1 5607 141 RSV-INDUCED H3K4 DEMETHYLASE KDM5B LEADS TO REGULATION OF DENDRITIC CELL-DERIVED INNATE CYTOKINES AND EXACERBATES PATHOGENESIS IN VIVO. RESPIRATORY SYNCYTIAL VIRUS (RSV) INFECTION CAN RESULT IN SEVERE DISEASE PARTIALLY DUE TO ITS ABILITY TO INTERFERE WITH THE INITIATION OF TH1 RESPONSES TARGETING THE PRODUCTION OF TYPE I INTERFERONS (IFN) AND PROMOTING A TH2 IMMUNE ENVIRONMENT. EPIGENETIC MODULATION OF GENE TRANSCRIPTION HAS BEEN SHOWN TO BE IMPORTANT IN REGULATING INFLAMMATORY PATHWAYS. RSV-INFECTED BONE MARROW-DERIVED DCS (BMDCS) UPREGULATED EXPRESSION OF KDM5B/JARID1B H3K4 DEMETHYLASE. KDM5B-SPECIFIC SIRNA INHIBITION IN BMDC LED TO A 10-FOLD INCREASE IN IFN-BETA AS WELL AS INCREASES IN IL-6 AND TNF-ALPHA COMPARED TO CONTROL-TRANSFECTED CELLS. THE GENERATION OF KDM5BFL/FL-CD11C-CRE+ MICE RECAPITULATED THE LATTER RESULTS DURING IN VITRO DC ACTIVATION SHOWING INNATE CYTOKINE MODULATION. IN VIVO, INFECTION OF KDM5BFL/FL-CD11C-CRE+ MICE WITH RSV RESULTED IN HIGHER PRODUCTION OF IFN-GAMMA AND REDUCED IL-4 AND IL-5 COMPARED TO LITTERMATE CONTROLS, WITH SIGNIFICANTLY DECREASED INFLAMMATION, IL-13, AND MUCUS PRODUCTION IN THE LUNGS. SENSITIZATION WITH RSV-INFECTED DCS INTO THE AIRWAYS OF NAIVE MICE LED TO AN EXACERBATED RESPONSE WHEN MICE WERE CHALLENGED WITH LIVE RSV INFECTION. WHEN KDM5B WAS BLOCKED IN DCS WITH SIRNA OR DCS FROM KDM5BFL/FL-CD11C-CRE MICE WERE USED, THE EXACERBATED RESPONSE WAS ABROGATED. IMPORTANTLY, HUMAN MONOCYTE-DERIVED DCS TREATED WITH A CHEMICAL INHIBITOR FOR KDM5B RESULTED IN INCREASED INNATE CYTOKINE LEVELS AS WELL AS ELICITED DECREASED TH2 CYTOKINES WHEN CO-CULTURED WITH RSV REACTIVATED CD4+ T CELLS. THESE RESULTS SUGGEST THAT KDM5B ACTS TO REPRESS TYPE I IFN AND OTHER INNATE CYTOKINES TO PROMOTE AN ALTERED IMMUNE RESPONSE FOLLOWING RSV INFECTION THAT CONTRIBUTES TO DEVELOPMENT OF CHRONIC DISEASE. 2015 2 6765 37 ZINC DEFICIENCY LEADS TO REDUCED INTERLEUKIN-2 PRODUCTION BY ACTIVE GENE SILENCING DUE TO ENHANCED CREMALPHA EXPRESSION IN T CELLS. BACKGROUND & AIMS: THE MICRONUTRIENT ZINC IS ESSENTIAL FOR PROPER IMMUNE FUNCTION. CONSEQUENTLY, ZINC DEFICIENCY LEADS TO IMPAIRED IMMUNE FUNCTION, AS SEEN IN DECREASED SECRETION OF INTERLEUKIN (IL)-2 BY T CELLS. ALTHOUGH THIS ASSOCIATION HAS BEEN KNOWN SINCE THE LATE 1980S, THE UNDERLYING MOLECULAR MECHANISMS ARE STILL UNKNOWN. ZINC DEFICIENCY AND REDUCED IL-2 LEVELS ARE ESPECIALLY FOUND IN THE ELDERLY, WHICH IN TURN ARE PRONE TO CHRONIC DISEASES. HERE, WE DESCRIBE A NEW MOLECULAR LINK BETWEEN ZINC DEFICIENCY AND REDUCED IL-2 EXPRESSION IN T CELLS. METHODS: THE EFFECTS OF ZINC DEFICIENCY WERE FIRST INVESTIGATED IN VITRO IN THE HUMAN T CELL LINES JURKAT AND HUT-78 AND COMPLEMENTED BY IN VIVO DATA FROM ZINC-SUPPLEMENTED PIGS. A SHORT- AND LONG-TERM MODEL FOR ZINC DEFICIENCY WAS ESTABLISHED. ZINC LEVELS WERE DETECTED BY FLOW CYTOMETRY AND EXPRESSION PROFILES WERE INVESTIGATED ON THE MRNA AND PROTEIN LEVEL. RESULTS: THE EXPRESSION OF THE TRANSCRIPTION FACTOR CAMP-RESPONSIVE-ELEMENT MODULATOR ALPHA (CREMALPHA) IS INCREASED DURING ZINC DEFICIENCY IN VITRO, DUE TO INCREASED PROTEIN PHOSPHATASE 2A (PP2A) ACTIVITY, RESULTING IN DECREASED IL-2 PRODUCTION. ADDITIONALLY, ZINC SUPPLEMENTATION IN VIVO REDUCED CREMALPHA LEVELS CAUSING INCREASED IL-2 EXPRESSION. ON EPIGENETIC LEVELS INCREASED CREMALPHA BINDING TO THE IL-2 PROMOTER IS MEDIATED BY HISTONE DEACETYLASE 1 (HDAC1). THE HDAC1 ACTIVITY IS INHIBITED BY ZINC. MOREOVER, DEACETYLATION OF THE ACTIVATING HISTONE MARK H3K9 WAS INCREASED UNDER ZINC DEFICIENCY, RESULTING IN REDUCED IL-2 EXPRESSION. CONCLUSIONS: WITH THE TRANSCRIPTION FACTOR CREMALPHA A MOLECULAR LINK WAS UNCOVERED, CONNECTING ZINC DEFICIENCY WITH REDUCED IL-2 PRODUCTION DUE TO ENHANCED PP2A AND HDAC1 ACTIVITY. 