1 987 102 CHRONIC SCHISTOSOMIASIS DURING PREGNANCY EPIGENETICALLY REPROGRAMS T-CELL DIFFERENTIATION IN OFFSPRING OF INFECTED MOTHERS. SCHISTOSOMIASIS IS A NONTRANSPLACENTAL HELMINTH INFECTION. CHRONIC INFECTION DURING PREGNANCY SUPPRESSES ALLERGIC AIRWAY RESPONSES IN OFFSPRING. WE ADDRESSED THE QUESTION WHETHER IN UTERO EXPOSURE TO CHRONIC SCHISTOSOME INFECTION (REG PHASE) IN MICE AFFECTS B-CELL AND T-CELL DEVELOPMENT. THEREFORE, WE FOCUSED OUR ANALYSES ON T-CELL DIFFERENTIATION CAPACITY INDUCED BY EPIGENETIC CHANGES IN PROMOTER REGIONS OF SIGNATURE CYTOKINES IN OFFSPRING. HERE, WE SHOW THAT NAIVE T CELLS FROM OFFSPRING OF SCHISTOSOME INFECTED FEMALE MICE HAD A STRONG CAPACITY TO DIFFERENTIATE INTO T(H) 1 CELLS, WHEREAS T(H) 2 DIFFERENTIATION WAS IMPAIRED. IN ACCORDANCE, REDUCED LEVELS OF HISTONE ACETYLATION OF THE IL-4 PROMOTER REGIONS WERE OBSERVED IN NAIVE T CELLS. TO CONCLUDE, OUR MOUSE MODEL REVEALED DISTINCT EPIGENETIC CHANGES WITHIN THE NAIVE T-CELL COMPARTMENT AFFECTING T(H) 2 AND T(H) 1 CELL DIFFERENTIATION IN OFFSPRING OF MOTHERS WITH CHRONIC HELMINTH INFECTION. THESE FINDINGS COULD EVENTUALLY HELP UNDERSTAND HOW HELMINTHS ALTER T-CELL DRIVEN IMMUNE RESPONSES INDUCED BY ALLERGENS, BACTERIAL OR VIRAL INFECTIONS, AS WELL AS VACCINES. 2017 2 2022 36 EPIGENETIC CHANGES ASSOCIATED WITH DISEASE PROGRESSION IN A MOUSE MODEL OF CHILDHOOD ALLERGIC ASTHMA. DEVELOPMENT OF ASTHMA IN CHILDHOOD IS LINKED TO VIRAL INFECTIONS OF THE LOWER RESPIRATORY TRACT IN EARLY LIFE, WITH SUBSEQUENT CHRONIC EXPOSURE TO ALLERGENS. PROGRESSION TO PERSISTENT ASTHMA IS ASSOCIATED WITH A TH2-BIASED IMMUNOLOGICAL RESPONSE AND STRUCTURAL REMODELLING OF THE AIRWAYS. THE UNDERLYING MECHANISMS ARE UNCLEAR, BUT COULD INVOLVE EPIGENETIC CHANGES. TO INVESTIGATE THIS, WE EMPLOYED A RECENTLY DEVELOPED MOUSE MODEL IN WHICH SELF-LIMITED NEONATAL INFECTION WITH A PNEUMOVIRUS, FOLLOWED BY SENSITISATION TO OVALBUMIN VIA THE RESPIRATORY TRACT AND LOW-LEVEL CHRONIC CHALLENGE WITH AEROSOLISED ANTIGEN, LEADS TO DEVELOPMENT OF AN ASTHMATIC PHENOTYPE. WE ASSESSED EXPRESSION OF MICRORNA BY CELLS IN THE PROXIMAL AIRWAYS, COMPARING CHANGES OVER THE PERIOD OF DISEASE PROGRESSION, AND USED TARGET PREDICTION DATABASES TO IDENTIFY GENES LIKELY TO BE UP- OR DOWNREGULATED AS A CONSEQUENCE OF ALTERED REGULATION OF MICRORNA. IN PARALLEL, WE ASSESSED DNA METHYLATION IN PULMONARY CD4(+) T CELLS. WE FOUND THAT A LIMITED NUMBER OF MICRORNAS EXHIBITED MARKED UP- OR DOWNREGULATION FOLLOWING EARLY-LIFE INFECTION AND SENSITISATION, FOR MANY OF WHICH THE LEVELS OF EXPRESSION WERE FURTHER CHANGED FOLLOWING CHRONIC CHALLENGE WITH THE SENSITIZING ANTIGEN. TARGETS OF THESE MICRORNAS INCLUDED GENES INVOLVED IN IMMUNE OR INFLAMMATORY RESPONSES (E.G. GATA3, KITL) AND IN TISSUE REMODELLING (E.G. IGF1, TGFBR1), AS WELL AS GENES FOR VARIOUS TRANSCRIPTION FACTORS AND SIGNALLING PROTEINS. IN PULMONARY CD4(+) T CELLS, THERE WAS SIGNIFICANT DEMETHYLATION AT PROMOTER SITES FOR INTERLEUKIN-4 AND INTERFERON-GAMMA, THE LATTER INCREASING FOLLOWING CHRONIC CHALLENGE. WE CONCLUDE THAT, IN THIS MODEL, PROGRESSION TO AN ASTHMATIC PHENOTYPE IS LINKED TO EPIGENETIC REGULATION OF GENES ASSOCIATED WITH INFLAMMATION AND STRUCTURAL REMODELLING, AND WITH T-CELL COMMITMENT TO A TH2 IMMUNOLOGICAL RESPONSE. EPIGENETIC CHANGES ASSOCIATED WITH THIS PATTERN OF GENE ACTIVATION MIGHT PLAY A ROLE IN THE DEVELOPMENT OF CHILDHOOD ASTHMA. 