1 3808 148 INTRANASAL ADMINISTRATION OF ACINETOBACTER LWOFFII IN A MURINE MODEL OF ASTHMA INDUCES IL-6-MEDIATED PROTECTION ASSOCIATED WITH CECAL MICROBIOTA CHANGES. BACKGROUND: EARLY-LIFE EXPOSURE TO CERTAIN ENVIRONMENTAL BACTERIA INCLUDING ACINETOBACTER LWOFFII (AL) HAS BEEN IMPLICATED IN PROTECTION FROM CHRONIC INFLAMMATORY DISEASES INCLUDING ASTHMA LATER IN LIFE. HOWEVER, THE UNDERLYING MECHANISMS AT THE IMMUNE-MICROBE INTERFACE REMAIN LARGELY UNKNOWN. METHODS: THE EFFECTS OF REPEATED INTRANASAL AL EXPOSURE ON LOCAL AND SYSTEMIC INNATE IMMUNE RESPONSES WERE INVESTIGATED IN WILD-TYPE AND IL6(-/-) , IL10(-/-) , AND IL17(-/-) MICE EXPOSED TO OVALBUMIN-INDUCED ALLERGIC AIRWAY INFLAMMATION. THOSE INVESTIGATIONS WERE EXPANDED BY MICROBIOME ANALYSES. TO ASSESS FOR AL-ASSOCIATED CHANGES IN GENE EXPRESSION, THE PICTURE ARISING FROM ANIMAL DATA WAS SUPPLEMENTED BY IN VITRO EXPERIMENTS OF MACROPHAGE AND T-CELL RESPONSES, YIELDING EXPRESSION AND EPIGENETIC DATA. RESULTS: THE ASTHMA PREVENTIVE EFFECT OF AL WAS CONFIRMED IN THE LUNG. REPEATED INTRANASAL AL ADMINISTRATION TRIGGERED A PROINFLAMMATORY IMMUNE RESPONSE PARTICULARLY CHARACTERIZED BY ELEVATED LEVELS OF IL-6, AND CONSEQUENTLY, IL-6 INDUCED IL-10 PRODUCTION IN CD4(+) T-CELLS. BOTH IL-6 AND IL-10, BUT NOT IL-17, WERE REQUIRED FOR ASTHMA PROTECTION. AL HAD A PROFOUND IMPACT ON THE GENE REGULATORY LANDSCAPE OF CD4(+) T-CELLS WHICH COULD BE LARGELY RECAPITULATED BY RECOMBINANT IL-6. AL ADMINISTRATION ALSO INDUCED MARKED CHANGES IN THE GASTROINTESTINAL MICROBIOME BUT NOT IN THE LUNG MICROBIOME. BY COMPARING THE EFFECTS ON THE MICROBIOTA ACCORDING TO MOUSE GENOTYPE AND AL-TREATMENT STATUS, WE HAVE IDENTIFIED MICROBIAL TAXA THAT WERE ASSOCIATED WITH EITHER DISEASE PROTECTION OR ACTIVITY. CONCLUSION: THESE EXPERIMENTS PROVIDE A NOVEL MECHANISM OF ACINETOBACTER LWOFFII-INDUCED ASTHMA PROTECTION OPERATING THROUGH IL-6-MEDIATED EPIGENETIC ACTIVATION OF IL-10 PRODUCTION AND WITH ASSOCIATED EFFECTS ON THE INTESTINAL MICROBIOME. 2023 2 2290 54 EPIGENETIC REGULATION IN MURINE OFFSPRING AS A NOVEL MECHANISM FOR TRANSMATERNAL ASTHMA PROTECTION INDUCED BY MICROBES. BACKGROUND: BRONCHIAL ASTHMA IS A CHRONIC INFLAMMATORY DISEASE RESULTING FROM COMPLEX GENE-ENVIRONMENT INTERACTIONS. NATURAL MICROBIAL EXPOSURE HAS BEEN IDENTIFIED AS AN IMPORTANT ENVIRONMENTAL CONDITION THAT PROVIDES ASTHMA PROTECTION IN A PRENATAL WINDOW OF OPPORTUNITY. EPIGENETIC REGULATION IS AN IMPORTANT MECHANISM BY WHICH ENVIRONMENTAL FACTORS MIGHT INTERACT WITH GENES INVOLVED IN ALLERGY AND ASTHMA DEVELOPMENT. OBJECTIVE: THIS STUDY WAS DESIGNED TO TEST WHETHER EPIGENETIC MECHANISMS MIGHT CONTRIBUTE TO ASTHMA PROTECTION CONFERRED BY EARLY MICROBIAL EXPOSURE. METHODS: PREGNANT MATERNAL MICE WERE EXPOSED