1 4174 138 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 2 4933 32 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 3 3430 25 HYALURONAN AS TUNABLE DRUG DELIVERY SYSTEM. THE HYALURONAN (HA) POLYMER IS AN IMPORTANT MACROMOLECULE OF EXTRACELLULAR MATRIX WITH REMARKABLE STRUCTURE AND FUNCTIONS: IT IS A LINEAR AND UNBRANCHED POLYMER WITHOUT SULPHATE OR PHOSPHATE GROUPS AND HAS KEY ROLE IN SEVERAL BIOLOGICAL PROCESSES IN MAMMALS. IT IS UBIQUITOUS IN MAMMALIAN TISSUES WITH SEVERAL AND SPECIFIC FUNCTIONS, INFLUENCING CELL PROLIFERATION AND MIGRATION AS WELL AS ANGIOGENESIS AND INFLAMMATION. TO EXERT THESE IMPORTANT FUNCTIONS IN TISSUES HA MODIFIES THE CONCENTRATION AND SIZE. CONSIDERING THIS HA CONTENT IN TISSUES IS CAREFULLY CONTROLLED BY DIFFERENT MECHANISMS INCLUDING COVALENT MODIFICATION OF THE SYNTHETIC ENZYMES AND EPIGENETIC CONTROL OF THEIR GENE EXPRESSION. THE FUNCTION OF HA IS ALSO CRITICAL IN SEVERAL PATHOLOGIES INCLUDING CANCER, DIABETES AND CHRONIC INFLAMMATION. AMONG THESE BIOLOGICAL ROLES, THE STRUCTURAL PROPERTIES OF HA ALLOW TO USE THIS POLYMER IN REGENERATIVE MEDICINE INCLUDING COSMETICS AND DRUG DELIVERY. HA TAKES ADVANTAGE FROM ITS CAPACITY TO FORM GELS EVEN AT CONCENTRATION OF 1% PRODUCING SCAFFOLDS WITH VERY INTRIGUING MECHANICAL PROPERTIES. THESE HYDROGELS ARE USEFUL IN REGENERATIVE MEDICINE AS BIOCOMPATIBLE MATERIAL FOR ADVANCED THERAPEUTIC USES. IN THIS REVIEW WE HIGHLIGHT THE BIOLOGICAL ASPECTS OF HA ADDRESSING THE MECHANISMS CONTROLLING THE HA CONTENT IN TISSUES AND ITS ROLE AS DRUG DELIVERY SYSTEM. 2019 4 5864 31 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 5 3867 31 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 6 1905 46 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 1446 37 DIGESTED CINNAMON (CINNAMOMUM VERUM J. PRESL) BARK EXTRACT MODULATES CLAUDIN-2 GENE EXPRESSION AND PROTEIN LEVELS UNDER TNFALPHA/IL-1BETA INFLAMMATORY STIMULUS. EPIGENETIC CHANGES, HOST-GUT MICROBIOTA INTERACTIONS, AND ENVIRONMENTAL FACTORS CONTRIBUTE TO INFLAMMATORY BOWEL DISEASE (IBD) ONSET AND PROGRESSION. A HEALTHY LIFESTYLE MAY HELP TO SLOW DOWN THE CHRONIC OR REMITTING/RELAPSING INTESTINAL TRACT INFLAMMATION CHARACTERISTIC OF IBD. IN THIS SCENARIO, THE EMPLOYMENT OF A NUTRITIONAL STRATEGY TO PREVENT THE ONSET OR SUPPLEMENT DISEASE THERAPIES INCLUDED FUNCTIONAL FOOD CONSUMPTION. ITS FORMULATION CONSISTS OF THE ADDITION OF A PHYTOEXTRACT ENRICHED IN BIOACTIVE MOLECULES. A GOOD CANDIDATE AS AN INGREDIENT IS THE CINNAMON VERUM AQUEOUS