2013 3 1566 37 DNA METHYLATION OF TH1/TH2 CYTOKINE GENES AFFECTS SENSITIZATION AND PROGRESS OF EXPERIMENTAL ASTHMA. BACKGROUND: EPIGENETIC CHANGES IN DNA METHYLATION HAVE RECENTLY BEEN DEMONSTRATED TO BE INVOLVED IN EFFECTOR T-CELL POLARIZATION, RESULTING IN DIFFERENTIAL SECRETION OF T(H)1 AND T(H)2 CYTOKINES. HOWEVER, THE CONTRIBUTION TO THE DEVELOPMENT OF A CHRONIC INFLAMMATORY PHENOTYPE REMAINS STILL UNCLEAR. OBJECTIVE: WE SOUGHT TO INVESTIGATE CHANGES IN DNA METHYLATION IN MARKER GENES OF T-CELL SUBSETS DURING ALLERGEN SENSITIZATION/CHALLENGE AND THEIR INFLUENCE ON THE DEVELOPMENT OF AN ALLERGIC AIRWAY INFLAMMATORY RESPONSE. METHODS: THE RELATIONSHIP BETWEEN CHANGES IN DNA METHYLATION AND PHENOTYPE DEVELOPMENT WERE EXAMINED IN A WELL-ESTABLISHED MODEL OF EXPERIMENTAL ASTHMA. DNA METHYLATION WAS INVESTIGATED AT GENOMIC LOCI ASSOCIATED WITH T(H)1 (IFNG PROMOTER) OR T(H)2 (CONSERVED NONCODING SEQUENCE 1 [CNS1]) CYTOKINE PRODUCTION BY USING BISULFITE PYROSEQUENCING. RESULTS: ANALYSIS OF CD4(+) T CELLS REVEALED A SIGNIFICANT INCREASE IN DNA METHYLATION AT THE IFNG PROMOTER AFTER ALLERGEN SENSITIZATION/CHALLENGE, WHICH CORRELATED WITH DECREASED IFN-GAMMA CYTOKINE EXPRESSION, WHEREAS ONLY MINOR CHANGES WERE OBSERVED AT THE CNS1 LOCUS. FURTHERMORE, THE INCREASE IN DNA METHYLATION AT THE IFNG PROMOTER COULD BE REVERSED WITH A DNA METHYLTRANSFERASE (DNMT) INHIBITOR IN VITRO AND IN VIVO WITH BENEFICIAL EFFECTS ON SENSITIZATION STATUS AND ALLERGIC PHENOTYPE. THE SPECIFIC IMPORTANCE OF THE DNA METHYLATION STATUS IN CD4(+) T CELLS COULD BE CONFIRMED BY USING ADOPTIVE TRANSFER EXPERIMENTS. CONCLUSION: WE HERE REPORT THE NOVEL FINDING THAT EPIGENETIC REGULATION IN T CELLS CONTRIBUTES TO THE DEVELOPMENT OF EXPERIMENTAL ASTHMA AND CAN BE TARGETED PHARMACOLOGICALLY. 2012 4 6293 21 THE PRO- AND ANTI-INFLAMMATORY POTENTIAL OF IL-12: THE DUAL ROLE OF TH1 CELLS. THE DIFFERENTIATION OF T-HELPER (TH) LYMPHOCYTES INTO VARIOUS TYPES OF T-HELPER EFFECTOR AND MEMORY CELLS WITH DISTINCT FUNCTIONS DEPENDING ON THE TYPE OF CONCOMITANT SIGNALS THEY RECEIVE UPON ACTIVATION IS A CRITICAL EVENT DETERMINING THE COURSE OF AN IMMUNE REACTION. TH1 CELLS CHARACTERIZED BY THE EXPRESSION OF IFN-GAMMA AND THE RECENTLY DESCRIBED TH17 CELLS PROMOTE INFLAMMATION AND ARE CRITICALLY INVOLVED IN THE INDUCTION AND MAINTENANCE OF AUTOIMMUNITY, WHEREAS THE SECRETION OF IL-4 IS A HALLMARK OF TH2 CELLS MEDIATING PROTECTION FROM PARASITES AND ALLERGY. ORIGINAL STIMULATION IN THE PRESENCE OF IL-12 RESULTS IN THE IMPRINTING OF TH1 MEMORY CELLS FOR THE EXPRESSION OF IFN-GAMMA BY EXPRESSION OF THE TRANSCRIPTION FACTOR T-BET AND EPIGENETIC MODIFICATION OF THE IFNGAMMA GENE. IT HAS BEEN DEMONSTRATED THAT TH1 CELLS ARE POTENT INDUCERS OF INFLAMMATION. HOWEVER, IN THE CHRONIC PHASE OF SUCH INFLAMMATION, THE REGULATORY POTENTIAL OF IL-12 AND TH1 CELLS THEMSELVES MAY PLAY AN IMPORTANT ROLE IN LIMITING IMMUNOPATHOLOGY. 