TO THE FARM-DERIVED GRAM-NEGATIVE BACTERIUM ACINETOBACTER LWOFFII F78. EPIGENETIC MODIFICATIONS IN THE OFFSPRING WERE ANALYZED IN T(H)1- AND T(H)2-RELEVANT GENES OF CD4(+) T CELLS. RESULTS: PRENATAL ADMINISTRATION OF A LWOFFII F78 PREVENTED THE DEVELOPMENT OF AN ASTHMATIC PHENOTYPE IN THE PROGENY, AND THIS EFFECT WAS IFN-GAMMA DEPENDENT. FURTHERMORE, THE IFNG PROMOTER OF CD4(+) T CELLS IN THE OFFSPRING REVEALED A SIGNIFICANT PROTECTION AGAINST LOSS OF HISTONE 4 (H4) ACETYLATION, WHICH WAS CLOSELY ASSOCIATED WITH IFN-GAMMA EXPRESSION. PHARMACOLOGIC INHIBITION OF H4 ACETYLATION IN THE OFFSPRING ABOLISHED THE ASTHMA-PROTECTIVE PHENOTYPE. REGARDING T(H)2-RELEVANT GENES ONLY AT THE IL4 PROMOTER, A DECREASE COULD BE DETECTED FOR H4 ACETYLATION BUT NOT AT THE IL5 PROMOTER OR THE INTERGENIC T(H)2 REGULATORY REGION CONSERVED NONCODING SEQUENCE 1 (CNS1). CONCLUSION: THESE DATA SUPPORT THE HYGIENE CONCEPT AND INDICATE THAT MICROBES OPERATE BY MEANS OF EPIGENETIC MECHANISMS. THIS PROVIDES A NEW MECHANISM IN THE UNDERSTANDING OF GENE-ENVIRONMENT INTERACTIONS IN THE CONTEXT OF ALLERGY PROTECTION. 2011 3 2022 50 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 4 1566 49 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 5 5894 45 T CELL EPIGENETIC REMODELING AND ACCELERATED EPIGENETIC AGING ARE LINKED TO LONG-TERM IMMUNE ALTERATIONS IN CHILDHOOD CANCER SURVIVORS. BACKGROUND: CANCER TREATMENTS HAVE SUBSTANTIALLY IMPROVED CHILDHOOD CANCER SURVIVAL BUT ARE ACCOMPANIED BY LONG-TERM COMPLICATIONS, NOTABLY CHRONIC INFLAMMATORY DISEASES. WE HYPOTHESIZE THAT CANCER TREATMENTS COULD LEAD TO LONG-TERM EPIGENETIC CHANGES IN IMMUNE CELLS, RESULTING IN INCREASED PREVALENCE OF INFLAMMATORY DISEASES IN CANCER SURVIVORS. RESULTS: TO TEST THIS HYPOTHESIS, WE ESTABLISHED THE EPIGENETIC AND TRANSCRIPTOMIC PROFILES OF IMMUNE CELLS FROM 44 CHILDHOOD CANCER SURVIVORS (CCS, > 16 YEARS OLD) ON FULL REMISSION (> 5 YEARS) WHO HAD RECEIVED CHEMOTHERAPY ALONE OR IN COMBINATION WITH TOTAL BODY IRRADIATION (TBI) AND HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT). WE FOUND THAT MORE THAN 10 YEARS POST-TREATMENT, CCS TREATED WITH TBI/HSCT SHOWED AN ALTERED DNA METHYLATION SIGNATURE IN T CELL, PARTICULARLY AT GENES CONTROLLING IMMUNE AND INFLAMMATORY PROCESSES AND OXIDATIVE STRESS. DNA METHYLATION REMODELING IN T CELL WAS PARTIALLY ASSOCIATED WITH CHRONIC EXPRESSION CHANGES OF NEARBY GENES, INCREASED FREQUENCY OF TYPE 1 CYTOKINE-PRODUCING T CELL, ELEVATED SYSTEMIC LEVELS OF THESE CYTOKINES, AND OVER-ACTIVATION OF RELATED SIGNALING PATHWAYS. SURVIVORS EXPOSED TO TBI/HSCT WERE FURTHER CHARACTERIZED BY AN EPIGENETIC-AGING-SIGNATURE OF T CELL CONSISTENT WITH ACCELERATED EPIGENETIC AGING. TO INVESTIGATE THE POTENTIAL CONTRIBUTION OF