1 3536 104 IMMUNE CHROMATIN READER SP140 REGULATES MICROBIOTA AND RISK FOR INFLAMMATORY BOWEL DISEASE. INFLAMMATORY BOWEL DISEASE (IBD) IS DRIVEN BY HOST GENETICS AND ENVIRONMENTAL FACTORS, INCLUDING COMMENSAL MICROORGANISMS. SPECKLED PROTEIN 140 (SP140) IS AN IMMUNE-RESTRICTED CHROMATIN "READER" THAT IS ASSOCIATED WITH CROHN'S DISEASE (CD), MULTIPLE SCLEROSIS (MS), AND CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). HOWEVER, THE DISEASE-CAUSING MECHANISMS OF SP140 REMAIN UNDEFINED. HERE, WE IDENTIFY AN IMMUNE-INTRINSIC ROLE FOR SP140 IN REGULATING PHAGOCYTIC DEFENSE RESPONSES TO PREVENT THE EXPANSION OF INFLAMMATORY BACTERIA. MICE HARBORING ALTERED MICROBIOTA DUE TO HEMATOPOIETIC SP140 DEFICIENCY EXHIBITED SEVERE COLITIS THAT WAS TRANSMISSIBLE UPON COHOUSING AND AMELIORATED WITH ANTIBIOTICS. LOSS OF SP140 RESULTS IN BLOOMS OF PROTEOBACTERIA, INCLUDING HELICOBACTER IN SP140(-/-) MICE AND ENTEROBACTERIACEAE IN HUMANS BEARING THE CD-ASSOCIATED SP140 LOSS-OF-FUNCTION VARIANT. PHAGOCYTES FROM PATIENTS WITH THE SP140 LOSS-OF-FUNCTION VARIANT AND SP140(-/-) MICE EXHIBITED ALTERED ANTIMICROBIAL DEFENSE PROGRAMS REQUIRED FOR CONTROL OF PATHOBIONTS. THUS, MUTATIONS WITHIN THIS EPIGENETIC READER MAY CONSTITUTE A PREDISPOSING EVENT IN HUMAN DISEASES PROVOKED BY MICROBIOTA. 2022 2 2271 48 EPIGENETIC READER SP140 LOSS OF FUNCTION DRIVES CROHN'S DISEASE DUE TO UNCONTROLLED MACROPHAGE TOPOISOMERASES. HOW MIS-REGULATED CHROMATIN DIRECTLY IMPACTS HUMAN IMMUNE DISORDERS IS POORLY UNDERSTOOD. SPECKLED PROTEIN 140 (SP140) IS AN IMMUNE-RESTRICTED PHD AND BROMODOMAIN-CONTAINING EPIGENETIC "READER," AND SP140 LOSS-OF-FUNCTION MUTATIONS ASSOCIATE WITH CROHN'S DISEASE (CD), MULTIPLE SCLEROSIS (MS), AND CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). HOWEVER, THE RELEVANCE OF THESE MUTATIONS AND MECHANISMS UNDERLYING SP140-DRIVEN PATHOGENICITY REMAINS UNEXPLORED. USING A GLOBAL PROTEOMIC STRATEGY, WE IDENTIFIED SP140 AS A REPRESSOR OF TOPOISOMERASES (TOPS) THAT MAINTAINS HETEROCHROMATIN AND MACROPHAGE FATE. IN HUMANS AND MICE, SP140 LOSS RESULTED IN UNLEASHED TOP ACTIVITY, DE-REPRESSION OF DEVELOPMENTALLY SILENCED GENES, AND ULTIMATELY DEFECTIVE MICROBE-INDUCIBLE MACROPHAGE TRANSCRIPTIONAL PROGRAMS AND BACTERIAL KILLING THAT DRIVE INTESTINAL PATHOLOGY. PHARMACOLOGICAL INHIBITION OF TOP1/2 RESCUED THESE DEFECTS. FURTHERMORE, EXACERBATED COLITIS WAS RESTORED WITH TOP1/2 INHIBITORS IN SP140(-/-) MICE, BUT NOT WILD-TYPE MICE, IN VIVO. COLLECTIVELY, WE IDENTIFY SP140 AS A TOP REPRESSOR AND REVEAL REPURPOSING OF TOP INHIBITION TO REVERSE IMMUNE DISEASES DRIVEN BY SP140 LOSS. 2022 3 1099 29 COLONIC CARCINOGENESIS IN IBD: MOLECULAR EVENTS. PATIENTS WITH ULCERATIVE COLITIS (UC) AND CROHN'S DISEASE (CD) ARE AT INCREASED RISK OF DEVELOPING INTESTINAL CANCERS VIA MECHANISMS THAT REMAIN INCOMPLETELY UNDERSTOOD. SEVERAL EVIDENCES SUGGEST A CAUSAL LINK BETWEEN CHRONIC INFLAMMATION AND THE DEVELOPMENT OF CANCER IN THE GASTROINTESTINAL TRACT. IN FACT, PATIENTS WITH UC ARE EXPOSED TO REPEATED EPISODES OF INFLAMMATION THAT PREDISPOSE TO VARIOUS TUMORIGENIC EVENTS AND THE SEQUENCE OF THESE EVENTS ARE DIFFERENT FROM THOSE THAT CONTRIBUTE TO DEVELOP A SPORADIC COLORECTAL CANCER. IN UC CARCINOGENESIS THE EARLY EVENTS ARE REPRESENTED BY DNA METHYLATION THAT PRODUCE AN