2007 5 2056 26 EPIGENETIC CONTROL OF CD8(+) T CELL DIFFERENTIATION. UPON STIMULATION, SMALL NUMBERS OF NAIVE CD8(+) T CELLS PROLIFERATE AND DIFFERENTIATE INTO A VARIETY OF MEMORY AND EFFECTOR CELL TYPES. CD8(+) T CELLS CAN PERSIST FOR YEARS AND KILL TUMOUR CELLS AND VIRALLY INFECTED CELLS. THE FUNCTIONAL AND PHENOTYPIC CHANGES THAT OCCUR DURING CD8(+) T CELL DIFFERENTIATION ARE WELL CHARACTERIZED, BUT THE EPIGENETIC STATES THAT UNDERLIE THESE CHANGES ARE INCOMPLETELY UNDERSTOOD. HERE, WE REVIEW THE EPIGENETIC PROCESSES THAT DIRECT CD8(+) T CELL DIFFERENTIATION AND FUNCTION. WE FOCUS ON EPIGENETIC MODIFICATION OF DNA AND ASSOCIATED HISTONES AT GENES AND THEIR REGULATORY ELEMENTS. WE ALSO DESCRIBE STRUCTURAL CHANGES IN CHROMATIN ORGANIZATION THAT AFFECT GENE EXPRESSION. FINALLY, WE EXAMINE THE TRANSLATIONAL POTENTIAL OF EPIGENETIC INTERVENTIONS TO IMPROVE CD8(+) T CELL FUNCTION IN INDIVIDUALS WITH CHRONIC INFECTIONS AND CANCER. 2018 6 5996 33 TH2 CELLS IN HEALTH AND DISEASE. HELPER T (TH) CELL SUBSETS DIRECT IMMUNE RESPONSES BY PRODUCING SIGNATURE CYTOKINES. TH2 CELLS PRODUCE IL-4, IL-5, AND IL-13, WHICH ARE IMPORTANT IN HUMORAL IMMUNITY AND PROTECTION FROM HELMINTH INFECTION AND ARE CENTRAL TO THE PATHOGENESIS OF MANY ALLERGIC INFLAMMATORY DISEASES. MOLECULAR ANALYSIS OF TH2 CELL DIFFERENTIATION AND MAINTENANCE OF FUNCTION HAS LED TO RECENT DISCOVERIES THAT HAVE REFINED OUR UNDERSTANDING OF TH2 CELL BIOLOGY. EPIGENETIC REGULATION OF GATA3 EXPRESSION BY CHROMATIN REMODELING COMPLEXES SUCH AS POLYCOMB AND TRITHORAX IS CRUCIAL FOR MAINTAINING TH2 CELL IDENTITY. IN THE CONTEXT OF ALLERGIC DISEASES, MEMORY-TYPE PATHOGENIC TH2 CELLS HAVE BEEN IDENTIFIED IN BOTH MICE AND HUMANS. TO BETTER UNDERSTAND THESE DISEASE-DRIVING CELL POPULATIONS, WE HAVE DEVELOPED A MODEL CALLED THE PATHOGENIC TH POPULATION DISEASE INDUCTION MODEL. THE CONCEPT OF DEFINED SUBSETS OF PATHOGENIC TH CELLS MAY SPUR NEW, EFFECTIVE STRATEGIES FOR TREATING INTRACTABLE CHRONIC INFLAMMATORY DISORDERS. 2017 7 271 25 AGE-ASSOCIATED EPIGENETIC MODIFICATIONS IN HUMAN DNA INCREASE ITS IMMUNOGENICITY. CHRONIC INFLAMMATION, INCREASED REACTIVITY TO SELF-ANTIGENS AND INCIDENCES OF CANCER ARE HALLMARKS OF AGING. HOWEVER, THE UNDERLYING MECHANISMS ARE NOT WELL UNDERSTOOD. AGE-ASSOCIATED ALTERATIONS IN THE DNA EITHER DUE TO OXIDATIVE DAMAGE, DEFECTS IN DNA REPAIR OR EPIGENETIC MODIFICATIONS SUCH AS METHYLATION THAT LEAD TO MUTATIONS AND CHANGES IN THE EXPRESSION OF GENES ARE THOUGHT TO BE PARTIALLY RESPONSIBLE. HERE WE REPORT THAT EPIGENETIC MODIFICATIONS IN AGED DNA ALSO INCREASE ITS IMMUNOGENICITY RENDERING IT MORE REACTIVE TO INNATE IMMUNE SYSTEM CELLS SUCH AS THE DENDRITIC CELLS. WE OBSERVED INCREASED UPREGULATION OF COSTIMULATORY MOLECULES AS WELL AS ENHANCED SECRETION OF IFN-ALPHA FROM DENDRITIC CELLS IN RESPONSE TO DNA FROM AGED DONORS AS COMPARED TO DNA FROM YOUNG DONORS WHEN IT WAS DELIVERED INTRACELLULARLY VIA LIPOFECTAMINE. INVESTIGATIONS INTO THE MECHANISMS REVEALED THAT DNA FROM AGED SUBJECTS IS NOT DEGRADED, NEITHER IS IT MORE DAMAGED COMPARED TO DNA FROM YOUNG SUBJECTS. HOWEVER, THERE IS SIGNIFICANTLY DECREASED GLOBAL LEVEL OF METHYLATION SUGGESTING THAT AGE-ASSOCIATED HYPOMETHYLATION OF THE DNA MAY BE THE CAUSE OF ITS INCREASED IMMUNOGENICITY. INCREASED IMMUNOGENICITY OF SELF DNA MAY THUS BE ANOTHER MECHANISM THAT MAY CONTRIBUTE TO THE INCREASE IN AGE-ASSOCIATED CHRONIC INFLAMMATION, AUTOIMMUNITY AND CANCER. 