2021 3 3893 29 LACTATE INDUCES METABOLIC AND EPIGENETIC REPROGRAMMING OF PRO-INFLAMMATORY TH17 CELLS. INCREASED LACTATE LEVELS IN THE TISSUE MICROENVIRONMENT ARE A WELL-KNOWN FEATURE OF CHRONIC INFLAMMATION. HOWEVER, THE ROLE OF LACTATE IN REGULATING T CELL FUNCTION REMAINS CONTROVERSIAL. HERE, WE DEMONSTRATE THAT EXTRACELLULAR LACTATE PREDOMINANTLY INDUCES DEREGULATION OF THE TH17-SPECIFIC GENE EXPRESSION PROGRAM BY MODULATING THE METABOLIC AND EPIGENETIC STATUS OF TH17 CELLS. FOLLOWING LACTATE TREATMENT, TH17 CELLS SIGNIFICANTLY REDUCED THEIR IL-17A PRODUCTION AND UPREGULATED FOXP3 EXPRESSION THROUGH ROS-DRIVEN IL-2 SECRETION. MOREOVER, WE OBSERVED INCREASED LEVELS OF GENOME-WIDE HISTONE H3K18 LACTYLATION, A RECENTLY DESCRIBED MARKER FOR ACTIVE CHROMATIN IN MACROPHAGES, IN LACTATE-TREATED TH17 CELLS. IN ADDITION, WE SHOW THAT HIGH LACTATE CONCENTRATIONS SUPPRESS TH17 PATHOGENICITY DURING INTESTINAL INFLAMMATION IN MICE. THESE RESULTS INDICATE THAT LACTATE IS CAPABLE OF REPROGRAMMING PRO-INFLAMMATORY T CELL PHENOTYPES INTO REGULATORY T CELLS. 2022 4 698 48 BROMODOMAIN CONTAINING PROTEIN 4 (BRD4) REGULATES EXPRESSION OF ITS INTERACTING COACTIVATORS IN THE INNATE RESPONSE TO RESPIRATORY SYNCYTIAL VIRUS. BROMODOMAIN-CONTAINING PROTEIN 4 PLAYS A CENTRAL ROLE IN COORDINATING THE COMPLEX EPIGENETIC COMPONENT OF THE INNATE IMMUNE RESPONSE. PREVIOUS STUDIES IMPLICATED BRD4 AS A COMPONENT OF A CHROMATIN-MODIFYING COMPLEX THAT IS DYNAMICALLY RECRUITED TO A NETWORK OF PROTECTIVE CYTOKINES BY BINDING ACTIVATED TRANSCRIPTION FACTORS, POLYMERASES, AND HISTONES TO TRIGGER THEIR RAPID EXPRESSION VIA TRANSCRIPTIONAL ELONGATION. OUR PREVIOUS STUDY EXTENDED OUR UNDERSTANDING OF THE AIRWAY EPITHELIAL BRD4 INTERACTOME BY IDENTIFYING OVER 100 FUNCTIONALLY IMPORTANT COACTIVATORS AND TRANSCRIPTION FACTORS, WHOSE ASSOCIATION IS INDUCED BY RESPIRATORY SYNCYTIAL VIRUS (RSV) INFECTION. RSV IS AN ETIOLOGICAL AGENT OF RECURRENT RESPIRATORY TRACT INFECTIONS ASSOCIATED WITH EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE. USING A HIGHLY SELECTIVE SMALL-MOLECULE BRD4 INHIBITOR (ZL0454) DEVELOPED BY US, WE EXTEND THESE FINDINGS TO IDENTIFY THE GENE REGULATORY NETWORK DEPENDENT ON BRD4 BROMODOMAIN (BD) INTERACTIONS. HUMAN SMALL AIRWAY EPITHELIAL CELLS WERE INFECTED IN THE ABSENCE OR PRESENCE OF ZL0454, AND GENE EXPRESSION PROFILING WAS PERFORMED. A HIGHLY REPRODUCIBLE DATASET WAS OBTAINED WHICH INDICATED THAT BRD4 MEDIATES BOTH ACTIVATION AND REPRESSION OF RSV-INDUCIBLE GENE REGULATORY NETWORKS CONTROLLING CYTOKINE EXPRESSION, INTERFERON (IFN) PRODUCTION, AND EXTRACELLULAR MATRIX REMODELING. INDEX GENES OF FUNCTIONALLY SIGNIFICANT CLUSTERS WERE VALIDATED INDEPENDENTLY. WE DISCOVER THAT BRD4 REGULATES THE EXPRESSION OF ITS OWN GENE DURING THE INNATE IMMUNE RESPONSE. INTERESTINGLY, BRD4 ACTIVATES THE EXPRESSION OF NFKAPPAB/RELA, A COACTIVATOR THAT BINDS TO BRD4 IN A BD-DEPENDENT MANNER. WE EXTEND