND NOS2 WHICH IS BENEFICIAL IN MANAGING IBD TREATMENT. 2022 16 673 26 BRAHMA-RELATED GENE 1 (BRG1) EPIGENETICALLY REGULATES CAM ACTIVATION DURING HYPOXIC PULMONARY HYPERTENSION. AIMS: ESTABLISHMENT OF AN INFLAMMATORY MILIEU FOLLOWING ELEVATED LEUKOCYTE ADHESION TO THE VASCULAR ENDOTHELIUM, WHICH IS MEDIATED BY TRANSCRIPTIONAL ACTIVATION OF CELL ADHESION MOLECULES (CAMS), CONTRIBUTES TO THE PATHOGENESIS OF CHRONIC HYPOXIA-INDUCED PULMONARY HYPERTENSION (HPH). THE EPIGENETIC SWITCH THAT DICTATES CAM TRANSACTIVATION IN RESPONSE TO HYPOXIA IN ENDOTHELIAL CELLS LEADING UP TO HPH IS NOT FULLY APPRECIATED. METHODS AND RESULTS: WE REPORT HERE THAT BRAHMA-RELATED GENE 1 (BRG1) AND BRAHMA (BRM), TWO CATALYTIC COMPONENTS OF THE MAMMALIAN CHROMATIN REMODELLING COMPLEX, WERE INDUCED IN CULTURED ENDOTHELIAL CELLS CHALLENGED WITH HYPOXIA IN VITRO AS WELL AS IN PULMONARY ARTERIES IN AN ANIMAL MODEL OF HPH. OVER-EXPRESSION OF BRG1/BRM ENHANCED, WHILE THE DEPLETION OF BRG1/BRM ATTENUATED, CAM TRANSACTIVATION AND ADHESION OF LEUKOCYTES. ENDOTHELIAL-SPECIFIC DELETION OF BRG1/BRM AMELIORATED VASCULAR INFLAMMATION AND HPH IN MICE. CHROMATIN IMMUNOPRECIPITATION (CHIP) AND RE-CHIP ASSAYS REVEALED THAT HYPOXIA UP-REGULATED THE OCCUPANCIES OF BRG1 AND BRM ON CAM PROMOTERS IN A NUCLEAR FACTOR KAPPAB (NF-KAPPAB) -DEPENDENT MANNER. FINALLY, BRG1 AND BRM ACTIVATED CAM TRANSCRIPTION BY ALTERING THE CHROMATIN STRUCTURE SURROUNDING THE CAM PROMOTERS. CONCLUSION: OUR DATA SUGGEST THAT BRG1 PROVIDES THE CRUCIAL EPIGENETIC LINK TO HYPOXIA-INDUCED CAM INDUCTION AND LEUKOCYTE ADHESION THAT ENGENDERS ENDOTHELIAL MALFUNCTION AND PATHOGENESIS OF HPH. AS SUCH, TARGETING BRG1 IN ENDOTHELIAL CELLS MAY YIELD PROMISING STRATEGIES IN THE INTERVENTION AND/OR PREVENTION OF HPH. 2013 17 3373 29 HISTONE MODULATION BLOCKS TREG-INDUCED FOXP3 BINDING TO THE IL-2 PROMOTER OF VIRUS-SPECIFIC CD8(+) T CELLS FROM FELINE IMMUNODEFICIENCY VIRUS-INFECTED CATS. CD8(+) T CELLS ARE CRITICAL FOR CONTROLLING HIV INFECTION. DURING THE CHRONIC PHASE OF LENTIVIRAL INFECTION, CD8(+) T CELLS LOSE THEIR PROLIFERATIVE CAPACITY AND EXHIBIT IMPAIRED ANTIVIRAL FUNCTION. THIS LOSS OF CD8(+) T CELL FUNCTION IS DUE, IN PART, TO CD4(+)CD25(+) T REGULATORY (TREG) CELL-MEDIATED SUPPRESSION. OUR RESEARCH GROUP HAS DEMONSTRATED THAT LENTIVIRUS-ACTIVATED CD4(+)CD25(+) TREG CELLS INDUCE THE REPRESSIVE TRANSCRIPTION FACTOR FORKHEAD BOX P3 (FOXP3) IN AUTOLOGOUS