2010 8 6677 28 USING EPIGENETICS TO DEFINE VACCINE-INDUCED MEMORY T CELLS. MEMORY T CELLS GENERATED FROM ACUTE INFECTION OR VACCINATION HAVE THE POTENTIAL TO PROVIDE THE HOST WITH LIFE-LONG IMMUNITY AGAINST RE-INFECTION. PROTECTION BY MEMORY T CELLS IS ACHIEVED THROUGH THEIR ACQUIRED ABILITY TO PERSIST AT ANATOMICAL SITES OF THE PRIMARY INFECTION AS WELL AS MAINTAINING A HEIGHTENED ABILITY TO RECALL EFFECTOR FUNCTIONS. THE MAINTENANCE OF CD8 AND CD4 T CELL FUNCTION IN A STATE OF READINESS IS KEY TO LIFE-LONG IMMUNITY AND MANIFEST THROUGH CHANGES IN TRANSCRIPTIONAL REGULATION. YET, THE ABILITY TO IDENTIFY POISED TRANSCRIPTIONAL PROGRAMS AT THE MAINTENANCE STAGE OF THE RESPONSE IS LACKING FROM MOST TRANSCRIPTIONAL PROFILING STUDIES OF MEMORY T CELLS. EPIGENETIC PROFILING ALLOWS FOR THE ASSESSMENT OF TRANSCRIPTIONALLY POISED (PROMOTERS THAT ARE READILY ACCESSIBLE FOR TRANSCRIPTION) STATES OF ANTIGEN-SPECIFIC T CELLS WITHOUT MANIPULATION OF THE ACTIVATION STATE OF THE CELL. HERE WE REVIEW RECENT STUDIES THAT HAVE EXAMINED EPIGENETIC PROGRAMS OF EFFECTOR AND MEMORY T CELL SUBSETS. THESE REPORTS DEMONSTRATE THAT ACQUISITION OF EPIGENETIC PROGRAMS DURING MEMORY T CELL DIFFERENTIATION TO ACUTE AND CHRONIC INFECTIONS IS COUPLED TO, AND POTENTIALLY REGULATE, THE CELL'S RECALL RESPONSE. WE DISCUSS THE USEFULNESS OF EPIGENETIC PROFILING IN CHARACTERIZING T CELL DIFFERENTIATION STATE AND FUNCTION FOR PRECLINICAL EVALUATION OF VACCINES AND THE CURRENT METHODOLOGIES FOR SINGLE LOCUS VERSUS GENOME-WIDE EPIGENETIC PROFILING. 2013 9 5223 34 PRIMARY MURINE CD4+ T CELLS FAIL TO ACQUIRE THE ABILITY TO PRODUCE EFFECTOR CYTOKINES WHEN ACTIVE RAS IS PRESENT DURING TH1/TH2 DIFFERENTIATION. CONSTITUTIVE RAS SIGNALING HAS BEEN SHOWN TO AUGMENT IL-2 PRODUCTION, REVERSE ANERGY, AND FUNCTIONALLY REPLACE MANY ASPECTS OF CD28 CO-STIMULATION IN CD4+ T CELLS. THESE DATA RAISE THE POSSIBILITY THAT INTRODUCTION OF ACTIVE RAS INTO PRIMARY T CELLS MIGHT RESULT IN IMPROVED FUNCTIONALITY IN PATHOLOGIC SITUATIONS OF T CELL DYSFUNCTION, SUCH AS CANCER OR CHRONIC VIRAL INFECTION. TO TEST THE BIOLOGIC EFFECTS OF ACTIVE RAS IN PRIMARY T CELLS, CD4+ T CELLS FROM COXSACKIE-ADENOVIRUS RECEPTOR TRANSGENIC MICE WERE TRANSDUCED WITH AN ADENOVIRUS ENCODING ACTIVE RAS. AS EXPECTED, ACTIVE RAS AUGMENTED IL-2 PRODUCTION IN NAIVE CD4+ T CELLS. HOWEVER, WHEN CELLS WERE CULTURED FOR 4 DAYS UNDER CONDITIONS TO PROMOTE EFFECTOR CELL DIFFERENTIATION, ACTIVE RAS INHIBITED THE ABILITY OF CD4+ T CELLS TO ACQUIRE A TH1 OR TH2 EFFECTOR CYTOKINE PROFILE. THIS DIFFERENTIATION DEFECT WAS NOT DUE TO DEFICIENT STAT4 OR STAT6 ACTIVATION BY IL-12 OR IL-4, RESPECTIVELY, NOR WAS IT ASSOCIATED WITH DEFICIENT INDUCTION OF T-BET AND GATA-3 EXPRESSION. IMPAIRED EFFECTOR CYTOKINE PRODUCTION IN ACTIVE RAS-TRANSDUCED CELLS WAS ASSOCIATED WITH DEFICIENT DEMETHYLATION OF THE IL-4 GENE LOCUS. OUR RESULTS INDICATE THAT, DESPITE AUGMENTING ACUTE ACTIVATION OF NAIVE T CELLS, CONSTITUTIVE RAS SIGNALING INHIBITS THE ABILITY OF CD4+ T CELLS TO PROPERLY DIFFERENTIATE INTO TH1/TH2 EFFECTOR CYTOKINE-PRODUCING CELLS, IN PART BY INTERFERING WITH EPIGENETIC MODIFICATION OF EFFECTOR GENE LOCI. ALTERNATIVE STRATEGIES TO POTENTIATE RAS PATHWAY SIGNALING IN T CELLS IN A MORE REGULATED FASHION SHOULD BE CONSIDERED AS A THERAPEUTIC APPROACH TO IMPROVE IMMUNE RESPONSES IN VIVO. 2014 10 6533 28 TRANSCRIPTIONAL REGULATION OF INFLAMMATORY GENES ASSOCIATED WITH SEVERE ASTHMA. THE 10% OF PATIENTS WITH THE MOST SEVERE ASTHMA ARE RESPONSIBLE FOR A LARGE PART OF HEALTHCARE