INHIBITION OF ONCO-SUPPRESSOR GENES, MUTATION OF P53, ANEUPLOIDY AND MICROSATELLITE INSTABILITY. HYPERMETHYLATION OF TUMOR SUPPRESSORS AND DNA MISMATCH REPAIR GENE PROMOTER REGIONS, IS AN EPIGENETIC MECHANISM OF GENE SILENCING THAT CONTRIBUTES TO TUMORIGENESIS AND MIGHT REPRESENT THE FIRST STEP IN INFLAMMATORY CARCINOGENESIS. P53 IS FREQUENTLY MUTATED IN THE EARLY STAGES OF UC-ASSOCIATED CANCER, IN 33-67% OF PATIENTS WITH DYSPLASIA AND IN 83-95% OF UC RELATED CANCER PATIENTS. MOREOVER, ANEUPLOIDY IS AN INDEPENDENT RISK FACTOR FOR FORTHCOMING CARCINOGENESIS IN UC FINALLY, THE INCONSISTENCY BETWEEN THE HIGH CUMULATIVE RATE OF DYSPLASIA IN UC AND THE RELATIVELY LOWER INCIDENCE OF INVASIVE CANCER RAISES THE QUESTION ABOUT THE MECHANISMS OF IMMUNOSURVEILLANCE THAT MAY PREVENT MALIGNANT PROGRESSION OF NEOPLASM IN THE COLON IN MOST CASES. CO-STIMULATORY MOLECULE CD80 UP-REGULATION IN COLONIC MUCOSA IN UC DYSPLASIA MAY BE ONE OF THESE MECHANISM. 2011 4 3436 28 HYPERGLYCEMIC MEMORY OF INNATE IMMUNE CELLS PROMOTES IN VITRO PROINFLAMMATORY RESPONSES OF HUMAN MONOCYTES AND MURINE MACROPHAGES. IT HAS BEEN WELL ESTABLISHED THAT THE PRESENCE OF DIABETES IS ACCOMPANIED BY A CHRONIC INFLAMMATORY STATE PROMOTING VARIOUS DIABETES-ASSOCIATED COMPLICATIONS. ONE POTENTIAL DRIVER OF THIS ENHANCED INFLAMMATORY STATE IN PATIENTS WITH DIABETES IS HYPERGLYCEMIA. EVEN AFTER BLOOD GLUCOSE CONTROL IS ACHIEVED, DIABETES-ASSOCIATED COMPLICATIONS PERSIST, SUGGESTING THE PRESENCE OF A "HYPERGLYCEMIC MEMORY." INNATE IMMUNE CELLS, CRITICALLY INVOLVED IN VARIOUS COMPLICATIONS ASSOCIATED WITH DIABETES, CAN BUILD NONSPECIFIC, IMMUNOLOGICAL MEMORY (TRAINED IMMUNITY) VIA EPIGENETIC REGULATION. WE EXAMINE THE POTENTIAL INVOLVEMENT OF HYPERGLYCEMIA-INDUCED TRAINED IMMUNITY IN PROMOTING INFLAMMATION. OUR RESULTS SHOW THAT HYPERGLYCEMIA INDUCES A TRAINED PHENOTYPE IN VIVO IN MICE AND IN VITRO IN HUMAN MONOCYTES, REPRESENTATIVE BY AN INCREASED TNF-ALPHA SECRETION AFTER EX VIVO STIMULATION WITH LPS. THESE EFFECTS WERE LARGELY MEDIATED BY EPIGENETIC CHANGES CONTROLLED BY THE MIXED LINEAGE LEUKEMIA (MLL) FAMILY BECAUSE TREATMENT WITH THE MLL INHIBITOR MENIN-MLL DURING THE PROCESS OF TRAINED IMMUNITY ACQUISITION REPRESSED THE PROINFLAMMATORY PHENOTYPE. COLLECTIVELY, OUR RESULTS IDENTIFY A NOVEL LINK BETWEEN HYPERGLYCEMIA AND INFLAMMATION IN INNATE IMMUNE CELLS THAT MIGHT EXPLAIN THE INCREASED PROINFLAMMATORY STATE DURING DIABETES POTENTIALLY CONTRIBUTING TO THE DEVELOPMENT OF VARIOUS DIABETES-ASSOCIATED COMPLICATIONS. 2021 5 2368 26 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 6 2233 35 EPIGENETIC MODIFICATIONS OF THE NUCLEAR FACTOR KAPPA B SIGNALLING PATHWAY AND ITS IMPACT ON INFLAMMATORY BOWEL DISEASE. BACKGROUND: INFLAMMATORY BOWEL DISEASE (IBD) IS A MULTIFACTORIAL CONDITION INFLUENCED BY THE IMMUNE SYSTEM, THE INTESTINAL MICROBIOTA, ENVIRONMENTAL FACTORS, GENETIC AND EPIGENETIC FACTORS. GENETIC- AND ENVIRONMENT- INDUCED DYSREGULATION OF THE NUCLEAR FACTOR-KAPPA B (NF-KAPPAB) TRANSCRIPTION FACTOR PATHWAY HAS BEEN LINKED TO IBD PATHOGENESIS. OBJECTIVE: TO ASSESS THE CURRENT EVIDENCE IN RELATION TO THE CONTRIBUTION OF THE CLASSICAL AND ALTERNATIVE NF-KAPPAB PATHWAYS IN IBD AND TO DISCUSS THE EPIGENETIC MECHANISMS THAT IMPACT ON NF-KAPPAB FUNCTION. METHODS: A MEDLINE SEARCH FOR 