CD8(+) T CELLS FOLLOWING CO-CULTURE. WE HAVE RECENTLY REPORTED THAT TREG-INDUCED FOXP3 BINDS THE INTERLEUKIN-2 (IL-2), INTERFERON-GAMMA (IFN- GAMMA), AND TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA) PROMOTERS IN VIRUS-SPECIFIC CD8(+) T CELLS. THESE DATA SUGGEST AN IMPORTANT ROLE OF FOXP3-MEDIATED CD8(+) T CELL DYSFUNCTION IN LENTIVIRAL INFECTION. TO ELUCIDATE THE MECHANISM OF THIS SUPPRESSION, WE PREVIOUSLY REPORTED THAT DECREASED METHYLATION FACILITATES FOXP3 BINDING IN MITOGEN-ACTIVATED CD8(+) T CELLS FROM FELINE IMMUNODEFICIENCY VIRUS (FIV)-INFECTED CATS. WE DEMONSTRATED THE REDUCED BINDING OF FOXP3 TO THE IL-2 PROMOTER BY INCREASING METHYLATION OF CD8(+) T CELLS. IN THE STUDIES PRESENTED HERE, WE ASK IF ANOTHER FORM OF EPIGENETIC MODULATION MIGHT ALLEVIATE FOXP3-MEDIATED SUPPRESSION IN CD8(+) T CELLS. WE HYPOTHESIZED THAT DECREASING HISTONE ACETYLATION IN VIRUS-SPECIFIC CD8(+) T CELLS WOULD DECREASE TREG-INDUCED FOXP3 BINDING TO THE IL-2 PROMOTER. INDEED, USING ANACARDIC ACID (AA), A KNOWN HISTONE ACETYL TRANSFERASE (HAT) INHIBITOR, WE DEMONSTRATE A REDUCTION IN FOXP3 BINDING TO THE IL-2 PROMOTER IN VIRUS-SPECIFIC CD8(+) T CELLS CO-CULTURED WITH AUTOLOGOUS TREG CELLS. THESE DATA IDENTIFY A NOVEL MECHANISM OF FOXP3-MEDIATED CD8(+) T CELL DYSFUNCTION DURING LENTIVIRAL INFECTION. 2018 18 6661 33 UPREGULATION OF DNA METHYLTRANSFERASE-MEDIATED GENE SILENCING, ANCHORAGE-INDEPENDENT GROWTH, AND MIGRATION OF COLON CANCER CELLS BY INTERLEUKIN-6. INFLAMMATORY BOWEL DISEASE IS CHARACTERIZED BY CHRONIC INFLAMMATION WHICH PREDISPOSES TO COLORECTAL CANCER. THE MECHANISMS BY WHICH INFLAMMATION PROMOTES TUMORIGENESIS ARE NOT FULLY KNOWN. WE AIMED TO INVESTIGATE THE LINKS BETWEEN COLONIC INFLAMMATION AND TUMORIGENESIS VIA EPIGENETIC GENE SILENCING. COLON CANCER SPECIMENS WERE ASSESSED FOR THE EXPRESSION OF DNA METHYLTRANSFERASE-1 (DNMT-1) USING IMMUNOHISTOCHEMISTRY. COLORECTAL CARCINOMA CELL LINES WERE ASSESSED FOR DNMT1 EXPRESSION, METHYLCYTOSINE CONTENT, PROMOTER METHYLATION, GENE EXPRESSION, AND TUMORIGENESIS IN RESPONSE TO INTERLEUKIN (IL)-6. DNMT1 WAS EXPRESSED AT HIGHER LEVELS IN BOTH THE PERITUMORAL STROMA AND TUMOR IN INFLAMMATORY BOWEL DISEASE-ASSOCIATED CANCERS COMPARED WITH SPORADIC COLON CANCERS. IL-6 TREATMENT OF COLON CANCER CELLS RESULTED IN AN INCREASE IN DNMT1 EXPRESSION, INDEPENDENT OF DE NOVO GENE EXPRESSION. IL-6 INCREASED THE METHYLATION OF PROMOTER REGIONS OF