EXPENDITURE AND MORBIDITY. UNDERSTANDING THE PROCESSES INVOLVED IS KEY IF NEW THERAPEUTIC APPROACHES ARE TO BE DEVELOPED. EVIDENCE IS ACCUMULATING THAT CHRONIC DISEASES SUCH AS ASTHMA ARE ASSOCIATED WITH TEMPORAL AND SPATIAL ALTERATIONS IN THE PATTERN OF INFLAMMATORY GENE EXPRESSION WITHIN THE AIRWAYS. EXPRESSION OF THESE GENES CAN BE REGULATED BY TRANSCRIPTIONAL, POSTTRANSCRIPTIONAL, TRANSLATIONAL AND EPIGENETIC MECHANISMS. IT IS WELL ESTABLISHED THAT BINDING OF ACTIVATED TRANSCRIPTION FACTORS TO SPECIFIC INDUCIBLE GENE PROMOTER SITES IS TIGHTLY CONTROLLED BY CHROMATIN STATE AS A RESULT OF HISTONE MODIFICATIONS, PARTICULARLY THE BALANCE BETWEEN HISTONE ACETYLATION AND DEACETYLATION [1]. THE INTERACTION BETWEEN TRANSCRIPTION FACTORS AND THE PROMOTER IS KEY TO THE DIVERSIFICATION OF GENE EXPRESSION IN A TIME DEPENDENT MANNER LEADING TO ALTERED GENE EXPRESSION PROFILES. ALTERATIONS OF THE ACCESSIBILITY OF TRANSCRIPTION FACTORS TO THE DNA CAN HAVE RESIDING EFFECTS UPON GENE TRANSCRIPTION. THIS REVIEW WILL FOCUS ON THE REGULATION OF SEVERAL GROUPS OF KEY GENES WHICH ARE INVOLVED IN CHRONIC AIRWAY INFLAMMATION AND REMODELLING IN ASTHMA DRAWING MAINLY FROM OUR EXPERIENCE OF STUDYING THESE PROCESSES IN AIRWAY SMOOTH MUSCLE CELLS. AN OVERVIEW IS SHOWN IN FIGURE 1. 2011 11 3836 31 IONIZING RADIATION POTENTIATES HIGH-FAT DIET-INDUCED INSULIN RESISTANCE AND REPROGRAMS SKELETAL MUSCLE AND ADIPOSE PROGENITOR CELLS. EXPOSURE TO IONIZING RADIATION INCREASES THE RISK OF CHRONIC METABOLIC DISORDERS SUCH AS INSULIN RESISTANCE AND TYPE 2 DIABETES LATER IN LIFE. WE HYPOTHESIZED THAT IRRADIATION REPROGRAMS THE EPIGENOME OF METABOLIC PROGENITOR CELLS, WHICH COULD ACCOUNT FOR IMPAIRED METABOLISM AFTER CANCER TREATMENT. C57BL/6 MICE WERE TREATED WITH A SINGLE DOSE OF IRRADIATION AND SUBJECTED TO HIGH-FAT DIET (HFD). RNA SEQUENCING AND REDUCED REPRESENTATION BISULFITE SEQUENCING WERE USED TO CREATE TRANSCRIPTOMIC AND EPIGENOMIC PROFILES OF PREADIPOCYTES AND SKELETAL MUSCLE SATELLITE CELLS COLLECTED FROM IRRADIATED MICE. MICE SUBJECTED TO TOTAL BODY IRRADIATION SHOWED ALTERATIONS IN GLUCOSE METABOLISM AND, WHEN CHALLENGED WITH HFD, MARKED HYPERINSULINEMIA. INSULIN SIGNALING WAS CHRONICALLY DISRUPTED IN SKELETAL MUSCLE AND ADIPOSE PROGENITOR CELLS COLLECTED FROM IRRADIATED MICE AND DIFFERENTIATED IN CULTURE. EPIGENOMIC PROFILING OF SKELETAL MUSCLE AND ADIPOSE PROGENITOR CELLS FROM IRRADIATED ANIMALS REVEALED SUBSTANTIAL DNA METHYLATION CHANGES, NOTABLY FOR GENES REGULATING THE CELL CYCLE, GLUCOSE/LIPID METABOLISM, AND EXPRESSION OF EPIGENETIC MODIFIERS. OUR RESULTS SHOW THAT TOTAL BODY IRRADIATION ALTERS INTRACELLULAR SIGNALING AND EPIGENETIC PATHWAYS REGULATING CELL PROLIFERATION AND DIFFERENTIATION OF SKELETAL MUSCLE AND ADIPOSE PROGENITOR CELLS AND PROVIDE A POSSIBLE MECHANISM BY WHICH IRRADIATION USED IN CANCER TREATMENT INCREASES THE RISK FOR METABOLIC DISEASE LATER IN LIFE. 2016 12 6520 30 TRANSCRIPTIONAL AND EPIGENETIC REGULATION OF MONOCYTE AND MACROPHAGE DYSFUNCTION BY CHRONIC ALCOHOL CONSUMPTION. DRINKING ALCOHOL, EVEN IN MODERATION, CAN AFFECT THE IMMUNE SYSTEM. STUDIES HAVE SHOWN DISPROPORTIONATE EFFECTS OF ALCOHOL ON CIRCULATING AND TISSUE-RESIDENT MYELOID CELLS (GRANULOCYTES, MONOCYTES, MACROPHAGES, DENDRITIC CELLS). THESE CELLS ORCHESTRATE THE BODY'S FIRST LINE OF