THIS FINDING TO SHOW THAT BRD4 ALSO REGULATES OTHER COMPONENTS OF ITS FUNCTIONAL INTERACTOME, INCLUDING THE MEDIATOR (MED) COACTIVATOR COMPLEX AND THE SWI/SNF-RELATED, MATRIX-ASSOCIATED, ACTIN-DEPENDENT REGULATOR OF CHROMATIN (SMARC) SUBUNITS. TO PROVIDE FURTHER INSIGHT INTO MECHANISMS FOR BRD4 IN RSV EXPRESSION, WE MAPPED 7,845 RSV-INDUCIBLE TN5 TRANSPOSASE PEAKS ONTO THE BRD4-DEPENDENT GENE BODIES. THESE WERE LOCATED IN PROMOTERS AND INTRONS OF CYTOSTRUCTURAL AND EXTRACELLULAR MATRIX (ECM) FORMATION GENES. THESE DATA INDICATE THAT BRD4 MEDIATES THE DYNAMIC RESPONSE OF AIRWAY EPITHELIAL CELLS TO RNA INFECTION BY MODULATING THE EXPRESSION OF ITS COACTIVATORS, CONTROLLING THE EXPRESSION OF HOST DEFENSE MECHANISMS AND REMODELING GENES THROUGH CHANGES IN PROMOTER ACCESSIBILITY. 2021 5 5872 22 SUSTAINED TNF-ALPHA STIMULATION LEADS TO TRANSCRIPTIONAL MEMORY THAT GREATLY ENHANCES SIGNAL SENSITIVITY AND ROBUSTNESS. TRANSCRIPTIONAL MEMORY ALLOWS CERTAIN GENES TO RESPOND TO PREVIOUSLY EXPERIENCED SIGNALS MORE ROBUSTLY. HOWEVER, WHETHER AND HOW THE KEY PROINFLAMMATORY CYTOKINE TNF-ALPHA MEDIATES TRANSCRIPTIONAL MEMORY ARE POORLY UNDERSTOOD. USING HEK293F CELLS AS A MODEL SYSTEM, WE REPORT THAT SUSTAINED TNF-ALPHA STIMULATION INDUCES TRANSCRIPTIONAL MEMORY DEPENDENT ON TET ENZYMES. THE HYPOMETHYLATED STATUS OF TRANSCRIPTIONAL REGULATORY REGIONS CAN BE INHERITED, FACILITATING NF-KAPPAB BINDING AND MORE ROBUST SUBSEQUENT ACTIVATION. A HIGH INITIAL METHYLATION LEVEL AND CPG DENSITY AROUND KAPPAB SITES ARE CORRELATED WITH THE FUNCTIONAL POTENTIAL OF TRANSCRIPTIONAL MEMORY MODULES. INTERESTINGLY, THE CALCB GENE, ENCODING THE PROVEN MIGRAINE THERAPEUTIC TARGET CGRP, EXHIBITS THE BEST TRANSCRIPTIONAL MEMORY. A NEIGHBORING PRIMATE-SPECIFIC ENDOGENOUS RETROVIRUS STIMULATES MORE RAPID, MORE STRONG, AND AT LEAST 100-FOLD MORE SENSITIVE CALCB INDUCTION IN SUBSEQUENT TNF-ALPHA STIMULATION. OUR STUDY REVEALS THAT TNF-ALPHA-MEDIATED TRANSCRIPTIONAL MEMORY IS GOVERNED BY ACTIVE DNA DEMETHYLATION AND GREATLY SENSITIZES MEMORY GENES TO MUCH LOWER DOSES OF INFLAMMATORY CUES. 2020 6 2312 30 EPIGENETIC REGULATION OF DENDRITIC CELL-DERIVED INTERLEUKIN-12 FACILITATES IMMUNOSUPPRESSION AFTER A SEVERE INNATE IMMUNE RESPONSE. PATIENTS WHO SURVIVE SEPSIS HAVE SIGNIFICANT DEFICIENCIES IN THEIR IMMUNE RESPONSES CAUSED BY POORLY UNDERSTOOD MECHANISMS. WE HAVE EXPLORED THIS PHENOMENON BY STUDYING DENDRITIC CELLS (DCS) RECOVERED FROM ANIMALS SURVIVING SEVERE PERITONITIS-INDUCED SEPSIS, USING THE WELL-ESTABLISHED CECAL LIGATION AND PUNCTURE (CLP) MODEL. IMMEDIATELY AFTER THE INITIATION OF SEPSIS THERE IS A DEPLETION IN DCS FROM THE LUNG AND SPLEEN, WHICH IS FOLLOWED BY REPOPULATION OF THESE CELLS BACK TO THE RESPECTIVE ORGANS. DCS RECOVERED FROM SURVIVING ANIMALS EXHIBITED A SIGNIFICANT AND CHRONIC SUPPRESSION OF INTERLEUKIN-12 (IL-12), A KEY HOST DEFENSE CYTOKINE. THE SUPPRESSION OF DC-DERIVED IL-12 PERSISTED FOR AT LEAST 6 WEEKS AFTER CLP AND WAS NOT DUE TO IMMUNOREGULATORY CYTOKINES, SUCH AS IL-10. USING CHROMATIN IMMUNOPRECIPITATION (CHIP) TECHNIQUES, WE HAVE SHOWN THAT THE DEFICIENCY IN DC-DERIVED IL-12 WAS DUE TO EPIGENETIC ALTERATIONS. SPECIFICALLY, IL-12 EXPRESSION WAS REGULATED BY STABLE RECIPROCAL CHANGES IN HISTONE H3 LYSINE-4 TRIMETHYLATION (H3K4ME3) AND HISTONE H3 LYSINE-27 DIMETHYLATION (H3K27ME2), AS WELL AS CHANGES IN COGNATE HISTONE METHYLTRANSFERASE (HMT) COMPLEXES ON THE IL12P35 AND IL12P40 PROMOTERS. THESE DATA IMPLICATE HISTONE MODIFICATION ENZYMES IN SUPPRESSING DC-DERIVED IL-12, WHICH MAY PROVIDE ONE OF THE MECHANISMS OF LONG-TERM IMMUNOSUPPRESSION SUBSEQUENT TO THE SEPTIC RESPONSE. 