IRRADIATION TO THESE CHANGES, WE ESTABLISHED TWO CELL CULTURE MODELS. WE IDENTIFIED THAT RADIATION PARTIALLY RECAPITULATED THE IMMUNE CHANGES OBSERVED IN SURVIVORS THROUGH A BYSTANDER EFFECT THAT COULD BE MEDIATED BY CIRCULATING FACTORS. CONCLUSION: CANCER TREATMENTS, IN PARTICULAR TBI/HSCT, ARE ASSOCIATED WITH LONG-TERM IMMUNE DISTURBANCES. WE PROPOSE THAT EPIGENETIC REMODELING OF IMMUNE CELLS FOLLOWING CANCER THERAPY AUGMENTS INFLAMMATORY- AND AGE-RELATED DISEASES, INCLUDING METABOLIC COMPLICATIONS, IN CHILDHOOD CANCER SURVIVORS. 2018 6 6764 40 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 7 4391 39 MODERATE EXERCISE INDUCES TRAINED IMMUNITY IN MACROPHAGES. DESPITE ITS IMPORTANCE IN PROTECTING THE HOST FROM INFECTIONS AND INJURY, EXCESSIVE INFLAMMATION MAY LEAD TO SERIOUS HUMAN DISEASES INCLUDING AUTOIMMUNE DISORDERS, CARDIOVASCULAR DISEASES, DIABETES, AND CANCER. EXERCISE IS A KNOWN IMMUNOMODULATOR; HOWEVER, WHETHER EXERCISE CAUSES LONG-TERM CHANGES IN INFLAMMATORY RESPONSES AND HOW THESE CHANGES OCCUR ARE LACKING. HERE, WE SHOW THAT CHRONIC MODERATE-INTENSITY TRAINING OF MICE LEADS TO PERSISTENT METABOLIC REWIRING AND CHANGES TO CHROMATIN ACCESSIBILITY IN BONE MARROW-DERIVED MACROPHAGES (BMDMS), WHICH, IN TURN, TEMPERS THEIR INFLAMMATORY RESPONSES. WE SHOW THAT BMDMS FROM EXERCISED MICE EXHIBITED A DECREASE IN LIPOPOLYSACCHARIDE (LPS)-INDUCED NF-KAPPAB ACTIVATION AND PROINFLAMMATORY GENE EXPRESSION ALONG WITH AN INCREASE IN M2-LIKE-ASSOCIATED GENES WHEN COMPARED WITH BMDMS FROM SEDENTARY MICE. THIS WAS ASSOCIATED WITH IMPROVED MITOCHONDRIAL QUALITY AND INCREASED RELIANCE ON OXIDATIVE PHOSPHORYLATION ACCOMPANIED WITH REDUCED MITOCHONDRIAL REACTIVE OXYGEN SPECIES (ROS) PRODUCTION. MECHANISTICALLY, ASSAY FOR TRANSPOSASE-ACCESSIBLE CHROMATIN (ATAC)-SEQ ANALYSIS SHOWED CHANGES IN CHROMATIN ACCESSIBILITY OF GENES ASSOCIATED WITH INFLAMMATORY AND METABOLIC PATHWAYS. OVERALL, OUR DATA SUGGEST THAT CHRONIC MODERATE EXERCISE CAN INFLUENCE THE INFLAMMATORY RESPONSES OF MACROPHAGES BY REPROGRAMMING THEIR METABOLIC AND EPIGENETIC LANDSCAPE.NEW & NOTEWORTHY IN THIS STUDY, WE EXPLAIN HOW LONG-TERM MODERATE EXERCISE TRAINING CAN REDUCE INFLAMMATION IN MOUSE MACROPHAGES BY REPROGRAMMING THE WAY THEY SENSE AND RESPOND TO THE PRESENCE OF PATHOGENS. WE COMPLETED A THOROUGH ANALYSIS AND SHOWED THAT THESE CHANGES PERSIST IN MACROPHAGES BECAUSE EXERCISE IMPROVES THE ABILITY OF CELLS TO UTILIZE OXYGEN WITHOUT PRODUCING DAMAGING COMPOUNDS, AND CHANGES THE WAY THEY ACCESS THEIR DNA. 2023 8 5710 35 SIRT1 DEFICIENCY IN MICROGLIA CONTRIBUTES TO COGNITIVE DECLINE IN AGING AND NEURODEGENERATION VIA EPIGENETIC REGULATION OF IL-1BETA. AGING IS THE PREDOMINANT RISK FACTOR FOR NEURODEGENERATIVE DISEASES. ONE KEY PHENOTYPE