'NF-KAPPAB/NF-KAPPAB', IN COMBINATION WITH TERMS INCLUDING 'INFLAMMATORY BOWEL DISEASE/IBD', 'INTESTINAL INFLAMMATION', 'CROHN'S DISEASE', 'ULCERATIVE COLITIS', 'COLITIS'; 'EPIGENETICS', 'DNA METHYLATION', 'HISTONES', 'MICRORNAS/MIRNAS' AND 'SHORT NON-CODING/LONG NON-CODING RNAS' WAS PERFORMED. RESULTS: BOTH NF-KAPPAB PATHWAYS CONTRIBUTE TO THE CHRONIC INFLAMMATION UNDERLYING IBD BY REGULATING THE INFLAMMATORY IMMUNE RESPONSES AND HOMEOSTASIS OF THE INTESTINAL EPITHELIUM (CLASSICAL PATHWAY) OR REGULATING BOWEL INFLAMMATION AND EPITHELIAL MICROFOLD (M) CELL FUNCTION (ALTERNATIVE PATHWAY). DNA METHYLATION IS A COMMON EPIGENETIC MODIFICATION IN INTESTINAL INFLAMMATION, INCLUDING NFKB1 AND RELA LOCI. CONVERSELY, LITTLE IS UNDERSTOOD REGARDING EPIGENETIC EFFECTS ON GENES ENCODING OTHER NF-KAPPAB SUBUNITS, PARTICULARLY THOSE OF THE ALTERNATIVE PATHWAY, AND IN THE CONTEXT OF IBD. HOWEVER, NF-KAPPAB INTERACTION WITH CHROMATIN MODIFIERS IS ALSO SEEN TO BE AN ESSENTIAL MECHANISM OF REGULATION OF DOWNSTREAM TARGET GENES RELEVANT TO NF-KAPPAB-MEDIATED INFLAMMATORY RESPONSES. CONCLUSION: FURTHER RESEARCH IS CLEARLY WARRANTED IN THIS AREA, AS UNDERSTANDING THE CELL-SPECIFIC REGULATION OF THE NF-KAPPAB PATHWAYS WILL BRING RESEARCHERS INTO A POSITION TO ACHIEVE MORE EFFICIENT STRATIFICATION OF IBD PATIENTS, AND MORE TARGETED AND EFFECTIVE CHOICE OF TREATMENT. 2021 7 4732 32 NOVEL BIOMARKERS FOR INFLAMMATORY BOWEL DISEASE AND COLORECTAL CANCER: AN INTERPLAY BETWEEN METABOLIC DYSREGULATION AND EXCESSIVE INFLAMMATION. PERSISTENT INFLAMMATION CAN TRIGGER ALTERED EPIGENETIC, INFLAMMATORY, AND BIOENERGETIC STATES. INFLAMMATORY BOWEL DISEASE (IBD) IS AN IDIOPATHIC DISEASE CHARACTERIZED BY CHRONIC INFLAMMATION OF THE GASTROINTESTINAL TRACT, WITH EVIDENCE OF SUBSEQUENT METABOLIC SYNDROME DISORDER. STUDIES HAVE DEMONSTRATED THAT AS MANY AS 42% OF PATIENTS WITH ULCERATIVE COLITIS (UC) WHO ARE FOUND TO HAVE HIGH-GRADE DYSPLASIA, EITHER ALREADY HAD COLORECTAL CANCER (CRC) OR DEVELOP IT WITHIN A SHORT TIME. THE PRESENCE OF LOW-GRADE DYSPLASIA IS ALSO PREDICTIVE OF CRC. MANY SIGNALING PATHWAYS ARE SHARED AMONG IBD AND CRC, INCLUDING CELL SURVIVAL, CELL PROLIFERATION, ANGIOGENESIS, AND INFLAMMATORY SIGNALING PATHWAYS. CURRENT IBD THERAPEUTICS TARGET A SMALL SUBSET OF MOLECULAR DRIVERS OF IBD, WITH MANY FOCUSED ON THE INFLAMMATORY ASPECT OF THE PATHWAYS. THUS, THERE IS A GREAT NEED TO IDENTIFY BIOMARKERS OF BOTH IBD AND CRC, THAT CAN BE PREDICTIVE OF THERAPEUTIC EFFICACY, DISEASE SEVERITY, AND PREDISPOSITION TO CRC. IN THIS STUDY, WE EXPLORED THE CHANGES IN BIOMARKERS SPECIFIC FOR INFLAMMATORY, METABOLIC, AND PROLIFERATIVE PATHWAYS, TO HELP DETERMINE THE RELEVANCE TO BOTH IBD AND CRC. OUR ANALYSIS DEMONSTRATED, FOR THE FIRST TIME IN IBD, THE LOSS OF THE TUMOR SUPPRESSOR PROTEIN RAS ASSOCIATED FAMILY PROTEIN 1A (RASSF1A), VIA EPIGENETIC CHANGES, THE HYPERACTIVATION OF THE OBLIGATE KINASE OF THE NOD2 PATHOGEN RECOGNITION RECEPTOR (RECEPTOR INTERACTING PROTEIN KINASE 2 [RIPK2]), THE LOSS OF ACTIVATION OF THE METABOLIC KINASE, AMP ACTIVATED PROTEIN KINASE (AMPKALPHA1), AND, LASTLY, THE ACTIVATION OF THE TRANSCRIPTION FACTOR AND KINASE YES ASSOCIATED PROTEIN (YAP) KINASE, THAT IS INVOLVED IN PROLIFERATION OF CELLS. THE EXPRESSION AND ACTIVATION STATUS OF THESE FOUR ELEMENTS ARE