2008 7 2389 39 EPIGENETIC REPOLARIZATION OF T LYMPHOCYTES FROM CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS USING 5-AZA-2'-DEOXYCYTIDINE. T CELL IMMUNE DYSFUNCTION HAS AN IMPORTANT ROLE IN THE PROFOUND IMMUNE SUPPRESSION THAT CHARACTERIZES CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). IMPROPER POLARIZATION OF T CELLS HAS BEEN PROPOSED AS ONE OF THE MECHANISM INVOLVED. MOUNTING DATA IMPLICATES CHROMATIN REGULATION, NAMELY PROMOTER METHYLATION, IN THE PLASTICITY OF NAIVE HUMAN T CELLS. RECENT IN VITRO EVIDENCE INDICATES THAT THIS PLASTICITY MAY BE PHENOTYPICALLY ALTERED BY USING METHYLATION INHIBITORS WHICH ARE APPROVED FOR CLINICAL USE IN CERTAIN TYPES OF CANCER. THESE RESULTS BEG THE QUESTION: CAN THE INEFFECTIVE POLARIZATION OF T LYMPHOCYTES IN THE CONTEXT OF CLL BE EFFECTIVELY MODULATED USING METHYLATION INHIBITORS IN A SUSTAINABLE THERAPEUTIC FASHION? TO ANSWER THIS QUESTION OUR LABORATORY HAS STUDIED THE EFFECTS OF 5-AZA-2'-DEOXYCYTIDINE (5A2) IN HELPER AND CYTOTOXIC T LYMPHOCYTES FROM HEALTHY DONORS AND CLL PATIENTS IN WELL CHARACTERIZED MOLECULAR AND EPIGENETIC SIGNALING PATHWAYS INVOLVED IN EFFECTIVE POLARIZATION. MOREOVER, WE SOUGHT TO INVESTIGATE THE CONSEQUENCES OF METHYLATION INHIBITOR TREATMENT ON LYMPHOCYTE SURVIVAL, ACTIVATION INTENSITY, AND NAIVE CELL POLARIZATION. OUR DATA INDICATES THAT 5A2 TREATMENT CAN DEPOLARIZE TH2 CELLS TO EFFECTIVELY SECRETE INTERFERON GAMMA, SIGNAL VIA T-BET, AND ACHIEVE DEMETHYLATION OF CRITICAL TH1 SPECIFIC PROMOTERS. MOREOVER, WE DEMONSTRATE THAT 5A2 CAN FORCE TH1 POLARIZATION OF NAIVE T CELLS DESPITE A STRONG IL-4 STIMULI AND A LACK OF IL-12. IN CONCLUSION OUR DATA SEEKS TO DEFINE A MODALITY IN WHICH IMPROPER OR INEFFECTIVE T CELL POLARIZATION CAN BE ALTERED BY 5AZA AND COULD BE INCORPORATED IN FUTURE THERAPEUTIC INTERVENTIONS. 2011 8 2247 26 EPIGENETIC MODULATION OF MACROPHAGE POLARIZATION PREVENTS LUMBAR DISC DEGENERATION. INFLAMMATION PLAYS AN ESSENTIAL ROLE IN THE DEVELOPMENT OF LUMBAR DISC DEGENERATION (LDD), ALTHOUGH THE EXACT EFFECTS OF MACROPHAGE SUBTYPES ON LDD REMAIN UNCLEAR. BASED ON PREVIOUS STUDIES, WE HYPOTHESIZED THAT M2-POLARIZATION OF LOCAL MACROPHAGES AND SIMULTANEOUS SUPPRESSION OF THEIR PRODUCTION OF FIBROTIC TRANSFORMING GROWTH FACTOR BETA 1 (TGFBETA1) COULD INHIBIT PROGRESSION OF LDD. THUS, WE APPLIED AN ORTHOTOPIC INJECTION OF ADENO-ASSOCIATED VIRUS (AAV) CARRYING SHRNA FOR DNA METHYLTRANSFERASE 1 (DNMT1) AND/OR SHRNA FOR TGFBETA1 UNDER A MACROPHAGE-SPECIFIC CD68 PROMOTER TO SPECIFICALLY TARGET LOCAL MACROPHAGES IN A MOUSE MODEL FOR LDD. WE FOUND THAT SHDNMT1 SIGNIFICANTLY REDUCED LEVELS OF THE PRO-INFLAMMATORY CYTOKINES TNFALPHA, IL-1BETA AND IL-6, SIGNIFICANTLY INCREASED LEVELS OF THE ANTI-INFLAMMATORY CYTOKINES IL-4 AND IL-10, SIGNIFICANTLY INCREASED M2 MACROPHAGE POLARIZATION, SIGNIFICANTLY REDUCED CELL APOPTOSIS IN THE DISC DEGENERATION ZONE AND SIGNIFICANTLY REDUCED LDD-ASSOCIATED PAIN. THE ANTI-APOPTOTIC AND ANTI-PAIN EFFECTS WERE FURTHER STRENGTHENED BY CO-APPLICATION OF SHTGFBETA1. TOGETHER, THESE