DEFENSE AGAINST MICROBIAL CHALLENGES AS WELL AS MAINTAIN TISSUE HOMEOSTASIS AND REPAIR. ALCOHOL'S EFFECTS ON THESE CELLS ARE DEPENDENT ON EXPOSURE PATTERN, WITH ACUTE DRINKING DAMPENING BUT CHRONIC DRINKING ENHANCING PRODUCTION OF INFLAMMATORY MEDIATORS. ALTHOUGH CHRONIC DRINKING IS ASSOCIATED WITH HEIGHTENED SYSTEMIC INFLAMMATION, STUDIES ON TISSUE RESIDENT MACROPHAGE POPULATIONS IN SEVERAL ORGANS INCLUDING THE SPLEEN, LIVER, BRAIN, AND LUNG HAVE ALSO SHOWN COMPROMISED FUNCTIONAL AND METABOLIC CAPACITIES OF THESE CELLS. MANY OF THESE EFFECTS ARE THOUGHT TO BE MEDIATED BY OXIDATIVE STRESS CAUSED BY ALCOHOL AND ITS METABOLITES WHICH CAN DIRECTLY IMPACT THE CELLULAR EPIGENETIC LANDSCAPES. IN ADDITION, SINCE MYELOID CELLS ARE RELATIVELY SHORT-LIVED IN CIRCULATION AND ARE UNDER CONSTANT REPOPULATION FROM THE BONE MARROW COMPARTMENT, ALCOHOL'S EFFECTS ON BONE MARROW PROGENITORS AND HEMATOPOIESIS ARE IMPORTANT FOR UNDERSTANDING THE IMPACT OF ALCOHOL SYSTEMICALLY ON THESE MYELOID POPULATIONS. ALCOHOL-INDUCED DISRUPTION OF PROGENITOR, CIRCULATING, AND TISSUE RESIDENT MYELOID POPULATIONS CONTRIBUTE TO THE INCREASED SUSCEPTIBILITY OF PATIENTS WITH ALCOHOL USE DISORDERS TO VIRAL AND BACTERIAL INFECTIONS. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF THE IMPACT OF CHRONIC ALCOHOL CONSUMPTION ON THE FUNCTION OF MONOCYTES AND MACROPHAGES IN HOST DEFENSE, TISSUE REPAIR AND INFLAMMATION. WE THEN SUMMARIZE OUR CURRENT UNDERSTANDING OF THE MECHANISMS UNDERLYING ALCOHOL-INDUCED DISRUPTION AND EXAMINE CHANGES IN TRANSCRIPTOME AND EPIGENOME OF MONOCYTES AND MCROPHAGES. OVERALL, CHRONIC ALCOHOL CONSUMPTION LEADS TO HYPER-INFLAMMATION CONCOMITANT WITH DECREASED MICROBIAL AND WOUND HEALING RESPONSES BY MONOCYTES/MACROPHAGES DUE TO A REWIRING OF THE EPIGENTIC AND TRANSCRIPTIONAL LANDSCAPE. HOWEVER, IN ADVANCED ALCOHOLIC LIVER DISEASE, MYELOID CELLS BECOME IMMUNOSUPPRESSED AS A RESPONSE TO THE SURROUNDING HYPER-INFLAMMATORY MILIEU. THEREFORE, THE EFFECT OF CHRONIC ALCOHOL ON THE INFLAMMATORY RESPONSE DEPENDS ON DISEASE STATE AND THE IMMUNE CELL POPULATION. 2022 13 3436 25 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 14 6764 32 ZINC DEFICIENCY ENHANCED INFLAMMATORY RESPONSE BY INCREASING IMMUNE CELL ACTIVATION AND INDUCING IL6 PROMOTER DEMETHYLATION. SCOPE: ZINC DEFICIENCY RESULTS IN IMMUNE DYSFUNCTION AND PROMOTES SYSTEMIC INFLAMMATION. THE OBJECTIVE OF THIS STUDY WAS TO EXAMINE THE EFFECTS OF ZINC DEFICIENCY ON CELLULAR IMMUNE ACTIVATION AND EPIGENETIC MECHANISMS THAT PROMOTE INFLAMMATION. THIS WORK IS POTENTIALLY RELEVANT TO THE AGING POPULATION GIVEN THAT AGE-RELATED IMMUNE DEFECTS, INCLUDING CHRONIC INFLAMMATION, COINCIDE WITH DECLINING ZINC STATUS. METHODS AND RESULTS: AN IN VITRO CELL CULTURE SYSTEM AND THE AGED MOUSE MODEL WERE USED TO CHARACTERIZE IMMUNE ACTIVATION AND DNA METHYLATION PROFILES THAT MAY CONTRIBUTE TO THE ENHANCED PROINFLAMMATORY RESPONSE MEDIATED BY ZINC DEFICIENCY. ZINC DEFICIENCY UPREGULATED CELL ACTIVATION MARKERS ICAM1, MHC CLASS II, AND CD86 IN THP1 CELLS, WHICH COINCIDED WITH INCREASED IL1BETA AND IL6 RESPONSES FOLLOWING LPS STIMULATION. A DECREASED ZINC STATUS IN AGED MICE WAS SIMILARLY ASSOCIATED WITH INCREASED ICAM1 AND IL6 GENE EXPRESSION. REDUCED IL6 PROMOTER METHYLATION WAS OBSERVED IN ZINC-DEFICIENT THP1 CELLS, AS WELL AS IN AGED MICE AND HUMAN LYMPHOBLASTOID CELL LINES DERIVED FROM AGED INDIVIDUALS. CONCLUSION: ZINC DEFICIENCY INDUCED INFLAMMATORY RESPONSE IN PART BY ELICITING ABERRANT IMMUNE CELL ACTIVATION AND ALTERED PROMOTER METHYLATION. OUR RESULTS SUGGESTED POTENTIAL INTERACTIONS BETWEEN ZINC STATUS, EPIGENETICS, AND IMMUNE FUNCTION, AND HOW THEIR DYSREGULATION COULD CONTRIBUTE TO CHRONIC INFLAMMATION. 