MIRRORED IN IBD, CRC, AND IBD-CRC PATIENTS AND, IMPORTANTLY, IN MATCHED BLOOD AND BIOPSY SAMPLES. THE LATTER WOULD SUGGEST THAT BIOMARKER ANALYSIS CAN BE PERFORMED NON-INVASIVELY, TO UNDERSTAND IBD AND CRC, WITHOUT THE NEED FOR INVASIVE AND COSTLY ENDOSCOPIC ANALYSIS. THIS STUDY, FOR THE FIRST TIME, ILLUSTRATES THE NEED TO UNDERSTAND IBD OR CRC BEYOND AN INFLAMMATORY PERSPECTIVE AND THE VALUE OF THERAPEUTICS DIRECTED TO RESET ALTERED PROLIFERATIVE AND METABOLIC STATES WITHIN THE COLON. THE USE OF SUCH THERAPEUTICS MAY TRULY DRIVE PATIENTS INTO REMISSION. 2023 8 2228 30 EPIGENETIC MODIFICATIONS OF HISTONES IN PERIODONTAL DISEASE. PERIODONTITIS IS A CHRONIC INFECTIOUS DISEASE DRIVEN BY DYSBIOSIS, AN IMBALANCE BETWEEN COMMENSAL BACTERIA AND THE HOST ORGANISM. PERIODONTITIS IS A LEADING CAUSE OF TOOTH LOSS IN ADULTS AND OCCURS IN ABOUT 50% OF THE US POPULATION. IN ADDITION TO THE CLINICAL CHALLENGES ASSOCIATED WITH TREATING PERIODONTITIS, THE PROGRESSION AND CHRONIC NATURE OF THIS DISEASE SERIOUSLY AFFECT HUMAN HEALTH. EMERGING EVIDENCE SUGGESTS THAT PERIODONTITIS IS ASSOCIATED WITH MECHANISMS BEYOND BACTERIA-INDUCED PROTEIN AND TISSUE DEGRADATION. HERE, WE HYPOTHESIZE THAT BACTERIA ARE ABLE TO INDUCE EPIGENETIC MODIFICATIONS IN ORAL EPITHELIAL CELLS MEDIATED BY HISTONE MODIFICATIONS. IN THIS STUDY, WE FOUND THAT DYSBIOSIS IN VIVO LED TO EPIGENETIC MODIFICATIONS, INCLUDING ACETYLATION OF HISTONES AND DOWNREGULATION OF DNA METHYLTRANSFERASE 1. IN ADDITION, IN VITRO EXPOSURE OF ORAL EPITHELIAL CELLS TO LIPOPOLYSACCHARIDES RESULTED IN HISTONE MODIFICATIONS, ACTIVATION OF TRANSCRIPTIONAL COACTIVATORS, SUCH AS P300/CBP, AND ACCUMULATION OF NUCLEAR FACTOR-KAPPAB (NF-KAPPAB). GIVEN THAT ORAL EPITHELIAL CELLS ARE THE FIRST LINE OF DEFENSE FOR THE PERIODONTIUM AGAINST BACTERIA, WE ALSO EVALUATED WHETHER ACTIVATION OF PATHOGEN RECOGNITION RECEPTORS INDUCED HISTONE MODIFICATIONS. WE FOUND THAT ACTIVATION OF THE TOLL-LIKE RECEPTORS 1, 2, AND 4 AND THE NUCLEOTIDE-BINDING OLIGOMERIZATION DOMAIN PROTEIN 1 INDUCED HISTONE ACETYLATION IN ORAL EPITHELIAL CELLS. OUR FINDINGS CORROBORATE THE EMERGING CONCEPT THAT EPIGENETIC MODIFICATIONS PLAY A ROLE IN THE DEVELOPMENT OF PERIODONTITIS. 2016 9 1137 31 COMPREHENSIVE PHENOTYPING IN INFLAMMATORY BOWEL DISEASE: SEARCH FOR BIOMARKER ALGORITHMS IN THE TRANSKINGDOM INTERACTIONS CONTEXT. INFLAMMATORY BOWEL DISEASE (IBD) IS THE MOST COMMON FORM OF INTESTINAL INFLAMMATION ASSOCIATED WITH A DYSREGULATED IMMUNE SYSTEM RESPONSE TO THE COMMENSAL MICROBIOTA IN A GENETICALLY SUSCEPTIBLE HOST. IBD INCLUDES ULCERATIVE COLITIS (UC) AND CROHN'S DISEASE (CD), BOTH OF WHICH ARE REMARKABLY HETEROGENEOUS IN THEIR CLINICAL PRESENTATION AND RESPONSE TO TREATMENT. THIS TRANSLATES INTO A NOTABLE DIAGNOSTIC CHALLENGE, ESPECIALLY IN UNDERDEVELOPED COUNTRIES WHERE IBD IS ON THE RISE AND ACCESS TO DIAGNOSIS OR TREATMENT IS NOT ALWAYS ACCESSIBLE FOR CHRONIC DISEASES. THE PRESENT WORK CHARACTERIZED, FOR THE FIRST TIME IN OUR REGION, EPIGENETIC BIOMARKERS AND GUT MICROBIAL PROFILES ASSOCIATED WITH UC AND CD PATIENTS IN THE BUENOS AIRES METROPOLITAN AREA AND REVEALED DIFFERENCES BETWEEN NON-IBD CONTROLS AND IBD PATIENTS. GENERAL METABOLIC FUNCTIONS ASSOCIATED WITH THE GUT MICROBIOTA, AS WELL AS CORE MICROORGANISMS WITHIN GROUPS, WERE ALSO ANALYZED. ADDITIONALLY, THE GUT MICROBIOTA ANALYSIS WAS INTEGRATED WITH RELEVANT CLINICAL, BIOCHEMICAL AND EPIGENETIC MARKERS CONSIDERED IN THE FOLLOW-UP OF PATIENTS WITH IBD, WITH THE AIM OF GENERATING MORE POWERFUL DIAGNOSTIC TOOLS TO DISCRIMINATE PHENOTYPES. OVERALL, OUR STUDY PROVIDES NEW INSIGHTS INTO DATA ANALYSIS ALGORITHMS TO PROMOTE COMPREHENSIVE PHENOTYPING TOOLS USING QUANTITATIVE AND QUALITATIVE ANALYSIS IN A TRANSKINGDOM INTERACTIONS NETWORK CONTEXT. 