DATA SUGGEST THAT M2 POLARIZATION OF MACROPHAGES INDUCED BY BOTH EPIGENETIC MODULATION AND SUPPRESSED PRODUCTION AND RELEASE OF TGFBETA1 FROM POLARIZED M2 MACROPHAGES, MAY HAVE A DEMONSTRABLE THERAPEUTIC EFFECT ON LDD. 2020 9 3948 41 LNCRNA-CD160 DECREASES THE IMMUNITY OF CD8(+) T CELLS THROUGH EPIGENETIC MECHANISMS IN HEPATITIS B VIRUS INFECTION. THE TRANSFER AND DEVELOPMENT OF CHRONIC HEPATITIS B VIRUS (HBV) INFECTION IS ASSOCIATED WITH THE T CELL IMMUNE RESPONSE, THEREFORE INVESTIGATING THE KEY REGULATORS OF CELL IMMUNE RESPONSE IS NEEDED TO IMPROVE CHRONIC HBV TREATMENT. BLOOD SAMPLES FROM PATIENTS WITH CHRONIC HBV INFECTION WERE USED TO CONFIRM THE CORRELATION BETWEEN HBV INFECTION STAGE AND CD160 RECEPTOR EXPRESSION LEVELS IN CD8(+) T CELLS, THE CD8(+) T CELLS ARE USED TO RESEARCH THE MECHANISM OF T CELL IMMUNE RESPONSE MODULATION, MOREOVER, C3H/HEN MICE WITH REDUCED CD160 EXPRESSION LEVELS WERE USED TO INVESTIGATE THE ASSOCIATION BETWEEN LONG NON-CODING (LNC)RNA-CD160 AND HBV INFECTION. LONG NON-CODING (LNC)RNA-CD160 AND HISTONE-MODIFICATION ENZYME GENE HISTONE DEACETYLASE 11 (HDAC11) EXPRESSION LEVELS WERE NEGATIVELY ASSOCIATED WITH CD160 EXPRESSION. LNCRNA-CD160 CAN INHIBIT THE SECRETION OF IFN-GAMMA AND TNF-ALPHA THROUGH HDAC11 RECRUITMENT AND BIND TO HDAC11 TO FORM A COMPLEX ON THE PROMOTERS OF IFN-GAMMA AND TNF-ALPHA. THE HDAC11, IFN-GAMMA AND TNF-ALPHA FORM A COMPLEX AND ENHANCE THE METHYLATION OF H3K9ME1, CHROMATIN CHANGES INTO THE HETEROCHROMATIN AND THE TRANSCRIPTION OF IFN-GAMMA AND TNF-ALPHA IS BLOCKED; MOREOVER, THE HDAC11/IFN-GAMMA/TNF-ALPHA COMPLEX CAN ALSO INHIBIT THE SECRETION OF IFN-GAMMA AND TNF-ALPHA IN CD160(-) CD8(+) T CELLS AND SUPPRESSES THE FUNCTION OF CD8(+) T CELLS. FURTHERMORE, SMALL INTERFERING RNA TARGETING LNCRNA-CD160 CAN BLOCK HBV INFECTION PROGRESSION. LNCRNA-CD160 ACTS AS AN IMMUNE SUPPRESSIVE FACTOR AND IS EXPRESSED AT A HIGH LEVEL IN PERIPHERAL BLOOD CD8(+) T CELLS OF HBV INFECTED PATIENTS. FURTHERMORE, HIGH EXPRESSION LEVELS OF LNCRNA-CD160 CAN CONTRIBUTE TO THE INHIBITION OF IFN-GAMMA AND TNF-ALPHA SECRETION IN CD8(+) T CELLS AND DECREASE THE IMMUNE RESPONSE OF CD8(+) T CELLS. THEREFORE, LNCRNA-CD160 MAY BECOME A NEW TARGET FOR IMMUNOTHERAPY OF CHRONIC HBV INFECTION IN THE FUTURE AND MAY PROVIDE A NEW THERAPEUTIC STRATEGY FOR THE TREATMENT OF HBV INFECTION. 2020 10 3527 28 IL-6 ENHANCES THE NUCLEAR TRANSLOCATION OF DNA CYTOSINE-5-METHYLTRANSFERASE 1 (DNMT1) VIA PHOSPHORYLATION OF THE NUCLEAR LOCALIZATION SEQUENCE BY THE AKT KINASE. THE EPIGENETIC PROGRAMMING OF GENOMIC DNA IS ACCOMPLISHED, IN PART, BY SEVERAL DNA CYTOSINE-5-METHYLTRANSFERASES THAT ACT BY COVALENTLY MODIFYING CYTOSINES WITH THE ADDITION OF A METHYL GROUP. THIS COVALENT MODIFICATION IS MAINTAINED BY THE DNA CYTOSINE-5-METHYLTRANSFERASE-1 ENZYME (DNMT1), WHICH IS CAPABLE OF ACTING IN CONCERT WITH OTHER SIMILAR ENZYMES TO SILENCE IMPORTANT TUMOR SUPPRESSOR GENES. IL-6 IS A MULTIFUNCTIONAL MEDIATOR OF INFLAMMATION, ACTING THROUGH SEVERAL MAJOR SIGNALING CASCADES, INCLUDING THE PHOSPHATIDYLINOSITOL-3-KINASE PATHWAY (PI-3-K), WHICH ACTIVATES PROTEIN KINASE B (AKT/PKB) DOWNSTREAM. HERE, WE SHOW THAT THE SUBCELLULAR LOCALIZATION OF DNMT1 CAN BE ALTERED BY THE ADDITION OF IL-6, INCREASING THE RATE OF NUCLEAR TRANSLOCATION OF THE ENZYME FROM THE CYTOSOLIC COMPARTMENT. THE