AS THE BRAIN AGES IS AN ABERRANT INNATE IMMUNE RESPONSE CHARACTERIZED BY PROINFLAMMATION. HOWEVER, THE MOLECULAR MECHANISMS UNDERLYING AGING-ASSOCIATED PROINFLAMMATION ARE POORLY DEFINED. WHETHER CHRONIC INFLAMMATION PLAYS A CAUSAL ROLE IN COGNITIVE DECLINE IN AGING AND NEURODEGENERATION HAS NOT BEEN ESTABLISHED. HERE WE REPORT A MECHANISTIC LINK BETWEEN CHRONIC INFLAMMATION AND AGING MICROGLIA AND A CAUSAL ROLE OF AGING MICROGLIA IN NEURODEGENERATIVE COGNITIVE DEFICITS. WE SHOWED THAT SIRT1 IS REDUCED WITH THE AGING OF MICROGLIA AND THAT MICROGLIAL SIRT1 DEFICIENCY HAS A CAUSATIVE ROLE IN AGING- OR TAU-MEDIATED MEMORY DEFICITS VIA IL-1BETA UPREGULATION IN MICE. INTERESTINGLY, THE SELECTIVE ACTIVATION OF IL-1BETA TRANSCRIPTION BY SIRT1 DEFICIENCY IS LIKELY MEDIATED THROUGH HYPOMETHYLATING THE SPECIFIC CPG SITES ON IL-1BETA PROXIMAL PROMOTER. IN HUMANS, HYPOMETHYLATION OF IL-1BETA IS STRONGLY ASSOCIATED WITH CHRONOLOGICAL AGE AND WITH ELEVATED IL-1BETA TRANSCRIPTION. OUR FINDINGS REVEAL A NOVEL EPIGENETIC MECHANISM IN AGING MICROGLIA THAT CONTRIBUTES TO COGNITIVE DEFICITS IN AGING AND NEURODEGENERATIVE DISEASES. 2015 9 271 26 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 10 3436 35 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 11 6533 31 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 12 2228 23 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 13 706 49 BUTYRATE AND DIETARY SOLUBLE FIBER IMPROVE NEUROINFLAMMATION ASSOCIATED WITH AGING IN MICE. AGING RESULTS IN CHRONIC SYSTEMIC INFLAMMATION THAT CAN ALTER NEUROINFLAMMATION OF THE BRAIN. SPECIFICALLY, MICROGLIA SHIFT TO A PRO-INFLAMMATORY PHENOTYPE PREDISPOSING THEM TO HYPERACTIVATION UPON STIMULATION BY PERIPHERAL IMMUNE SIGNALS. IT IS PROPOSED THAT CERTAIN NUTRIENTS CAN DELAY BRAIN AGING BY PREVENTING OR REVERSING MICROGLIAL HYPERACTIVATION. BUTYRATE, A SHORT-CHAIN FATTY ACID (SCFA) PRODUCED PRIMARILY BY BACTERIAL FERMENTATION OF FIBER IN THE COLON, HAS BEEN EXTENSIVELY STUDIED PHARMACOLOGICALLY AS A HISTONE DEACETYLASE INHIBITOR AND SERVES AS AN ATTRACTIVE THERAPEUTIC CANDIDATE, AS BUTYRATE HAS ALSO BEEN SHOWN TO BE ANTI-INFLAMMATORY AND IMPROVE MEMORY IN ANIMAL MODELS. IN THIS STUDY, WE DEMONSTRATE THAT BUTYRATE CAN ATTENUATE PRO-INFLAMMATORY CYTOKINE EXPRESSION IN MICROGLIA IN AGED MICE. IT IS STILL NOT FULLY UNDERSTOOD, HOWEVER, IF AN INCREASE IN BUTYRATE-PRODUCING BACTERIA IN THE GUT AS A CONSEQUENCE OF A DIET HIGH IN SOLUBLE FIBER COULD AFFECT MICROGLIAL ACTIVATION DURING AGING. ADULT AND AGED MICE WERE FED EITHER A 1% CELLULOSE (LOW FIBER) OR 5% INULIN (HIGH FIBER) DIET FOR 4 WEEKS. FINDINGS INDICATE THAT MICE FED INULIN HAD AN ALTERED GUT MICROBIOME AND INCREASED BUTYRATE, ACETATE, AND TOTAL SCFA PRODUCTION. IN