2022 10 5528 26 RNA MODIFICATION IN INFLAMMATORY BOWEL DISEASES. INFLAMMATORY BOWEL DISEASE (IBD) IS A CHRONIC INFLAMMATORY DISORDER CHARACTERIZED BY DAMAGE TO THE INTESTINAL MUCOSA, WHICH IS CAUSED BY A COMBINATION OF FACTORS. THESE INCLUDE GENETIC AND EPIGENETIC ALTERATIONS, ENVIRONMENTAL INFLUENCE, MICROORGANISM INTERACTIONS, AND IMMUNE CONDITIONS. SOME POPULATIONS WITH IBD SHOW A CANCER-PRONE PHENOTYPE. RECENT STUDIES HAVE PROVIDED INSIGHT INTO THE INVOLVEMENT OF RNA MODIFICATIONS IN THE SPECIFIC PATHOGENESIS OF IBD THROUGH REGULATION OF RNA BIOLOGY IN EPITHELIAL AND IMMUNE CELLS. STUDIES OF SEVERAL RNA MODIFICATION-TARGETING REAGENTS HAVE SHOWN PREFERABLE OUTCOMES IN PATIENTS WITH COLITIS. HERE, WE NOTE A NEW AWARENESS OF RNA MODIFICATION IN THE TARGETING OF IBD AND RELATED DISEASES, WHICH WILL CONTRIBUTE TO EARLY DIAGNOSIS, DISEASE MONITORING, AND POSSIBLE CONTROL BY INNOVATIVE THERAPEUTIC APPROACHES. 2022 11 5566 29 ROLE OF INFLAMMATION IN THE DEVELOPMENT OF COLORECTAL CANCER. CHRONIC INFLAMMATION CAN LEAD TO THE DEVELOPMENT OF MANY DISEASES, INCLUDING CANCER. INFLAMMATORY BOWEL DISEASE (IBD) THAT INCLUDES BOTH ULCERATIVE COLITIS (UC) AND CROHNMP'S DISEASE (CD) ARE RISK FACTORS FOR THE DEVELOPMENT OF COLORECTAL CANCER (CRC). MANY CYTOKINES PRODUCED PRIMARILY BY THE GUT IMMUNE CELLS EITHER DURING OR IN RESPONSE TO LOCALIZED INFLAMMATION IN THE COLON AND RECTUM ARE KNOWN TO STIMULATE THE COMPLEX INTERACTIONS BETWEEN THE DIFFERENT CELL TYPES IN THE GUT ENVIRONMENT RESULTING IN ACUTE INFLAMMATION. SUBSEQUENTLY, CHRONIC INFLAMMATION, TOGETHER WITH GENETIC AND EPIGENETIC CHANGES, HAVE BEEN SHOWN TO LEAD TO THE DEVELOPMENT AND PROGRESSION OF CRC. VARIOUS CELL TYPES PRESENT IN THE COLON, SUCH AS ENTEROCYTES, PANETH CELLS, GOBLET CELLS, AND MACROPHAGES, EXPRESS RECEPTORS FOR INFLAMMATORY CYTOKINES AND RESPOND TO TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA), INTERLEUKIN-1 BETA (IL-1BETA), IL-6, AND OTHER CYTOKINES. AMONG THE SEVERAL CYTOKINES PRODUCED, TNF-ALPHA AND IL-1BETA ARE THE KEY PRO-INFLAMMATORY MOLECULES THAT PLAY CRITICAL ROLES IN THE DEVELOPMENT OF CRC. THE CURRENT REVIEW IS INTENDED TO CONSOLIDATE THE PUBLISHED FINDINGS TO FOCUS ON THE ROLE OF PRO-INFLAMMATORY CYTOKINES, NAMELY TNF-ALPHA AND IL-1BETA, ON INFLAMMATION (AND THE ALTERED IMMUNE RESPONSE) IN THE GUT, TO BETTER UNDERSTAND THE DEVELOPMENT OF CRC IN IBD, USING VARIOUS EXPERIMENTAL MODEL SYSTEMS, PRECLINICAL AND CLINICAL STUDIES. MOREOVER, THIS REVIEW ALSO HIGHLIGHTS THE CURRENT THERAPEUTIC STRATEGIES AVAILABLE (MONOTHERAPY AND COMBINATION THERAPY) TO ALLEVIATE THE SYMPTOMS OR TREAT INFLAMMATION-ASSOCIATED CRC BY USING MONOCLONAL ANTIBODIES OR APTAMERS TO BLOCK PRO-INFLAMMATORY MOLECULES, INHIBITORS OF TYROSINE KINASES IN THE INFLAMMATORY SIGNALING CASCADE, COMPETITIVE INHIBITORS OF PRO-INFLAMMATORY MOLECULES, AND THE NUCLEIC ACID DRUGS LIKE SMALL ACTIVATING RNAS (SARNAS) OR MICRORNA (MIRNA) MIMICS TO ACTIVATE TUMOR SUPPRESSOR OR REPRESS ONCOGENE/PRO-INFLAMMATORY CYTOKINE GENE EXPRESSION. 