GENES ASSOCIATED WITH TUMOR SUPPRESSION, ADHESION, AND APOPTOSIS RESISTANCE. EXPRESSION OF A SUBSET OF THESE GENES WAS DOWNREGULATED BY IL-6, AN EFFECT THAT WAS PREVENTED BY PREINCUBATION WITH 5-AZADEOXYCYTIDINE, A DNMT1 INHIBITOR. ANCHORAGE-INDEPENDENT GROWTH AND MIGRATION OF COLON CANCER CELLS WAS ALSO INCREASED BY IL-6 IN A 5-AZADEOXYCYTIDINE-SENSITIVE MANNER. OUR RESULTS INDICATE THAT DNMT-MEDIATED GENE SILENCING MAY PLAY A ROLE IN INFLAMMATION-ASSOCIATED COLON TUMORIGENESIS. 2010 19 6126 40 THE EPIGENETIC MODIFIER PBRM1 RESTRICTS THE BASAL ACTIVITY OF THE INNATE IMMUNE SYSTEM BY REPRESSING RETINOIC ACID-INDUCIBLE GENE-I-LIKE RECEPTOR SIGNALLING AND IS A POTENTIAL PROGNOSTIC BIOMARKER FOR COLON CANCER. IT HAS LONG BEEN KNOWN THAT PATIENTS SUFFERING FROM INFLAMMATORY BOWEL DISEASE (IBD) HAVE AN INCREASED RISK OF DEVELOPING COLORECTAL CANCER (CRC). THE INNATE IMMUNE SYSTEM OF HOST CELLS PROVIDES A FIRST-LINE DEFENCE AGAINST PATHOGENIC INFECTION, WHEREAS AN UNCONTROLLED INFLAMMATORY RESPONSE UNDER HOMEOSTATIC CONDITIONS USUALLY LEADS TO PATHOLOGICAL CONSEQUENCES, AS EXEMPLIFIED BY THE CHRONIC INFLAMMATION OF IBD. THE KEY MOLECULES AND PATHWAYS KEEPING INNATE IMMUNITY IN CHECK ARE STILL POORLY DEFINED. HERE, WE REPORT THAT THE CHROMATIN REMODELLER POLYBROMO-1 (PBRM1) IS A REPRESSOR OF INNATE IMMUNE SIGNALLING MEDIATED BY RETINOIC ACID-INDUCIBLE GENE-I (RIG-I)-LIKE RECEPTORS (RLRS). KNOCKDOWN OF PBRM1 IN COLON CANCER CELLS INCREASED THE EXPRESSION OF TWO RECEPTOR GENES (RIG-I AND MDA5) AND UPREGULATED INTERFERON (IFN)-RELATED AND INFLAMMATION-RELATED GENE SIGNATURES. THE INNATE IMMUNE SIGNAL STIMULATED BY A DOUBLE-STRANDED RNA VIRAL MIMIC WAS EXAGGERATED BY PBRM1 SUPPRESSION. PBRM1 COOPERATED WITH POLYCOMB PROTEIN EZH2 TO DIRECTLY BIND THE CIS-REGULATORY ELEMENTS OF RIG-I AND MDA5, THEREBY SUPPRESSING THEIR TRANSCRIPTION. MOREOVER, UPREGULATION OF RIG-I AND MDA5 IS REQUIRED FOR IFN RESPONSE ACTIVATION INDUCED BY PBRM1 SILENCING. TRIM25, A PROTEIN STIMULATED BY THE RLR PATHWAY AND IFN PRODUCTION, PHYSICALLY INTERACTED WITH PBRM1 AND INDUCED PBRM1 PROTEIN DESTABILIZATION BY PROMOTING ITS UBIQUITINATION. THESE FINDINGS REVEAL A PBRM1-RLR REGULATORY CIRCUIT THAT CAN KEEP INNATE IMMUNE ACTIVITY AT A MINIMAL LEVEL IN RESTING CELLS, AND ALSO ENSURE A ROBUST INFLAMMATORY RESPONSE IN THE CASE OF PATHOGEN INVASION. PBRM1 WAS FOUND TO BE DOWNREGULATED IN PRIMARY TISSUES FROM PATIENTS WITH CRC