ADDITION, HISTOLOGICAL SCORING OF THE DISTAL COLON DEMONSTRATED THAT AGED ANIMALS ON THE LOW FIBER DIET HAD INCREASED INFLAMMATORY INFILTRATE THAT WAS SIGNIFICANTLY REDUCED IN ANIMALS CONSUMING THE HIGH FIBER DIET. FURTHERMORE, GENE EXPRESSION OF INFLAMMATORY MARKERS, EPIGENETIC REGULATORS, AND THE MICROGLIAL SENSORY APPARATUS (I.E., THE SENSOME) WERE ALTERED BY BOTH DIET AND AGE, WITH AGED ANIMALS EXHIBITING A MORE ANTI-INFLAMMATORY MICROGLIAL PROFILE ON THE HIGH FIBER DIET. TAKEN TOGETHER, HIGH FIBER SUPPLEMENTATION IN AGING IS A NON-INVASIVE STRATEGY TO INCREASE BUTYRATE LEVELS, AND THESE DATA SUGGEST THAT AN INCREASE IN BUTYRATE THROUGH ADDED SOLUBLE FIBER SUCH AS INULIN COULD COUNTERBALANCE THE AGE-RELATED MICROBIOTA DYSBIOSIS, POTENTIALLY LEADING TO NEUROLOGICAL BENEFITS. 2018 14 6535 36 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 15 3643 37 INCREASED INFLAMMATORY RESPONSE IN AGED MICE IS ASSOCIATED WITH AGE-RELATED ZINC DEFICIENCY AND ZINC TRANSPORTER DYSREGULATION. AGING IS A COMPLEX PROCESS ASSOCIATED WITH PHYSIOLOGICAL CHANGES IN NUMEROUS ORGAN SYSTEMS. IN PARTICULAR, AGING OF THE IMMUNE SYSTEM IS CHARACTERIZED BY PROGRESSIVE DYSREGULATION OF IMMUNE RESPONSES, RESULTING IN INCREASED SUSCEPTIBILITY TO INFECTIOUS DISEASES, IMPAIRED VACCINATION EFFICACY AND SYSTEMIC LOW-GRADE CHRONIC INFLAMMATION. INCREASING EVIDENCE SUGGEST THAT INTRACELLULAR ZINC HOMEOSTASIS, REGULATED BY ZINC TRANSPORTER EXPRESSION, IS CRITICALLY INVOLVED IN THE SIGNALING AND ACTIVATION OF IMMUNE CELLS. WE HYPOTHESIZE THAT EPIGENETIC ALTERATIONS AND NUTRITIONAL DEFICITS ASSOCIATED WITH AGING MAY LEAD TO ZINC TRANSPORTER DYSREGULATION, RESULTING IN DECREASES IN CELLULAR ZINC LEVELS AND ENHANCED INFLAMMATION WITH AGE. THE GOAL OF THIS STUDY WAS TO EXAMINE THE CONTRIBUTION OF AGE-RELATED ZINC DEFICIENCY AND ZINC TRANSPORTER DYSREGULATION ON THE INFLAMMATORY RESPONSE IN IMMUNE CELLS. THE EFFECTS OF ZINC DEFICIENCY AND AGE ON THE INDUCTION OF INFLAMMATORY RESPONSES WERE DETERMINED USING AN IN VITRO CELL CULTURE SYSTEM AND AN AGED MOUSE MODEL. WE SHOWED THAT ZINC DEFICIENCY, PARTICULARLY THE REDUCTION IN INTRACELLULAR ZINC IN IMMUNE CELLS, WAS ASSOCIATED WITH INCREASED INFLAMMATION WITH AGE. FURTHERMORE, REDUCED ZIP 6 EXPRESSION ENHANCED PROINFLAMMATORY RESPONSE, AND AGE-SPECIFIC ZIP 6 DYSREGULATION CORRELATED WITH AN INCREASE IN ZIP 6 PROMOTER METHYLATION. FURTHERMORE, RESTORING ZINC STATUS VIA DIETARY SUPPLEMENTATION REDUCED AGED-ASSOCIATED INFLAMMATION. OUR DATA SUGGESTED THAT AGE-RELATED EPIGENETIC DYSREGULATION IN ZINC TRANSPORTER EXPRESSION MAY INFLUENCE CELLULAR ZINC LEVELS AND CONTRIBUTE TO INCREASED SUSCEPTIBILITY TO INFLAMMATION WITH AGE. 2013 16 5318 32 PSYCHONEUROENDOCRINE INTERVENTIONS AIMED AT ATTENUATING