2021 12 2601 33 EPIGENETICS, DNA ORGANIZATION, AND INFLAMMATORY BOWEL DISEASE. INFLAMMATORY BOWEL DISEASES (IBDS) ARE CHRONIC INFLAMMATORY DISORDERS AFFECTING THE GASTROINTESTINAL TRACT. THE INCIDENCE OF IBD IS INCREASING, WITH MORE CASES OCCURRING IN DEVELOPED COUNTRIES. MULTIPLE FACTORS SUCH AS GENETICS, ENVIRONMENTAL CHANGES, GUT MICROBIOTA, AND IMMUNE ABNORMALITIES HAVE BEEN ASSOCIATED WITH DEVELOPMENT OF IBD. IN RECENT YEARS, IT HAS BECOME INCREASINGLY APPARENT THAT EPIGENETIC MODIFICATIONS OF CHROMATIN AND THE MANNER IN WHICH CHROMATIN IS ORGANIZED IN THE NUCLEUS ARE ADDITIONALLY IMPORTANT ELEMENTS THAT CAN INFLUENCE RESPONSES INDUCED BY THE FACTORS DESCRIBED ABOVE, AND MAY THEREFORE CONTRIBUTE TO THE ONSET AND PATHOGENESIS OF IBD. EPIGENETICS AND CHROMATIN ORGANIZATION REGULATE DIVERSE FUNCTIONS THAT INCLUDE MAINTENANCE OF HOMEOSTASIS IN THE INTESTINAL EPITHELIUM, THE DEVELOPMENT AND DIFFERENTIATION OF IMMUNE CELLS, AND MODULATION OF RESPONSES GENERATED BY THE IMMUNE SYSTEM TO DEFEND AGAINST POTENTIAL PATHOGENS. FURTHERMORE, CHANGES IN EPIGENETIC CHROMATIN MARKS AND IN CHROMATIN ORGANIZATION HAVE NOW BEEN LINKED TO DIFFERENTIAL GENE EXPRESSION IN IBD PATIENT CELLS. ALTHOUGH DIRECT EVIDENCE FOR A ROLE OF HISTONE MODIFICATIONS IN IBD IS CURRENTLY VERY LIMITED, IN THIS REVIEW, WE SUMMARIZE THE LINKS BETWEEN VARIOUS EPIGENETIC MODIFICATIONS, THE PROTEINS THAT CATALYZE OR RECOGNIZE THESE MODIFICATIONS, AND THE DEVELOPMENT OR PROGRESSION OF IBD IN HUMAN AND EXPERIMENTAL IBD. WE ALSO DISCUSS HOW EPIGENETICS INFLUENCE THE ORGANIZATION OF DNA CONTACTS TO REGULATE GENE EXPRESSION AND THE IMPLICATIONS THIS MAY HAVE FOR DIAGNOSING AND TREATING IBD. 2019 13 6326 21 THE ROLE OF BCL-2 FAMILY PROTEINS IN CHRONIC LYMPHOCYTIC LEUKAEMIA. BCL-2 FAMILY PROTEINS HAVE LONG BEEN IMPLICATED IN THE PATHOLOGY OF CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL). INDEED, A NUMBER OF THESE PROTEINS HAVE BEEN SHOWN TO HAVE PROGNOSTIC IMPORTANCE IN THIS DISEASE. THE PRECISE WAYS IN WHICH THESE PROTEINS IMPACT UPON CLL AND THE WAYS IN WHICH THEY ARE REGULATED REMAIN INCOMPLETELY RESOLVED. HOWEVER, SIGNIFICANT ADVANCES HAVE BEEN RECENTLY MADE IN OUR UNDERSTANDING OF HOW THESE PROTEINS ARE CONTROLLED BY GENETIC, EPIGENETIC AND MICROENVIRONMENTAL CUES. FURTHERMORE, MAJOR PROGRESS HAS BEEN MADE IN TRYING TO TARGET THESE PROTEINS THERAPEUTICALLY. HERE WE REVIEW THE CURRENT KNOWLEDGE ABOUT THIS FAMILY OF APOPTOSIS-REGULATING PROTEINS AND HOW THEY IMPACT UPON DRUG RESISTANCE AND DISEASE PROGRESSION. WE ALSO SUMMARISE EVOLUTION IN THE DEVELOPMENT OF BCL-2 FAMILY INHIBITORS FOR THE TREATMENT OF CLL AND OTHER CANCERS. 