OR IBD, AND ITS EXPRESSION CORRELATED NEGATIVELY WITH THAT OF RLR GENES AND INTERFERON-STIMULATED GENES IN CRC SAMPLES. LOWER PBRM1 EXPRESSION WAS ASSOCIATED WITH ADVANCED PATHOLOGICAL GRADE AND POORER SURVIVAL OF CRC PATIENTS, INDICATING THAT PBRM1 COULD SERVE AS A POTENTIAL PROGNOSTIC BIOMARKER FOR CRC. COPYRIGHT (C) 2017 PATHOLOGICAL SOCIETY OF GREAT BRITAIN AND IRELAND. PUBLISHED BY JOHN WILEY & SONS, LTD. 2018 20 3864 24 JAK-STAT PATHWAY INHIBITION PARTIALLY RESTORES INTESTINAL HOMEOSTASIS IN HDAC1- AND HDAC2-INTESTINAL EPITHELIAL CELL-DEFICIENT MICE. WE HAVE PREVIOUSLY REPORTED THAT HISTONE DEACETYLASE EPIGENETIC REGULATOR HDAC1 AND HDAC2 DELETION IN INTESTINAL EPITHELIAL CELLS (IEC) DISRUPTS MUCOSAL TISSUE ARCHITECTURE AND BARRIER, CAUSING CHRONIC INFLAMMATION. IN THIS STUDY, PROTEOME AND TRANSCRIPTOME ANALYSIS REVEALED THE IMPORTANCE OF SIGNALING PATHWAYS INDUCED UPON GENETIC IEC-HDAC1 AND HDAC2 DELETION. INDEED, GENE ONTOLOGY BIOLOGICAL PROCESS ANALYSIS OF ENRICHED DEFICIENT IEC RNA AND PROTEINS IDENTIFIED COMMON PATHWAYS, INCLUDING LIPID METABOLIC AND OXIDATION-REDUCTION PROCESS, CELL ADHESION, AND ANTIGEN PROCESSING AND PRESENTATION, RELATED TO IMMUNE RESPONSES, CORRELATING WITH DYSREGULATION OF MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) CLASS II GENES. TOP UPSTREAM REGULATORS INCLUDED REGULATORS ASSOCIATED WITH ENVIRONMENTAL SENSING PATHWAYS TO XENOBIOTICS, MICROBIAL AND DIET-DERIVED LIGANDS, AND ENDOGENOUS METABOLITES. PROTEOME ANALYSIS REVEALED MTOR SIGNALING IEC-SPECIFIC DEFECTS. IN ADDITION TO MTOR, THE STAT AND NOTCH PATHWAYS WERE DYSREGULATED SPECIFICALLY IN JEJUNAL IEC. TO DETERMINE THE IMPACT OF PATHWAY DYSREGULATION ON MUTANT JEJUNUM ALTERATIONS, WE TREATED MUTANT MICE WITH TOFACITINIB, A JAK INHIBITOR. TREATMENT WITH THE INHIBITOR PARTIALLY CORRECTED PROLIFERATION AND TIGHT JUNCTION DEFECTS, AS WELL AS NICHE STABILIZATION BY INCREASING PANETH CELL NUMBERS. THUS, IEC-SPECIFIC HISTONE DEACETYLASES 1 (HDAC1) AND 2 (HDAC2) SUPPORT INTESTINAL HOMEOSTASIS BY REGULATING SURVIVAL AND TRANSLATION PROCESSES, AS WELL AS DIFFERENTIATION AND METABOLIC PATHWAYS. HDAC1 AND HDAC2 MAY PLAY AN IMPORTANT ROLE IN THE REGULATION OF IEC-SPECIFIC INFLAMMATORY RESPONSES BY CONTROLLING, DIRECTLY OR INDIRECTLY, THE JAK/STAT PATHWAY. IEC-SPECIFIC JAK/STAT PATHWAY DEREGULATION MAY BE, AT LEAST IN PART, RESPONSIBLE FOR INTESTINAL HOMEOSTASIS DISRUPTION IN MUTANT MICE. 2021