EXTRACT. INDEED, THIS EXTRACT, SUBJECTED TO A PROCESS OF GASTROINTESTINAL DIGESTION SIMULATION (INFOGEST), EXHIBITS BENEFICIAL ANTIOXIDANT AND ANTI-INFLAMMATORY PROPERTIES IN AN IN VITRO MODEL OF THE INFLAMED INTESTINAL BARRIER. HERE, WE DEEPEN THE STUDY OF THE MECHANISMS RELATED TO THE EFFECT OF DIGESTED CINNAMON EXTRACT PRE-TREATMENT, SHOWING A CORRELATION BETWEEN TRANSEPITHELIAL ELECTRICAL RESISTANCE (TEER) DECREMENT AND ALTERATIONS IN CLAUDIN-2 EXPRESSION UNDER TUMOR NECROSIS FACTOR-ALPHA/INTERLEUKIN-1BETA (TNF-ALPHA/IL-1) BETA CYTOKINE ADMINISTRATION. OUR RESULTS SHOW THAT PRE-TREATMENT WITH CINNAMON EXTRACT PREVENTS TEER LOSS BY CLAUDIN-2 PROTEIN LEVEL REGULATION, INFLUENCING BOTH GENE TRANSCRIPTION AND AUTOPHAGY-MEDIATED DEGRADATION. HENCE, CINNAMON POLYPHENOLS AND THEIR METABOLITES PROBABLY WORK AS MEDIATORS IN GENE REGULATION AND RECEPTOR/PATHWAY ACTIVATION, LEADING TO AN ADAPTIVE RESPONSE AGAINST RENEWED INSULTS. 2023 8 4291 32 MICRORNA PROFILES IN INTESTINAL EPITHELIAL CELLS IN A MOUSE MODEL OF SEPSIS. SEPSIS IS A SYSTEMIC INFLAMMATORY DISORDER THAT LEADS TO THE DYSFUNCTION OF MULTIPLE ORGANS. IN THE INTESTINE, THE DEREGULATION OF THE EPITHELIAL BARRIER CONTRIBUTES TO THE DEVELOPMENT OF SEPSIS BY TRIGGERING CONTINUOUS EXPOSURE TO HARMFUL FACTORS. HOWEVER, SEPSIS-INDUCED EPIGENETIC CHANGES IN GENE-REGULATION NETWORKS WITHIN INTESTINAL EPITHELIAL CELLS (IECS) REMAIN UNEXPLORED. IN THIS STUDY, WE ANALYZED THE EXPRESSION PROFILE OF MICRORNAS (MIRNAS) IN IECS ISOLATED FROM A MOUSE MODEL OF SEPSIS GENERATED VIA CECAL SLURRY INJECTION. AMONG 239 MIRNAS, 14 MIRNAS WERE UPREGULATED, AND 9 MIRNAS WERE DOWNREGULATED IN THE IECS BY SEPSIS. UPREGULATED MIRNAS IN IECS FROM SEPTIC MICE, PARTICULARLY MIR-149-5P, MIR-466Q, MIR-495, AND MIR-511-3P, WERE SEEN TO EXHIBIT COMPLEX AND GLOBAL EFFECTS ON GENE REGULATION NETWORKS. INTERESTINGLY, MIR-511-3P HAS EMERGED AS A DIAGNOSTIC MARKER IN THIS SEPSIS MODEL DUE TO ITS INCREASE IN BLOOD IN ADDITION TO IECS. AS EXPECTED, MRNAS IN THE IECS WERE REMARKABLY ALTERED BY SEPSIS; SPECIFICALLY, 2248 MRNAS WERE DECREASED, WHILE 612 MRNAS WERE INCREASED. THIS QUANTITATIVE BIAS MAY BE POSSIBLY DERIVED, AT LEAST PARTLY, FROM THE DIRECT EFFECTS OF THE SEPSIS-INCREASED MIRNAS ON THE COMPREHENSIVE EXPRESSION OF MRNAS. THUS, CURRENT IN SILICO DATA INDICATE THAT THERE ARE DYNAMIC REGULATORY RESPONSES OF MIRNAS TO SEPSIS IN IECS. IN ADDITION, THE MIRNAS THAT WERE INCREASED WITH SEPSIS HAD ENRICHED DOWNSTREAM PATHWAYS INCLUDING WNT SIGNALING, WHICH IS ASSOCIATED WITH