IMMUNOSENESCENCE: A REVIEW. THERE IS EVIDENCE SUGGESTING THAT IMMUNOSENESCENCE CAN BE ACCELERATED BY EXTERNAL FACTORS SUCH AS CHRONIC STRESS. HERE WE REVIEW POTENTIAL PSYCHONEUROENDOCRINE DETERMINANTS OF PREMATURE AGING OF THE IMMUNE SYSTEM AND DISCUSS AVAILABLE INTERVENTIONS AIMED AT ATTENUATING IMMUNOSENESCENCE. CHRONIC STRESS MAY ACCELERATE VARIOUS FEATURES OF IMMUNOSENESCENCE BY ACTIVATING KEY ALLOSTATIC SYSTEMS, NOTABLY THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS. THE IMMUNOLOGICAL IMPACT OF SUCH NEUROENDOCRINE DYSREGULATION MAY BE FURTHER AMPLIFIED BY A DRAMATIC DECLINE IN DEHYDROEPIANDROSTERONE (DHEA) LEVELS, ACTING IN PART AS AN ENDOGENOUS GLUCOCORTICOID ANTAGONIST. STRESS-BUFFERING STRATEGIES SHOW BENEFICIAL EFFECTS ON VARIOUS BIOMARKERS IN ELDERLY POPULATIONS. LIKEWISE, SUPPLEMENTATION OF DHEA, MELATONIN OR GROWTH HORMONE HAS YIELDED SIGNIFICANT BENEFICIAL EFFECTS IN A NUMBER OF STUDIES, INCLUDING: INCREASED WELL-BEING, MEMORY PERFORMANCE, BONE MINERAL DENSITY AND IMPROVED IMMUNOCOMPETENCE AS EVIDENCED BY RESULTS OF IN VITRO (T CELL PROLIFERATION, CYTOTOXICITY, CYTOKINE PRODUCTION), AND IN VIVO IMMUNE CHALLENGES. HOWEVER, THE SIDE-EFFECTS OF HORMONAL SUPPLEMENTATION ARE ALSO DISCUSSED. FINALLY, MODERATE EXERCISE VIA THE PROMOTION OF CORTISOL/DHEA BALANCE OR EPIGENETIC MODIFICATIONS, IS ASSOCIATED WITH LOWER SERUM PRO-INFLAMMATORY CYTOKINES, GREATER LYMPHOPROLIFERATIVE RESPONSES AND LOWER COUNTS OF SENESCENT T CELLS. TAKEN TOGETHER, THESE DATA SUGGEST THAT IMMUNE SYSTEM IS PLASTIC AND IMMUNOSENESCENCE CAN BE ATTENUATED PSYCHONEUROENDOCRINE INTERVENTIONS. 2013 17 6564 38 TRANSIENT EXPOSURE TO ELEVATED GLUCOSE LEVELS CAUSES PERSISTENT CHANGES IN DERMAL MICROVASCULAR ENDOTHELIAL CELL RESPONSES TO INJURY. BACKGROUND: THE PURPOSE OF THIS STUDY WAS TO DETERMINE WHETHER ELEVATED GLUCOSE CAN INDUCE A DERMAL MICROVASCULAR ENDOTHELIAL CELL METABOLIC MEMORY, THUS AFFECTING ANGIOGENESIS IN THE REPAIR PROCESS OF MAMMALIAN CUTANEOUS WOUND. WE HYPOTHESIZED THAT TRANSIENT ELEVATED GLUCOSE LEVELS CAUSE SUSTAINED ALTERATION OF ENDOTHELIAL CELL RESPONSES TO INJURY AND PERSISTENT EPIGENETIC CHANGES IN GENE EXPRESSION. METHODS: HUMAN DERMAL MICROVASCULAR ENDOTHELIAL CELLS WERE EXPOSED TO EXPERIMENTAL CONDITIONS WITH OR WITHOUT 30 MM D-GLUCOSE. THE CONTROL GROUP WAS MAINTAINED AT 5 MM D-GLUCOSE; WHILE IN THE TRANSIENT GLUCOSE GROUP, AFTER BEING EXPOSED TO 30 MM D-GLUCOSE FOR TWO DAYS, THEN BEING PUT UNDER THE CONTROL CONDITIONS DURING THE EXPERIMENT. BESIDES, IN THE WHOLE PROCESS OF THE EXPERIMENT, THE CHRONIC GLUCOSE GROUP WAS KEPT IN THE CONDITION WITH 30 MM D-GLUCOSE. PROLIFERATION, MIGRATION, TUBE FORMATION, GENE EXPRESSION AND HISTONE METHYLATION WERE ASSESSED FOR INDIVIDUAL CONDITIONS. RESULTS: TRANSIENT ELEVATED GLUCOSE CAUSED SUSTAINED EFFECTS ON ENDOTHELIAL CELL MIGRATION, TUBE FORMATION AND TIMP3 GENE EXPRESSION. THE EFFECTS ON TIMP3 EXPRESSION WERE ASSOCIATED WITH PERSISTENT CHANGES IN HISTONE MODIFICATION AT THE 5' END OF THE TIMP3 GENE, SUGGESTING AN EPIGENETIC EFFECT. CONCLUSIONS: HYPERGLYCEMIA INDUCED METABOLIC MEMORY COULD PROMOTE THE REGULATION OF TIMP3, AND IT CAN BE USED AS A POSSIBLE INNOVATIVE MOLECULAR TARGET FOR THERAPEUTIC INTERVENTION IN THE TREATMENT OF CHRONIC NON-HEALING DIABETIC WOUNDS. 2021 18 2297 32 EPIGENETIC REGULATION OF ACUTE INFLAMMATORY PAIN. ACUTE PAIN IS ASSOCIATED WITH TISSUE DAMAGE, WHICH RESULTS IN THE RELEASE OF INFLAMMATORY MEDIATORS. RECENT STUDIES POINT TO THE INVOLVEMENT OF EPIGENETIC MECHANISMS (DNA METHYLATION) IN THE DEVELOPMENT OF PAIN. WE HAVE FOUND THAT DURING ACUTE INFLAMMATORY PAIN INDUCED BY THE APPLICATION OF 10% MUSTARD OIL ON THE TONGUES OF RATS, LEVELS OF DNMT3A AND 3B WERE ELEVATED MARKEDLY (36 AND 42 % RESPECTIVELY), WHEREAS THE LEVEL OF DNMT1 WAS NOT CHANGED SIGNIFICANTLY. PREVIOUS INJECTION OF XEFOCAM WITH 0,4 MG/KG DOSE DECREASED LEVELS OF DNMT3A AND 3B (25 AND 24% RESPECTIVELY). THE LEVEL OF DNMT1 WAS NOT CHANGED SIGNIFICANTLY COMPARED TO THE CONTROL GROUP. THE FINDINGS SUPPORT THE IDEA THAT INHIBITORS OF DNA-METHYLTRANSFERASES COULD BE USEFUL FOR PAIN MANAGEMENT. OUR DATA SUGGEST THAT NSAIDS (ALONE OR IN COMBINATION WITH DNMT INHIBITORS) MAY BE PROPOSED AS POSSIBLE EPIGENETIC REGULATORY AGENTS, WHICH MAY PLAY A ROLE IN EPIGENETIC MECHANISMS INDIRECTLY THROUGH ALTERING THE ACTIVITY OF INFLAMMATORY MEDIATORS INVOLVED IN PAIN DEVELOPMENT. 2014 19 1508 39 DNA METHYLATION AND MRNA AND MICRORNA EXPRESSION OF SLE CD4+ T CELLS CORRELATE WITH DISEASE PHENOTYPE. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS AN AUTOIMMUNE DISEASE WELL KNOWN FOR ITS CLINICAL HETEROGENEITY, AND ITS ETIOLOGY SECONDARY TO A CROSS-TALK INVOLVING GENETIC PREDISPOSITION AND ENVIRONMENTAL STIMULI. ALTHOUGH GENOME-WIDE ANALYSIS HAS CONTRIBUTED GREATLY TO OUR UNDERSTANDING OF THE GENETIC BASIS OF SLE, THERE IS INCREASING EVIDENCE FOR A ROLE OF EPIGENETICS. INDEED, RECENT DATA HAVE DEMONSTRATED THAT IN PATIENTS WITH SLE, THERE ARE STRIKING ALTERATIONS OF DNA METHYLATION, HISTONE MODIFICATIONS, AND DEREGULATED MICRORNA EXPRESSION, THE SUM OF WHICH CONTRIBUTE TO OVER-EXPRESSION OF SELECT AUTOIMMUNE-RELATED GENES AND LOSS OF TOLERANCE. TO ADDRESS THIS ISSUE AT THE LEVEL OF CLINICAL PHENOTYPE, WE PERFORMED DNA METHYLATION, MRNA AND MICRORNA EXPRESSION SCREENING USING HIGH-THROUGHPUT SEQUENCING OF PURIFIED CD4+ T CELLS FROM PATIENTS WITH SLE, COMPARED TO AGE AND SEX MATCHED CONTROLS. IN PARTICULAR, WE STUDIED 42 PATIENTS WITH SLE AND DIVIDED THIS GROUP INTO THREE