2010 14 1479 23 DIVERSE TARGETS OF THE TRANSCRIPTION FACTOR STAT3 CONTRIBUTE TO T CELL PATHOGENICITY AND HOMEOSTASIS. STAT3, AN ESSENTIAL TRANSCRIPTION FACTOR WITH PLEIOTROPIC FUNCTIONS, PLAYS CRITICAL ROLES IN THE PATHOGENESIS OF AUTOIMMUNITY. DESPITE RECENT DATA LINKING STAT3 WITH INFLAMMATORY BOWEL DISEASE, EXACTLY HOW IT CONTRIBUTES TO CHRONIC INTESTINAL INFLAMMATION IS NOT KNOWN. USING A T CELL TRANSFER MODEL OF COLITIS, WE FOUND THAT STAT3 EXPRESSION IN T CELLS WAS ESSENTIAL FOR THE INDUCTION OF BOTH COLITIS AND SYSTEMIC INFLAMMATION. STAT3 WAS CRITICAL IN MODULATING THE BALANCE OF T HELPER 17 (TH17) AND REGULATORY T (TREG) CELLS, AS WELL AS IN PROMOTING CD4(+) T CELL PROLIFERATION. WE USED CHROMATIN IMMUNOPRECIPITATION AND MASSIVE PARALLEL SEQUENCING (CHIP-SEQ) TO DEFINE THE GENOME-WIDE TARGETS OF STAT3 IN CD4(+) T CELLS. WE FOUND THAT STAT3 BOUND TO MULTIPLE GENES INVOLVED IN TH17 CELL DIFFERENTIATION, CELL ACTIVATION, PROLIFERATION, AND SURVIVAL, REGULATING BOTH EXPRESSION AND EPIGENETIC MODIFICATIONS. THUS, STAT3 ORCHESTRATES MULTIPLE CRITICAL ASPECTS OF T CELL FUNCTION IN INFLAMMATION AND HOMEOSTASIS. 2010 15 4670 24 NEW INSIGHTS INTO THE EPIGENETIC REGULATION OF INFLAMMATORY BOWEL DISEASE. INFLAMMATORY BOWEL DISEASE (IBD) IS A CHRONIC INFLAMMATORY DISEASE OF THE COLONIC MUCOSA. ENVIRONMENTAL FACTORS, GENETICS, INTESTINAL MICROBIOTA, AND THE IMMUNE SYSTEM ARE ALL INVOLVED IN THE PATHOPHYSIOLOGY OF IBD. LATELY, ACCUMULATING EVIDENCE HAS SHOWN THAT ABNORMAL EPIGENETIC CHANGES IN DNA METHYLATION, HISTONE MARKERS, AND NON-CODING RNA EXPRESSION GREATLY CONTRIBUTE TO THE DEVELOPMENT OF THE ENTIRE DISEASE. EPIGENETICS REGULATES MANY FUNCTIONS, SUCH AS MAINTAINING THE HOMEOSTASIS OF THE INTESTINAL EPITHELIUM AND REGULATING THE IMMUNE SYSTEM OF THE IMMUNE CELLS. IN THE PRESENT STUDY, WE SYSTEMATICALLY SUMMARIZED THE LATEST ADVANCES IN EPIGENETIC MODIFICATION OF IBD AND HOW EPIGENETICS REVEALS NEW MECHANISMS OF IBD. OUR PRESENT REVIEW PROVIDED NEW INSIGHTS INTO THE PATHOPHYSIOLOGY OF IBD. MOREOVER, EXPLORING THE PATTERNS OF DNA METHYLATION AND HISTONE MODIFICATION THROUGH EPIGENETICS CAN NOT ONLY BE USED AS BIOMARKERS OF IBD BUT ALSO AS A NEW TARGET FOR THERAPEUTIC INTERVENTION IN IBD PATIENTS. 2022 16 2065 28 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 17 4439 30 MOLECULAR GENETIC AND EPIGENETIC BASIS OF MULTIPLE SCLEROSIS. MULTIPLE SCLEROSIS (MS) IS A CHRONIC IMMUNE-MEDIATED DISEASE OF SPINAL CORD AND BRAIN. THE INITIAL EVENT IN MS OCCURS WHEN ACTIVATED CD4(+) T CELLS IN PERIPHERY EXACERBATES IMMUNE RESPONSES BY STIMULATING IMMUNE CELLS SUCH AS B CELLS, CD8(+) CELLS, MAST CELLS, GRANULOCYTES AND MONOCYTES. THESE PROINFLAMMATORY CELLS PASS BLOOD BRAIN BARRIER BY SECRETING PROINFLAMMATORY CYTOKINES INCLUDING TNF-ALPHA AND INF-(GAMMA) WHICH ACTIVATE ADHESION FACTORS. APCS (ANTIGEN-PRESENTING CELLS) REACTIVATE CD4(+) T CELLS AFTER INFILTRATING THE CNS AND CD4(+) T CELLS PRODUCE CYTOKINES AND CHEMOKINES. THESE PROINFLAMMATORY CYTOKINES AGGRAVATE INFLAMMATION BY INDUCING MYELIN PHAGOCYTOSIS THROUGH MICROGLIA AND ASTROCYTES ACTIVATION. MS IS BELIEVED TO HAVE A MULTIFACTORIAL ORIGIN THAT INCLUDES A COMBINATION OF MULTIPLE GENETIC, ENVIRONMENTAL AND STOCHASTIC FACTORS. ALTHOUGH THE EXACT COMPONENT OF MS RISKS THAT CAN BE EXPLAINED BY THESE FACTORS IS DIFFICULT TO DETERMINE, ESTIMATES BASED ON GENETIC AND EPIDEMIOLOGICAL STUDIES SUGGEST THAT UP TO 60-70 % OF THE TOTAL RISK OF MS MAY BE CONTRIBUTE TO GENETIC FACTORS. IN CONTINUE, FIRSTLY WE PROVIDE AN OVERVIEW OF THE CURRENT UNDERSTANDING OF EPIGENETIC MECHANISMS, AND SO PRESENT EVIDENCE OF HOW THE EPIGENETIC MODIFICATIONS CONTRIBUTE TO INCREASED SUSCEPTIBILITY OF MS. WE ALSO EXPLAIN HOW SPECIFIED EPIGENETIC MODIFICATIONS MAY INFLUENCE THE PATHOPHYSIOLOGY AND KEY ASPECTS OF DISEASE IN MS (DEMYELINATION, REMYELINATION, INFLAMMATION, AND NEURODEGENERATION). FINALLY, WE TEND TO DISCUSS HOW ENVIRONMENTAL FACTORS AND EPIGENETIC MECHANISMS MAY INTERACT TO HAVE AN EFFECT ON MS RISK AND CLINICAL OUTCOME AND RECOMMEND NEW THERAPEUTIC INTERVENTIONS THAT MIGHT MODULATE PATIENTS' EPIGENETIC PROFILES. 