WOUND HEALING, AND FGF/FGFR SIGNALING, WHICH HAS BEEN LINKED TO CHRONIC INFLAMMATION AND FIBROSIS. THESE MODIFICATIONS IN MIRNA NETWORKS IN IECS MAY LEAD TO BOTH PRO- AND ANTI-INFLAMMATORY EFFECTS IN SEPSIS. THE FOUR MIRNAS DISCOVERED ABOVE WERE SHOWN TO PUTATIVELY TARGET LOX, PTCH1, COL22A1, FOXO1, OR HMGA2, VIA IN SILICO ANALYSIS, WHICH WERE ASSOCIATED WITH WNT OR INFLAMMATORY PATHWAYS AND SELECTED FOR FURTHER STUDY. THE EXPRESSIONS OF THESE TARGET GENES WERE DOWNREGULATED IN SEPSIS IECS, POSSIBLY THROUGH POSTTRANSCRIPTIONAL MODIFICATIONS OF THESE MIRNAS. TAKEN TOGETHER, OUR STUDY SUGGESTS THAT IECS DISPLAY A DISTINCTIVE MIRNA PROFILE WHICH IS CAPABLE OF COMPREHENSIVELY AND FUNCTIONALLY RESHAPING THE IEC-SPECIFIC MRNA LANDSCAPE IN A SEPSIS MODEL. 2023 9 4611 31 NEONATAL IMMUNE CHALLENGE FOLLOWED BY ADULT IMMUNE CHALLENGE INDUCES EPIGENETIC-SUSCEPTIBILITY TO AGGRAVATED VISCERAL HYPERSENSITIVITY. BACKGROUND: ABDOMINAL PAIN IS ONE OF THE MAJOR SYMPTOMS OF INFLAMMATORY BOWEL DISEASE (IBD). THE INFLAMMATORY MEDIATORS RELEASED BY COLON INFLAMMATION ARE KNOWN TO SENSITIZE THE AFFERENT NEURONS, WHICH IS ONE OF THE CONTRIBUTORS TO ABDOMINAL PAIN. HOWEVER, NOT ALL IBD PATIENTS HAVE ABDOMINAL PAIN, AND SOME PATIENTS REPORT ABDOMINAL PAIN DURING REMISSION, SUGGESTING CONTRIBUTIONS OF OTHER PATHOLOGICAL FACTORS TO ABDOMINAL PAIN IN IBD. EPIDEMIOLOGICAL STUDIES FOUND EARLY-LIFE GASTROINTESTINAL INFECTIONS A RISK FACTOR FOR IBD SYMPTOMS AND ADULT-LIFE GASTROINTESTINAL INFECTIONS MAY TRIGGER THE ONSET OF IBD. WE INVESTIGATED THE HYPOTHESIS THAT NEONATAL COLON IMMUNE CHALLENGE FOLLOWED BY AN ADULT COLON IMMUNE CHALLENGE UPREGULATES SPINAL CORD BDNF THAT AGGRAVATES VISCERAL SENSITIVITY OVER AND ABOVE THAT INDUCED BY ADULT COLON IMMUNE CHALLENGE ALONE. METHODS: WE INDUCED NEONATAL AND ADULT COLON IMMUNE CHALLENGES BY INTRALUMINAL ADMINISTRATION OF TRINITROBENZENE SULFONIC ACID TO THE RAT COLON. KEY RESULTS: WE FOUND THAT NEONATAL IMMUNE CHALLENGE TRIGGERS EPIGENETIC PROGRAMMING THAT UPREGULATES TYROSINE HYDROXYLASE IN THE LOCUS CERULEUS WHEN THESE RATS ARE SUBJECTED TO AN ADULT COLON IMMUNE CHALLENGE. THE UPREGULATION OF LOCUS CERULEUS TYROSINE HYDROXYLASE, UPREGULATES NOREPINEPHRINE IN THE CEREBROSPINAL FLUID THAT ACTS ON ADRENERGIC RECEPTORS TO ENHANCE PCREB BINDING TO THE CAMP RESPONSE ELEMENT, WHICH RECRUITS HISTONE ACETYLENE TRANSFERASE (HAT) TO THE BDNF GENE TO ENHANCE ITS TRANSCRIPTION RESULTING IN AGGRAVATED VISCEROMOTOR RESPONSE TO COLORECTAL DISTENSION. HAT AND ADRENERGIC RECEPTOR