MECHANISM OF NUCLEAR TRANSLOCATION OF DNMT1 IS GREATLY ENHANCED BY PHOSPHORYLATION OF THE DNMT1 NUCLEAR LOCALIZATION SIGNAL (NLS) BY PKB/AKT KINASE. MUTAGENIC ALTERATION OF THE TWO AKT TARGET AMINO ACIDS WITHIN THE NLS RESULTS IN A MAJOR LOSS OF DNMT1 NUCLEAR TRANSLOCATION, WHILE THE CREATION OF A "PHOSPHO-MIMIC" AMINO ACID (MUTATION TO ACIDIC RESIDUES) RESTORES THIS COMPARTMENTATION ABILITY. THESE OBSERVATIONS SUGGEST AN INTERESTING HYPOTHESIS REGARDING HOW MEDIATORS OF CHRONIC INFLAMMATION MAY DISTURB THE DELICATE BALANCE OF CELLULAR COMPARTMENTALIZATION OF IMPORTANT PROTEINS, AND REVEALS A POTENTIAL MECHANISM FOR THE INDUCTION OR ENHANCEMENT OF TUMOR GROWTH VIA ALTERATION OF THE COMPONENTS INVOLVED IN THE EPIGENETIC PROGRAMMING OF A CELL. 2007 11 5088 34 PIPERLONGUMINE REGULATES EPIGENETIC MODULATION AND ALLEVIATES PSORIASIS-LIKE SKIN INFLAMMATION VIA INHIBITION OF HYPERPROLIFERATION AND INFLAMMATION. PSORIASIS IS AN AUTOIMMUNE SKIN DISEASE, WHERE CHRONIC IMMUNE RESPONSES DUE TO EXAGGERATED CYTOKINE SIGNALING, ABNORMAL DIFFERENTIATION, AND EVASION OF KERATINOCYTES APOPTOSIS PLAYS A CRUCIAL ROLE IN MEDIATING ABNORMAL KERATINOCYTES HYPERPROLIFERATION. FROM THE THERAPEUTIC PERSPECTIVE, THE MOLECULES WITH STRONG ANTI-PROLIFERATIVE AND ANTI-INFLAMMATORY PROPERTIES COULD HAVE TREMENDOUS RELEVANCE. IN THIS STUDY, WE DEMONSTRATED THAT PIPERLONGUMINE (PPL) TREATMENT EFFECTIVELY ABROGATED THE HYPERPROLIFERATION AND DIFFERENTIATION OF KERATINOCYTES BY INDUCING ROS-MEDIATED LATE APOPTOSIS WITH LOSS OF MITOCHONDRIAL MEMBRANE POTENTIAL. BESIDES, THE ARREST OF CELL CYCLE WAS FOUND AT SUB-G1 PHASE AS A RESULT OF DNA FRAGMENTATION. MOLECULARLY, INHIBITION OF STAT3 AND AKT SIGNALING WAS OBSERVED WITH A DECREASE IN PROLIFERATIVE MARKERS SUCH AS PCNA, KI67, AND CYCLIN D1 ALONG WITH ANTI-APOPTOTIC BCL-2 PROTEIN EXPRESSION. KERATIN 17 IS A CRITICAL REGULATOR OF KERATINOCYTE DIFFERENTIATION, AND IT WAS FOUND TO BE DOWNREGULATED WITH PPL SIGNIFICANTLY. FURTHERMORE, PROMINENT ANTI-INFLAMMATORY EFFECTS WERE OBSERVED BY INHIBITION OF LIPOPOLYSACCHARIDE (LPS)/IMIQUIMOD (IMQ)-INDUCED P65 NF-KAPPAB SIGNALING CASCADE AND STRONGLY INHIBITED THE PRODUCTION OF CYTOKINE STORM INVOLVED IN PSORIASIS-LIKE SKIN INFLAMMATION, THUS LED TO THE RESTORATION OF NORMAL EPIDERMAL ARCHITECTURE WITH REDUCTION OF EPIDERMAL HYPERPLASIA AND SPLENOMEGALY. IN ADDITION, PPL EPIGENETICALLY INHIBITED HISTONE-MODIFYING ENZYMES, WHICH INCLUDE HISTONE DEACETYLASES (HDACS) OF CLASS I (HDAC1-4) AND CLASS II (HDAC6) EVALUATED BY IMMUNOBLOTTING AND HDAC ENZYME ASSAY KIT. IN ADDITION, OUR RESULTS SHOW THAT PPL EFFECTIVELY INHIBITS THE NUCLEAR TRANSLOCATION OF P65 AND A HISTONE MODULATOR HDAC3, THUS SEQUESTERED IN THE CYTOPLASM OF MACROPHAGES. FURTHERMORE, PPL EFFECTIVELY ENHANCED THE PROTEIN-PROTEIN INTERACTIONS OF HDAC3 AND P65 WITH IKAPPABALPHA, WHICH WAS DISRUPTED BY LPS STIMULATION AND WERE EVALUATED BY CO-IP AND MOLECULAR MODELING. COLLECTIVELY, OUR FINDINGS INDICATE THAT PIPERLONGUMINE MAY SERVE AS AN ANTI-PROLIFERATIVE AND ANTI-INFLAMMATORY AGENT AND COULD SERVE AS A POTENTIAL THERAPEUTIC OPTION IN TREATING PSORIASIS. 