2015 15 1520 31 DNA METHYLATION AT DIFFERENTIALLY METHYLATED REGIONS OF IMPRINTED GENES IS RESISTANT TO DEVELOPMENTAL PROGRAMMING BY MATERNAL NUTRITION. THE NUTRITIONAL ENVIRONMENT IN WHICH THE MAMMALIAN FETUS OR INFANT DEVELOP IS RECOGNIZED AS INFLUENCING THE RISK OF CHRONIC DISEASES, SUCH AS TYPE 2 DIABETES AND HYPERTENSION, IN A PHENOMENON THAT HAS BECOME KNOWN AS DEVELOPMENTAL PROGRAMMING. THE LATE ONSET OF SUCH DISEASES IN RESPONSE TO EARLIER TRANSIENT EXPERIENCES HAS LED TO THE SUGGESTION THAT DEVELOPMENTAL PROGRAMMING MAY HAVE AN EPIGENETIC COMPONENT, BECAUSE EPIGENETIC MARKS SUCH AS DNA METHYLATION OR HISTONE TAIL MODIFICATIONS COULD PROVIDE A PERSISTENT MEMORY OF EARLIER NUTRITIONAL STATES. ONE CLASS OF GENES THAT HAS BEEN CONSIDERED A POTENTIAL TARGET OR MEDIATOR OF PROGRAMMING EVENTS IS IMPRINTED GENES, BECAUSE THESE GENES CRITICALLY DEPEND UPON EPIGENETIC MODIFICATIONS FOR CORRECT EXPRESSION AND BECAUSE MANY IMPRINTED GENES HAVE ROLES IN CONTROLLING FETAL GROWTH AS WELL AS NEONATAL AND ADULT METABOLISM. IN THIS STUDY, WE HAVE USED AN ESTABLISHED MODEL OF DEVELOPMENTAL PROGRAMMING-ISOCALORIC PROTEIN RESTRICTION TO FEMALE MICE DURING GESTATION OR LACTATION-TO EXAMINE WHETHER THERE ARE EFFECTS ON EXPRESSION AND DNA METHYLATION OF IMPRINTED GENES IN THE OFFSPRING. WE FIND THAT ALTHOUGH EXPRESSION OF SOME IMPRINTED GENES IN LIVER OF OFFSPRING IS ROBUSTLY AND SUSTAINABLY CHANGED, METHYLATION OF THE DIFFERENTIALLY METHYLATED REGIONS (DMRS) THAT CONTROL THEIR MONOALLELIC EXPRESSION REMAINS LARGELY UNALTERED. WE CONCLUDE THAT DEREGULATION OF IMPRINTING THROUGH A GENERAL EFFECT ON DMR METHYLATION IS UNLIKELY TO BE A COMMON FACTOR IN DEVELOPMENTAL PROGRAMMING. 2012 16 5898 30 T(H)2 CELL DEVELOPMENT AND FUNCTION. T HELPER 2 (T(H)2) CELLS ORCHESTRATE PROTECTIVE TYPE 2 IMMUNE RESPONSES, SUCH AS THOSE THAT TARGET HELMINTHS AND FACILITATE TISSUE REPAIR, BUT ALSO CONTRIBUTE TO CHRONIC INFLAMMATORY DISEASES, SUCH AS ASTHMA AND ALLERGY. HERE, WE REVIEW RECENT INSIGHTS INTO HOW DIVERSE MOLECULAR SIGNALS FROM CELLULAR SOURCES, INCLUDING DENDRITIC CELLS, INNATE LYMPHOID CELLS AND THE EPITHELIUM, ARE INTEGRATED BY T CELLS TO GUIDE THE TRANSCRIPTIONAL AND EPIGENETIC CHANGES NECESSARY FOR T(H)2 CELL DIFFERENTIATION. OUR IMPROVED UNDERSTANDING OF THESE PATHWAYS HAS OPENED NEW AVENUES FOR THERAPEUTICALLY TARGETING T(H)2 CELLS IN ASTHMA AND ALLERGY. THE ADVENT OF COMPREHENSIVE SINGLE-CELL TRANSCRIPTOMICS ALONG WITH IMPROVEMENTS IN SINGLE-CELL PROTEOMICS AND THE GENERATION OF NOVEL IN VIVO CELL FATE MAPPING TECHNIQUES PROMISE TO EXPAND OUR UNDERSTANDING OF T CELL DIVERSITY AND OFFER NEW INSIGHT INTO DISEASE-RELATED HETEROGENEITY AND PLASTICITY OF T(H) CELL RESPONSES. 