ANTAGONISTS BLOCK THE AGGRAVATION OF VISCERAL SENSITIVITY. CONCLUSION & INFERENCES: HAT AND ADRENERGIC RECEPTOR INHIBITORS MAY SERVE AS ALTERNATES TO OPIOIDS AND NSAIDS IN SUPPRESSING ABDOMINAL PAIN IN IBD. 2017 10 5794 33 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 11 1997 23 EPIGENETIC AND INFLAMMATORY EVENTS IN EXPERIMENTAL PERIODONTITIS FOLLOWING SYSTEMIC MICROBIAL CHALLENGE. AIM: THE PURPOSE OF THIS STUDY WAS TO DETERMINE INFLAMMATORY AND EPIGENETIC FEATURES FOLLOWING INDUCTION OF ORAL AND GUT DYSBIOSIS IN EXPERIMENTAL PERIODONTITIS IN ORDER TO EXAMINE THE INTERPLAY BETWEEN ORAL AND SYSTEMIC INFECTION. MATERIALS AND METHODS: PERIODONTITIS WAS INDUCED IN 6- TO 8-WEEK-OLD C57BL/6 MICE BY (A) LIGATURE PLACEMENT (LIG GROUP) (ORAL CHALLENGE); (B) P. GINGIVALIS GAVAGE (PG GROUP) (SYSTEMIC CHALLENGE); AND (C) THE COMBINATION OF THE TWO MODELS ORAL AND SYSTEMIC CHALLENGE (PG + LIG). THE DURATION OF THE EXPERIMENT WAS 60 DAYS, AND THE ANIMALS WERE THEN SACRIFICED FOR ANALYSES. ALVEOLAR BONE LOSS WAS ASSESSED, AND A MULTIPLEX IMMUNOASSAY WAS PERFORMED. MAXILLAE AND GUT TISSUES WERE IMMUNOSTAINED FOR DNMT3B (DE NOVO METHYLATION MARKER), B AND T LYMPHOCYTE ATTENUATOR (BTLA) AND IL-18R1 (INFLAMMATION MARKERS). RESULTS: PG AND PG + LIG GROUPS EXHIBITED HIGHER BONE LOSS WHEN COMPARED TO SHAM. BAFF, VEGF, RANKL, RANTES AND IP-10 WERE SIGNIFICANTLY HIGHER WITH PG GAVAGE. LIKEWISE, DNMT3B WAS OVEREXPRESSED IN BOTH GUT AND MAXILLA AFTER THE PG ADMINISTRATION. THE SAME PATTERN WAS OBSERVED FOR BTLA AND IL-18R1 IN GUT TISSUES. CONCLUSIONS: THE SYSTEMIC MICROBIAL CHALLENGE EITHER ALONE OR IN COMBINATION WITH LOCAL CHALLENGE LEADS TO DISTINCT PATTERNS OF INFLAMMATORY AND EPIGENETIC FEATURES WHEN COMPARED TO SIMPLY LOCALLY INDUCED EXPERIMENTAL PERIODONTITIS. 2019 12 4947 27 PATERNAL SEPSIS INDUCES ALTERATIONS OF THE SPERM METHYLOME AND DAMPENS OFFSPRING IMMUNE RESPONSES-AN ANIMAL STUDY. BACKGROUND: SEPSIS REPRESENTS THE UTMOST SEVERE CONSEQUENCE OF INFECTION, INVOLVING A DYSREGULATED AND SELF-DAMAGING IMMUNE RESPONSE OF THE HOST. WHILE DIFFERENT ENVIRONMENTAL EXPOSURES LIKE CHRONIC STRESS OR MALNUTRITION HAVE BEEN WELL DESCRIBED TO REPROGRAM THE GERMLINE AND SUBSEQUENTLY OFFSPRING ATTRIBUTES, THE INTERGENERATIONAL IMPACT OF SEPSIS AS A TREMENDOUS IMMUNOLOGICAL STRESSOR HAS NOT BEEN EXAMINED YET. METHODS: POLYMICROBIAL SEPSIS IN 12-WEEK-OLD MALE C57BL/6 MICE WAS INDUCED BY CECAL LIGATION AND PUNCTURE (CLP), FOLLOWED BY A MATING OF THE MALE SURVIVORS (OR APPROPRIATE SHAM CONTROL