2020 12 164 29 ABNORMAL HISTONE METHYLATION IS RESPONSIBLE FOR INCREASED VASCULAR ENDOTHELIAL GROWTH FACTOR 165A SECRETION FROM AIRWAY SMOOTH MUSCLE CELLS IN ASTHMA. VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF), A KEY ANGIOGENIC MOLECULE, IS ABERRANTLY EXPRESSED IN SEVERAL DISEASES INCLUDING ASTHMA WHERE IT CONTRIBUTES TO BRONCHIAL VASCULAR REMODELING AND CHRONIC INFLAMMATION. ASTHMATIC HUMAN AIRWAY SMOOTH MUSCLE CELLS HYPERSECRETE VEGF, BUT THE MECHANISM IS UNCLEAR. IN THIS STUDY, WE DEFINED THE MECHANISM IN HUMAN AIRWAY SMOOTH MUSCLE CELLS FROM NONASTHMATIC AND ASTHMATIC PATIENTS. WE FOUND THAT ASTHMATIC CELLS LACKED A REPRESSION COMPLEX AT THE VEGF PROMOTER, WHICH WAS PRESENT IN NONASTHMATIC CELLS. RECRUITMENT OF G9A, TRIMETHYLATION OF HISTONE H3 AT LYSINE 9 (H3K9ME3), AND A RESULTANT DECREASE IN RNA POLYMERASE II AT THE VEGF PROMOTER WAS CRITICAL TO REPRESSION OF VEGF SECRETION IN NONASTHMATIC CELLS. AT THE ASTHMATIC PROMOTER, H3K9ME3 WAS ABSENT BECAUSE OF FAILED RECRUITMENT OF G9A; RNA POLYMERASE II BINDING, IN ASSOCIATION WITH TATA-BINDING PROTEIN-ASSOCIATED FACTOR 1, WAS INCREASED; H3K4ME3 WAS PRESENT; AND SP1 BINDING WAS EXAGGERATED AND SUSTAINED. IN CONTRAST, DNA METHYLATION AND HISTONE ACETYLATION WERE SIMILAR IN ASTHMATIC AND NONASTHMATIC CELLS. THIS IS THE FIRST STUDY, TO OUR KNOWLEDGE, TO SHOW THAT AIRWAY CELLS IN ASTHMA HAVE ALTERED EPIGENETIC REGULATION OF REMODELING GENE(S). HISTONE METHYLATION AT GENES SUCH AS VEGF MAY BE AN IMPORTANT NEW THERAPEUTIC TARGET. 2012 13 1618 35 DNA METHYLTRANSFERASE INHIBITORS INCREASE NOD-LIKE RECEPTOR ACTIVITY AND EXPRESSION IN A MONOCYTIC CELL LINE. BACKGROUND: THE INTRACELLULAR NOD-LIKE RECEPTOR (NLR) FAMILY OF PATHOGEN RECOGNITION RECEPTORS (PRRA) IS INVOLVED IN INITIATING THE INNATE IMMUNE RESPONSE OF WHICH NOD1 AND NOD2 ARE THE BEST-CHARACTERIZED MEMBERS. ABERRANT EXPRESSION OF NOD1 AND NOD2 HAS BEEN UNCOVERED IN A NUMBER OF CHRONIC INFLAMMATORY DISEASES, SUCH AS INFLAMMATORY BOWEL DISEASE AND RHEUMATOID ARTHRITIS. HOWEVER, THE MECHANISM UNDERLYING NOD1/NOD2 GENE EXPRESSION REGULATION IS STILL IN ITS INFANCY. EPIGENETIC MODIFICATIONS SUCH AS DNA METHYLATION AND HISTONE ACETYLATION REGULATE THE EXPRESSION OF GENES AND ALTERATIONS IN THEIR PATTERNS HAVE BEEN LINKED TO MANY INFLAMMATORY DISEASES. THIS STUDY INVESTIGATED WHETHER EPIGENETIC MODIFYING DRUGS AFFECT THE REGULATION OF NOD1/NOD2 ACTIVITY AND EXPRESSION. DNA METHYLTRANSFERASE INHIBITORS HAVE RECENTLY BEEN USED IN THE TREATMENT OF MYELODYSPLASTIC SYNDROME AND AS COMBINATION THERAPY IN CANCER BUT THE FULL EXTENT OF THEIR EFFECTS HAS NOT BEEN QUANTIFIED.METHODS: PHARMACOLOGICAL INHIBITION OF EPIGENETIC ENZYMES IN A HUMAN MONOCYTIC THP-1 CELL LINE WAS CARRIED OUT AND NOD1/NOD2 EXPRESSION AND PRO-INFLAMMATORY RESPONSES WERE QUANTIFIED.RESULTS: CELLS PRIMED WITH A DNA METHYLTRANSFERASE INHIBITOR (BUT NOT A HISTONE DEACETYLASE [HDAC] INHIBITOR) WERE FOUND TO BE CONSISTENTLY MORE RESPONSIVE TO NOD1/NOD2 STIMULATION AND HAD INCREASED BASAL EXPRESSION.CONCLUSION: THE NOVEL EXPERIMENTATION CARRIED OUT HERE SUGGESTS FOR THE FIRST TIME THAT NOD1/NOD2 RECEPTOR ACTIVITY AND EXPRESSION IN MONOCYTES ARE POSSIBLY REGULATED DIRECTLY BY DNA METHYLATION. 