2018 17 925 22 CHRONIC INFLAMMATION INDUCES A NOVEL EPIGENETIC PROGRAM THAT IS CONSERVED IN INTESTINAL ADENOMAS AND IN COLORECTAL CANCER. CHRONIC INFLAMMATION REPRESENTS A MAJOR RISK FACTOR FOR TUMOR FORMATION, BUT THE UNDERLYING MECHANISMS HAVE REMAINED LARGELY UNKNOWN. EPIGENETIC MECHANISMS CAN RECORD THE EFFECTS OF ENVIRONMENTAL CHALLENGES ON THE GENOME LEVEL AND COULD THEREFORE PLAY AN IMPORTANT ROLE IN THE PATHOGENESIS OF INFLAMMATION-ASSOCIATED TUMORS. USING SINGLE-BASE METHYLATION MAPS AND TRANSCRIPTOME ANALYSES OF A COLITIS-INDUCED MOUSE COLON CANCER MODEL, WE IDENTIFIED A NOVEL EPIGENETIC PROGRAM THAT IS CHARACTERIZED BY HYPERMETHYLATION OF DNA METHYLATION VALLEYS THAT ARE CHARACTERIZED BY LOW CPG DENSITY AND ACTIVE CHROMATIN MARKS. THIS PROGRAM IS CONSERVED AND FUNCTIONAL IN MOUSE INTESTINAL ADENOMAS AND RESULTS IN SILENCING OF ACTIVE INTESTINAL GENES THAT ARE INVOLVED IN GASTROINTESTINAL HOMEOSTASIS AND INJURY RESPONSE. FURTHER ANALYSES REVEAL THAT THE PROGRAM REPRESENTS A PROMINENT FEATURE OF HUMAN COLORECTAL CANCER AND CAN BE USED TO CORRECTLY CLASSIFY COLORECTAL CANCER SAMPLES WITH HIGH ACCURACY. TOGETHER, OUR RESULTS SHOW THAT INFLAMMATORY SIGNALS ESTABLISH A NOVEL EPIGENETIC PROGRAM THAT SILENCES A SPECIFIC SET OF GENES THAT CONTRIBUTE TO INFLAMMATION-INDUCED CELLULAR TRANSFORMATION. 2015 18 2228 29 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 19 5279 24 PROMOTER-SPECIFIC RELEVANCE OF HISTONE MODIFICATIONS INDUCED BY DEXAMETHASONE DURING THE REGULATION OF PRO-INFLAMMATORY MEDIATORS. GLUCOCORTICOSTEROIDS (GCS) ARE WIDELY USED TO TREAT DIFFERENT KINDS OF CHRONIC INFLAMMATORY AND IMMUNE DISEASES THROUGH TRANSCRIPTIONAL REGULATION OF INFLAMMATORY GENES. MODULATION OF GENE EXPRESSION BY GCS IS KNOWN TO OCCUR THROUGH DIVERSE MECHANISMS OF VARYING RELEVANCE TO SPECIFIC CLASSES OF GENES. EPIGENETIC MODIFICATIONS ARE INDEED A PIVOTAL REGULATORY FEATURE OF GLUCOCORTICOID RECEPTOR AND OTHER TRANSCRIPTION FACTORS. IN THIS STUDY, HISTONE POST-TRANSLATIONAL MODIFICATIONS WERE INVESTIGATED FOR THEIR INVOLVEMENT IN THE REGULATION OF SELECTED PRO-INFLAMMATORY GENES - EXPRESSED IN HUMAN MONOCYTE-DERIVED MACROPHAGES - IN RESPONSE TO TREATMENT WITH SYNTHETIC GC DEXAMETHASONE (DEX). WE SHOW THAT HISTONE TAIL ACETYLATION STATUS IS MODIFIED FOLLOWING DEX ADMINISTRATION, THROUGH DISTINCT AND ALTERNATIVE MECHANISMS AT THE PROMOTERS OF INTERLEUKIN-8 AND INTERLEUKIN-23. IN ADDITION TO HISTONE H3 ACETYLATION, OUR RESULTS DEMONSTRATE THAT H3 LYSINE 4 TRIMETHYLATION IS AFFECTED FOLLOWING DRUG TREATMENT. 2014 20 1283 23 DECIPHERING THE EPIGENETIC CODE OF T LYMPHOCYTES. THE MULTIPLE LINEAGES AND DIFFERENTIATION STATES THAT CONSTITUTE THE T-CELL COMPARTMENT ALL DERIVE FROM A COMMON THYMIC PRECURSOR. THESE DISTINCT TRANSCRIPTIONAL STATES ARE MAINTAINED BOTH IN TIME AND AFTER MULTIPLE ROUNDS OF CELL DIVISION BY THE CONCERTED ACTIONS OF A SMALL SET OF LINEAGE-DEFINING TRANSCRIPTION FACTORS THAT ACT IN CONJUNCTION WITH A SUITE OF CHROMATIN-MODIFYING ENZYMES TO ACTIVATE, REPRESS, AND FINE-TUNE GENE EXPRESSION. THESE CHROMATIN MODIFICATIONS COLLECTIVELY PROVIDE AN EPIGENETIC CODE THAT ALLOWS THE STABLE AND HERITABLE MAINTENANCE OF THE T-CELL PHENOTYPE. RECENTLY, IT HAS BECOME APPARENT THAT THE EPIGENETIC CODE REPRESENTS A THERAPEUTIC TARGET FOR A VARIETY OF IMMUNE CELL DISORDERS, INCLUDING LYMPHOMA AND ACUTE AND CHRONIC INFLAMMATORY DISEASES. HERE, WE REVIEW THE RECENT ADVANCES IN EPIGENETIC REGULATION OF GENE EXPRESSION, PARTICULARLY AS IT RELATES TO THE T-CELL DIFFERENTIATION AND FUNCTION. 2014