ANIMALS) 6 WEEKS LATER WITH HEALTHY FEMALES. ALVEOLAR MACROPHAGES OF OFFSPRING ANIMALS WERE ISOLATED AND STIMULATED WITH EITHER LPS OR ZYMOSAN, AND SUPERNATANT LEVELS OF TNF-ALPHA WERE QUANTIFIED BY ELISA. FURTHERMORE, SYSTEMIC CYTOKINE RESPONSE TO INTRAPERITONEALLY INJECTED LPS WAS ASSESSED AFTER 24 H. ALSO, MORPHOLOGY, MOTILITY, AND GLOBAL DNA METHYLATION OF THE SEPSIS SURVIVORS' SPERM WAS EXAMINED. RESULTS: COMPARATIVE REDUCED REDUCTION BISULFITE SEQUENCING (RRBS) OF SPERM REVEALED CHANGES OF DNA METHYLATION (N = 381), MOST PRONOUNCED IN THE INTERGENIC GENOME AS WELL AS WITHIN INTRONS OF DEVELOPMENTALLY RELEVANT GENES. OFFSPRING OF SEPSIS FATHERS EXHIBITED A SLIGHT DECREASE IN BODY WEIGHT, WITH A MORE PRONOUNCED WEIGHT DIFFERENCE IN MALE ANIMALS (CLP VS. SHAM). MALE DESCENDANTS OF SEPSIS FATHERS, BUT NOT FEMALE DESCENDANTS, EXHIBITED LOWER PLASMA CONCENTRATIONS OF IL-6, TNF-ALPHA, AND IL-10 24 H AFTER INJECTION OF LPS. IN LINE, ONLY ALVEOLAR MACROPHAGES OF MALE DESCENDANTS OF SEPSIS FATHERS PRODUCED LESS TNF-ALPHA UPON ZYMOSAN STIMULATION COMPARED TO SHAM DESCENDANTS, WHILE LPS RESPONSES KEPT UNCHANGED. CONCLUSION: WE CAN PROVE THAT MALE-BUT SURPRISINGLY NOT FEMALE-DESCENDANTS OF POST-SEPSIS FATHERS SHOW A DAMPENED SYSTEMIC AS WELL AS PULMONARY IMMUNE RESPONSE. BASED ON THIS OBSERVATION OF AN IMMUNE HYPO-RESPONSIVITY, WE PROPOSE THAT MALE DESCENDANTS OF SEPSIS FATHERS ARE AT RISK TO DEVELOP FUNGAL AND BACTERIAL INFECTIONS AND MIGHT BENEFIT FROM THERAPEUTIC IMMUNE MODULATION. 2018 13 5783 38 SPONTANEOUS AND TRANSGENIC RODENT MODELS OF INFLAMMATORY BOWEL DISEASE. INFLAMMATORY BOWEL DISEASE (IBD) IS A MULTIFACTORIAL DISORDER WITH MANY DIFFERENT PUTATIVE INFLUENCES MEDIATING DISEASE ONSET, SEVERITY, PROGRESSION AND DIMINUTION. SPONTANEOUS NATURAL IBD IS CLASSICALLY EXPRESSED AS CROHN'S DISEASE (CD) AND ULCERATIVE COLITIS (UC) COMMONLY FOUND IN PRIMATES; LYMPHOPLASMOCYTIC ENTERITIS, EOSINOPHILIC GASTRITIS AND COLITIS, AND ULCERATIVE COLITIS WITH NEURONAL HYPERPLASIA IN DOGS; AND COLITIS IN HORSES. SPONTANEOUS INFLAMMATORY BOWEL DISEASE HAS BEEN NOTED IN A NUMBER OF RODENT MODELS WHICH DIFFER IN GENETIC STRAIN BACKGROUND, INDUCED MUTATION, MICROBIOTA INFLUENCES AND IMMUNOPATHOGENIC PATHWAYS. HISTOLOGICAL LESIONS IN CROHN'S DISEASE FEATURE NONCASEATING GRANULOMATOUS INFLAMMATION WHILE UC LESIONS TYPICALLY EXHIBIT ULCERATION, LAMINA PROPRIA INFLAMMATORY INFILTRATES AND LACK OF GRANULOMA DEVELOPMENT. INTESTINAL INFLAMMATION CAUSED BY CD AND UC IS ALSO ASSOCIATED WITH INCREASED INCIDENCE