CLINICAL PHENOTYPES: A) THE PRESENCE OF SKIN LESIONS WITHOUT SIGNS OF SYSTEMIC PATHOLOGY; B) SKIN LESIONS BUT ALSO CHRONIC RENAL PATHOLOGY; AND C) SKIN LESIONS, CHRONIC RENAL PATHOLOGY AND POLYARTICULAR DISEASE. INTERESTINGLY, AND AS EXPECTED, SEQUENCING DATA REVEALED CHANGES IN DNA METHYLATION IN SLE COMPARED TO CONTROLS. HOWEVER, AND MORE IMPORTANTLY, ALTHOUGH THERE WERE COMMON METHYLATION CHANGES FOUND IN ALL GROUPS OF SLE COMPARED TO CONTROLS, THERE WAS SPECIFIC DNA METHYLATION CHANGES THAT CORRELATED WITH CLINICAL PHENOTYPE. THESE INCLUDED CHANGES IN THE NOVEL KEY TARGET GENES NLRP2, CD300LB AND S1PR3, AS WELL AS CHANGES IN THE CRITICAL PATHWAYS, INCLUDING THE ADHERENS JUNCTION AND LEUKOCYTE TRANSENDOTHELIAL MIGRATION. WE ALSO NOTED THAT A SIGNIFICANT PROPORTION OF GENES UNDERGOING DNA METHYLATION CHANGES WERE INVERSELY CORRELATED WITH GENE EXPRESSION AND THAT MIRNA SCREENING REVEALED THE EXISTENCE OF SUBSETS WITH CHANGES IN EXPRESSION. INTEGRATED ANALYSIS OF THIS DATA HIGHLIGHTS SPECIFIC SETS OF MIRNAS CONTROLLED BY DNA METHYLATION, AND GENES THAT ARE ALTERED BY METHYLATION AND TARGETED BY MIRNAS. IN CONCLUSION, OUR FINDINGS SUGGEST SELECT EPIGENETIC MECHANISMS THAT CONTRIBUTE TO CLINICAL PHENOTYPES AND FURTHER SHED LIGHT ON A NEW VENUE FOR BASIC SLE RESEARCH. 2014 20 2926 28 GENERATION OF AN EPIGENETIC SIGNATURE BY CHRONIC HYPOXIA IN PROSTATE CELLS. INCREASING LEVELS OF TISSUE HYPOXIA HAVE BEEN REPORTED AS A NATURAL FEATURE OF THE AGING PROSTATE GLAND AND MAY BE A RISK FACTOR FOR THE DEVELOPMENT OF PROSTATE CANCER. IN THIS STUDY, WE HAVE USED PWR-1E BENIGN PROSTATE EPITHELIAL CELLS AND AN EQUIVALENTLY AGED HYPOXIA-ADAPTED PWR-1E SUB-LINE TO IDENTIFY PHENOTYPIC AND EPIGENETIC CONSEQUENCES OF CHRONIC HYPOXIA IN PROSTATE CELLS. WE HAVE IDENTIFIED A SIGNIFICANTLY ALTERED CELLULAR PHENOTYPE IN RESPONSE TO CHRONIC HYPOXIA AS CHARACTERIZED BY INCREASED RECEPTOR-MEDIATED APOPTOTIC RESISTANCE, THE INDUCTION OF CELLULAR SENESCENCE, INCREASED INVASION AND THE INCREASED SECRETION OF IL-1 BETA, IL6, IL8 AND TNFALPHA CYTOKINES. IN ASSOCIATION WITH THESE PHENOTYPIC CHANGES AND THE ABSENCE OF HIF-1 ALPHA PROTEIN EXPRESSION, WE HAVE DEMONSTRATED SIGNIFICANT INCREASES IN GLOBAL LEVELS OF DNA METHYLATION AND H3K9 HISTONE ACETYLATION IN THESE CELLS, CONCOMITANT WITH THE INCREASED EXPRESSION OF DNA METHYLTRANSFERASE DMNT3B AND GENE-SPECIFIC CHANGES IN DNA METHYLATION AT KEY IMPRINTING LOCI. IN CONCLUSION, WE HAVE DEMONSTRATED A GENOME-WIDE ADJUSTMENT OF DNA METHYLATION AND HISTONE ACETYLATION UNDER CHRONIC HYPOXIC CONDITIONS IN THE PROSTATE. THESE EPIGENETIC SIGNATURES MAY REPRESENT AN ADDITIONAL MECHANISM TO PROMOTE AND MAINTAIN A HYPOXIC-ADAPTED CELLULAR PHENOTYPE WITH A POTENTIAL ROLE IN TUMOUR DEVELOPMENT. 2009