2017 18 5783 25 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 19 5477 25 RESTORING THE FUNCTIONAL IMMUNOGENICITY OF CHRONIC LYMPHOCYTIC LEUKEMIA USING EPIGENETIC MODIFIERS. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS A MALIGNANCY ARISING FROM IMMUNE CELLS (B-LYMPHOCYTES) ENDOWED WITH INTRINSIC ANTIGEN-PRESENTING CAPABILITIES. SUCH A FUNCTION HOWEVER IS LOST DURING MALIGNANT TRANSFORMATION AND CLL CELLS ARE WELL KNOWN FOR THEIR INABILITY TO PROCESS AND PRESENT ANTIGENS TO THE T-CELL ARM OF THE IMMUNE SYSTEM. INSTEAD, MALIGNANT CLL CELLS ELICIT A VAST ARRAY OF IMMUNE REGULATORY MECHANISMS CONDUCIVE TO T-CELL DYSFUNCTION AND IMMUNOSUPPRESSION. PREVIOUSLY, WE HAVE SHOWN THAT TREATMENT OF CLL CELLS WITH THE DEMETHYLATING AGENT 5-AZA-2'-DEOXYCYTIDINE UNLEASHED TARGET ANTIGEN EXPRESSION. HERE WE SHOW FOR THE FIRST TIME THAT COMBINING TWO EPIGENETIC MODIFIERS, 5-AZA-2'-DEOXYCYTIDINE AND THE HISTONE DEACETYLASE INHIBITOR LAQ824 EFFECTIVELY RESTORES THE IMMUNOGENICITY OF CLL CELL LINES AS WELL AS PRIMARY CELLS OBTAINED FROM CLL PATIENTS. INDEED, SUCH A COMBINATION INDUCES THE EXPRESSION OF NOVEL AND HIGHLY ANTIGENIC CANCER-TESTIS ANTIGENS (CTAS) AND COSTIMULATORY MOLECULES. THESE CHANGES FACILITATE THE FORMATION OF ROBUST SUPRAMOLECULAR ACTIVATION COMPLEXES (SMAC) BETWEEN CLL CELLS AND RESPONDER T-CELLS LEADING TO INTRACELLULAR SIGNALING, LYTIC GRANULE MOBILIZATION, AND POLARIZATION OF FUNCTIONAL AND RELEVANT T-CELL RESPONSES. THIS CASCADE OF T-CELL ACTIVATING EVENTS TRIGGERED BY CLL CELLS WITH RESTORED APC FUNCTION, POINTS TO COMBINED EPIGENETIC MODIFIER TREATMENT AS A POTENTIAL IMMUNOTHERAPEUTIC STRATEGY FOR CLL PATIENTS. 2011 20 6535 33 TRANSCRIPTIONAL REGULATION OF THE ANTI-INFLAMMATORY CYTOKINE IL-10 IN ACQUIRED IMMUNE CELLS. ALTHOUGH THE MAJOR ROLE OF THE IMMUNE RESPONSE IS HOST DEFENSE FROM A WIDE RANGE OF POTENTIALLY PATHOGENIC MICROORGANISMS, EXCESS IMMUNE RESPONSES CAN RESULT IN SEVERE HOST DAMAGE. THE HOST THUS REQUIRES ANTI-INFLAMMATORY MECHANISMS TO PREVENT REACTIVITY TO SELF. INTERLEUKIN-10 (IL-10) IS A CYTOKINE WITH BROAD ANTI-INFLAMMATORY PROPERTIES INVOLVED IN THE PATHOGENESIS OF VARIOUS DISEASES. IL-10 WAS ORIGINALLY DESCRIBED AS A T HELPER (T(H)2) DERIVED CYTOKINE, BUT FURTHER STUDIES INDICATED THAT IL-10 IS EXPRESSED NOT ONLY BY MANY CELLS OF THE ADAPTIVE IMMUNE SYSTEM, INCLUDING T AND B CELLS, BUT ALSO BY THE INNATE IMMUNE CELLS, INCLUDING DENDRITIC CELLS (DCS), MACROPHAGES, MAST CELLS, AND NATURAL KILLER (NK) CELLS. IN ADDITION, IL-10 CAN BE INDUCED IN T(H)1 AND T(H)17 CELLS BY CHRONIC INFLAMMATION AS A SYSTEM OF FEEDBACK REGULATION. IN THIS REVIEW, WE FOCUS ON THE MOLECULAR MECHANISMS UNDERLYING IL10 GENE EXPRESSION IN ADAPTIVE IMMUNE CELLS AND SUMMARIZE THE RECENT PROGRESSES IN EPIGENETIC AND TRANSCRIPTIONAL REGULATION OF THE IL10 GENE. UNDERSTANDING THE TRANSCRIPTIONAL REGULATORY EVENTS MAY HELP IN THE DEVELOPMENT OF NEW STRATEGIES TO CONTROL INFLAMMATORY DISEASES. 2012