OF INTESTINAL NEOPLASIA. TRANSGENIC MURINE MODELS HAVE DETERMINED UNDERLYING ETIOLOGICAL INFLUENCES AND APPROPRIATE THERAPEUTIC TARGETS IN IBD. THIS LITERATURE REVIEW WILL DISCUSS CURRENT OPINION AND FINDINGS IN SPONTANEOUS IBD, HIGHLIGHT SELECTED TRANSGENIC RODENT MODELS OF IBD AND DISCUSS THEIR RESPECTIVE PATHOGENIC MECHANISMS. IT IS VERY IMPORTANT TO PROVIDE ACCOMMODATION OF INDUCED PUTATIVE DEFICITS IN ACTIVITIES OF DAILY LIVING AND TO ASSESS DISCOMFORT AND PAIN LEVELS IN THE FACE OF SIGNIFICANT MORBIDITY AND/OR MORTALITY IN THESE MODELS. EPIGENETIC, ENVIRONMENTAL (MICROBIOME, METABOLOME) AND NUTRITIONAL FACTORS ARE IMPORTANT IN IBD PATHOGENESIS, AND EVALUATING WAYS IN WHICH THEY INFLUENCE DISEASE EXPRESSION REPRESENT POTENTIAL INVESTIGATIVE APPROACHES WITH THE GREATEST POTENTIAL FOR NEW DISCOVERIES. 2015 14 2065 21 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 3920 22 LINKING IMMUNITY, EPIGENETICS, AND CANCER IN INFLAMMATORY BOWEL DISEASE. MOST OF WHAT IS KNOWN ABOUT THE PATHOGENESIS OF INFLAMMATORY BOWEL DISEASE (IBD) PERTAINS TO COMPLEX INTERPLAY BETWEEN HOST GENETICS, IMMUNITY, AND ENVIRONMENTAL FACTORS. EPIGENETIC MODIFICATIONS PLAY PIVOTAL ROLES IN INTESTINAL IMMUNITY AND MUCOSAL HOMEOSTASIS AS WELL AS MEDIATING GENE-ENVIRONMENT INTERACTIONS. IN THIS ARTICLE, WE PROVIDE A HISTORICAL ACCOUNT OF EPIGENETIC RESEARCH EITHER DIRECTLY RELATED OR PERTINENT TO THE PATHOGENESIS AND MANAGEMENT OF IBD. WE FURTHER COLLATE EMERGING EVIDENCE SUPPORTING ROLES FOR EPIGENETIC MECHANISMS IN RELEVANT ASPECTS OF IBD BIOLOGY, INCLUDING DEREGULATED IMMUNITY, HOST-PATHOGEN RECOGNITION AND MUCOSAL INTEGRITY. FINALLY, WE HIGHLIGHT KEY EPIGENETIC MECHANISMS THAT LINK CHRONIC INFLAMMATION TO SPECIFIC IBD COMORBIDITIES, INCLUDING COLITIS-ASSOCIATED CANCER AND DISCUSS THEIR POTENTIAL UTILITY AS NOVEL BIOMARKERS OR PHARMACOLOGIC TARGETS IN IBD THERAPY. 2014 16 2368 21 EPIGENETIC REGULATION OF T HELPER CELLS AND INTESTINAL PATHOGENICITY. INFLAMMATORY BOWEL DISEASES (IBDS) ARE CHARACTERIZED BY RELAPSING AND REMITTING CHRONIC INTESTINAL INFLAMMATION. PREVIOUS STUDIES HAVE DEMONSTRATED THE CONTRIBUTIONS OF GENETIC BACKGROUND, ENVIRONMENTAL FACTORS (FOOD, MICROBIOTA, USE OF ANTIBIOTICS), AND HOST IMMUNITY IN THE DEVELOPMENT OF IBDS. MORE THAN 200 GENES HAVE BEEN SHOWN TO INFLUENCE IBD SUSCEPTIBILITY, MOST OF WHICH ARE INVOLVED IN IMMUNITY. THE VERTEBRATE IMMUNE SYSTEM COMPRISES A COMPLEX NETWORK OF INNATE AND ADAPTIVE IMMUNE CELLS THAT PROTECT THE HOST FROM INFECTION AND CANCER. DYSREGULATION OF THE MUTUALISTIC RELATIONSHIP BETWEEN THE IMMUNE SYSTEM AND THE GUT ENVIRONMENT RESULTS IN IBD. CONSIDERING THE FUNDAMENTAL ROLE OF EPIGENETIC REGULATION IN IMMUNE CELLS, EPIGENETIC MECHANISMS, PARTICULARLY IN T HELPER (TH) CELLS, MAY PLAY A MAJOR ROLE IN THE COMPLEX REGULATION OF MUCOSAL IMMUNITY. EPIGENETIC REGULATION AND DYSREGULATION OF TH CELLS ARE INVOLVED IN THE MAINTENANCE OF INTESTINAL HOMEOSTASIS AND ITS BREAKDOWN IN IBD. 2019 17 1275 29 DAMAGE-ASSOCIATED MOLECULAR PATTERNS IN INFLAMMATORY BOWEL DISEASE: FROM BIOMARKERS TO THERAPEUTIC TARGETS. THE CHRONIC INFLAMMATORY PROCESS UNDERLYING INFLAMMATORY BOWEL DISEASE (IBD), COMPRISING CROHN'S DISEASE AND ULCERATIVE COLITIS, DERIVES FROM THE INTERPLAY OF SEVERAL COMPONENTS IN A GENETICALLY SUSCEPTIBLE HOST. THESE COMPONENTS INCLUDE ENVIRONMENTAL ELEMENTS AND GUT MICROBIOTA A DYSBIOSIS. FOR DECADES, IMMUNE ABNORMALITIES HAVE BEEN INVESTIGATED AS CRITICALLY IMPORTANT IN IBD PATHOGENESIS, AND ATTEMPTS TO DEVELOP EFFECTIVE THERAPIES HAVE PREDOMINANTLY TARGETED THE IMMUNE SYSTEM. NEVERTHELESS, IMMUNE EVENTS REPRESENT ONLY ONE OF THE CONSTITUENTS CONTRIBUTING TO IBD PATHOGENESIS WITHIN THE CONTEXT OF THE COMPLEX CELLULAR AND MOLECULAR NETWORK UNDERLYING CHRONIC INTESTINAL INFLAMMATION. THESE FACTORS NEED TO BE APPRECIATED WITHIN THE MILIEU OF NON-IMMUNE COMPONENTS. DAMAGE-ASSOCIATED MOLECULAR PATTERNS (DAMPS), WHICH ARE ESSENTIALLY ENDOGENOUS STRESS PROTEINS EXPRESSED OR RELEASED AS A RESULT OF CELL OR TISSUE DAMAGE, HAVE BEEN SHOWN TO ACT AS DIRECT PRO-INFLAMMATORY MEDIATORS. EXCESSIVE OR PERSISTENT SIGNALLING MEDIATED BY SUCH MOLECULES CAN UNDERLIE SEVERAL CHRONIC INFLAMMATORY DISORDERS, INCLUDING IBD. THE RELEASE OF ENDOGENOUS DAMPS AMPLIFIES THE INFLAMMATORY RESPONSE DRIVEN BY IMMUNE AND NON-IMMUNE CELLS AND PROMOTES EPIGENETIC REPROGRAMMING IN IBD. THE EFFECTS DETERMINE PATHOLOGIC CHANGES, WHICH MAY SUSTAIN CHRONIC INTESTINAL INFLAMMATION AND ALSO UNDERLIE SPECIFIC DISEASE PHENOTYPES. IN ADDITION TO HIGHLIGHTING THE POTENTIAL USE OF DAMPS SUCH AS CALPROTECTIN AS BIOMARKERS, RESEARCH ON DAMPS MAY REVEAL NOVEL MECHANISTIC ASSOCIATIONS IN IBD PATHOGENESIS AND IS EXPECTED TO UNCOVER PUTATIVE THERAPEUTIC TARGETS. 2018 18 2875 26 FUNCTIONAL ROLE AND THERAPEUTIC TARGETING OF MICRORNAS IN INFLAMMATORY BOWEL DISEASE. INFLAMMATORY BOWEL DISEASES (IBD) ARE CHRONIC INFLAMMATORY GASTROINTESTINAL DISEASES, PRIMARILY CONSISTING OF ULCERATIVE COLITIS AND CROHN'S DISEASE. THE COMPLEX NATURE OF THE DISEASE, AS WELL AS THE LIMITED THERAPEUTIC OPTIONS CHARACTERIZED BY LOW EFFICIENCY AND MAJOR SIDE EFFECTS, HIGHLIGHTS THE IMPORTANCE OF DEVELOPING NOVEL STRATEGIES OF THERAPEUTIC INTERVENTION IN IBD. SUSCEPTIBILITY LOCI RELATED TO IBD ARE PRESENT ONLY IN A SMALL PERCENTAGE OF IBD PATIENTS, IMPLYING THAT EPIGENETIC MODIFICATIONS COULD INFLUENCE THE PATHOGENESIS OF THE DISEASE. MICRORNAS (MIRNAS) ARE SMALL NONCODING RNAS THAT REGULATE MULTIPLE MOLECULAR PATHWAYS INVOLVED IN IBD PATHOBIOLOGY. MIRNA INHIBITORS TARGETING THE IBD-ACTIVATED MIRNAS COULD HAVE THERAPEUTIC VALUE FOR IBD PATIENTS. THIS REVIEW PROVIDES AN OVERVIEW OF THE RECENT ADVANCES IN MIRNA BIOLOGY RELATED TO IBD PATHOGENESIS AND THE PHARMACOLOGICAL DEVELOPMENT OF MIRNA-BASED THERAPEUTICS. 2018 19 5999 28 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 20 2784 32 EZH2 PROMOTES EXTRACELLULAR MATRIX DEGRADATION VIA NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) AND P38 SIGNALING PATHWAYS IN PULPITIS. PULPITIS IS A COMPLICATED CHRONIC INFLAMMATORY PROCESS WHICH CAN BE IN A DYNAMIC BALANCE BETWEEN DAMAGE AND REPAIR. THE EXTRACELLULAR MATRIX PLAYS AN IMPORTANT REGULATORY ROLE IN WOUND HEALING AND TISSUE REPAIR. THE AIM OF THIS STUDY WAS TO EXPLORE THE ROLE OF THE EPIGENETIC MARK, ENHANCER OF ZESTE HOMOLOG 2 (EZH2) ON THE DEGRADATION OF EXTRACELLULAR MATRIX DURING PULPITIS. QUANTITATIVE POLYMERASE CHAIN REACTION WAS USED TO ASSESS THE EXPRESSION OF MATRIX METALLOPROTEINASES (MMPS) AND TYPE I COLLAGEN IN HUMAN DENTAL PULP CELLS (HDPCS) UPON EZH2 AND EI1 (EZH2 INHIBITOR) STIMULATION. THE MECHANISM OF EZH2 AFFECTING EXTRACELLULAR MATRIX WAS EXPLORED THROUGH QUANTITATIVE POLYMERASE CHAIN REACTION AND WESTERN BLOT. A RAT MODEL OF DENTAL PULP INFLAMMATION WAS ESTABLISHED, AND THE EXPRESSION OF TYPE I COLLAGEN IN DENTAL PULP UNDER EZH2 STIMULATION WAS DETECTED BY IMMUNOHISTOCHEMICAL STAINING. EZH2 UPREGULATED THE EXPRESSION OF MMP-1, MMP-3, MMP-8, AND MMP-10 AND DECREASED THE PRODUCTION OF TYPE I COLLAGEN IN HDPCS, WHILE EI1 HAD THE OPPOSITE EFFECT. EZH2 ACTIVATED THE NUCLEAR FACTOR-KAPPA B (NF-KAPPAB) AND P38 SIGNALING PATHWAYS IN HDPCS, THE INHIBITION OF WHICH REVERSED THE INDUCTION OF MMPS AND THE SUPPRESSION OF TYPE I COLLAGEN. EZH2 CAN DOWNREGULATE THE TYPE I COLLAGEN LEVELS IN AN EXPERIMENTAL MODEL OF DENTAL PULPITIS IN RATS. EZH2 PROMOTES EXTRACELLULAR MATRIX DEGRADATION VIA NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) AND P38 SIGNALING PATHWAYS IN PULPITIS. EZH2 CAN DECREASE THE TYPE I COLLAGEN LEVELS IN VIVO AND IN VITRO. 2021