2022 14 5972 23 TET REPRESSION AND INCREASED DNMT ACTIVITY SYNERGISTICALLY INDUCE ABERRANT DNA METHYLATION. CHRONIC INFLAMMATION IS DEEPLY INVOLVED IN VARIOUS HUMAN DISORDERS, SUCH AS CANCER, NEURODEGENERATIVE DISORDERS, AND METABOLIC DISORDERS. INDUCTION OF EPIGENETIC ALTERATIONS, ESPECIALLY ABERRANT DNA METHYLATION, IS ONE OF THE MAJOR MECHANISMS, BUT HOW IT IS INDUCED IS STILL UNCLEAR. HERE, WE FOUND THAT EXPRESSION OF TET GENES, METHYLATION ERASERS, WAS DOWNREGULATED IN INFLAMED MOUSE AND HUMAN TISSUES, AND THAT THIS WAS CAUSED BY UPREGULATION OF TET-TARGETING MIRNAS SUCH AS MIR20A, MIR26B, AND MIR29C, LIKELY DUE TO ACTIVATION OF NF-KAPPAB SIGNALING DOWNSTREAM OF IL-1BETA AND TNF-ALPHA. HOWEVER, TET KNOCKDOWN INDUCED ONLY MILD ABERRANT METHYLATION. NITRIC OXIDE (NO), PRODUCED BY NOS2, ENHANCED ENZYMATIC ACTIVITY OF DNA METHYLTRANSFERASES (DNMTS), METHYLATION WRITERS, AND NO EXPOSURE INDUCED MINIMAL ABERRANT METHYLATION. IN CONTRAST, A COMBINATION OF TET KNOCKDOWN AND NO EXPOSURE SYNERGISTICALLY INDUCED ABERRANT METHYLATION, INVOLVING GENOMIC REGIONS NOT METHYLATED BY EITHER ALONE. THE RESULTS SHOWED THAT A VICIOUS COMBINATION OF TET REPRESSION, DUE TO NF-KAPPAB ACTIVATION, AND DNMT ACTIVATION, DUE TO NO PRODUCTION, IS RESPONSIBLE FOR ABERRANT METHYLATION INDUCTION IN HUMAN TISSUES. 2020 15 5223 51 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 16 5114 34 PORPHYROMONAS GINGIVALIS LIPOPOLYSACCHARIDE STIMULATION IN HUMAN PERIODONTAL LIGAMENT STEM CELLS: ROLE OF EPIGENETIC MODIFICATIONS TO THE INFLAMMATION. PERIODONTITIS IS A CHRONIC ORAL INFLAMMATORY DISEASE PRODUCED BY BACTERIA. GINGIVAL RETRACTION AND BONE AND CONNECTIVE TISSUES RESORPTION ARE THE HALLMARKS OF THIS DISEASE. CHRONIC PERIODONTITIS MAY CONTRIBUTE TO THE RISK OF ONSET OR PROGRESSION OF NEUROINFLAMMATORY PATHOLOGICAL CONDITIONS, SUCH AS ALZHEIMER'S DISEASE. THE MAIN GOAL OF THE PRESENT STUDY WAS TO INVESTIGATE IF THE ROLE OF EPIGENETIC MODULATIONS IS INVOLVED IN PERIODONTITIS USING HUMAN PERIODONTAL LIGAMENT STEM CELLS (HPDLSCS) AS AN IN VITRO MODEL SYSTEM. HPDLSCS WERE TREATED WITH LIPOPOLYSACCHARIDE OF PORPHYROMONAS GINGIVALIS AND THE EXPRESSION OF PROTEINS ASSOCIATED WITH DNA METHYLATION AND HISTONE ACETYLATION, SUCH AS DNMT1 AND P300, RESPECTIVELY, AND INFLAMMATORY TRANSCRIPTION FACTOR NF-KB, WERE EXAMINED. IMMUNOFLUORESCENCE, WESTERN BLOT AND NEXT GENERATION SEQUENCING RESULTS DEMONSTRATED THAT P. GINGIVALIS LIPOPOLYSACCHARIDE SIGNIFICANTLY REDUCED DNA METHYLASE DNMT1, WHILE IT MARKEDLY UPREGULATED THE LEVEL OF HISTONE ACETYLTRANSFERASE P300 AND NF-KB IN HPDLSCS. OUR RESULTS SHOWED THAT P. GINGIVALIS LIPOPOLYSACCHARIDE MARKEDLY REGULATE THE GENES INVOLVED IN EPIGENETIC MECHANISM, WHICH MAY RESULT IN INFLAMMATION INDUCTION. WE PROPOSE THAT P. GINGIVALIS LIPOPOLYSACCHARIDE-TREATED HPDLSCS COULD BE A POTENTIAL IN VITRO MODEL SYSTEM TO STUDY EPIGENETICS MODULATIONS ASSOCIATED WITH PERIODONTITIS, WHICH MIGHT BE HELPFUL TO IDENTIFY NOVEL BIOMARKERS LINKED TO THIS ORAL INFLAMMATORY DISEASE. 2017 17 5982 33 TET2 REGULATES IMMUNE TOLERANCE IN CHRONICALLY ACTIVATED MAST CELLS. MUTATION OF THE TET2 DNA-HYDROXYMETHYLASE HAS BEEN ASSOCIATED WITH A NUMBER OF IMMUNE PATHOLOGIES. THE DISPARITY IN PHENOTYPE AND CLINICAL PRESENTATION AMONG THESE PATHOLOGIES LEADS TO QUESTIONS REGARDING THE ROLE OF TET2 MUTATION IN PROMOTING DISEASE EVOLUTION IN DIFFERENT IMMUNE CELL TYPES. HERE WE SHOW THAT, IN PRIMARY MAST CELLS, TET2 EXPRESSION IS INDUCED IN RESPONSE TO CHRONIC AND ACUTE ACTIVATION SIGNALS. IN TET2-DEFICIENT MAST CELLS, CHRONIC ACTIVATION VIA THE ONCOGENIC KITD816V ALLELE ASSOCIATED WITH MASTOCYTOSIS, SELECTS FOR A SPECIFIC EPIGENETIC SIGNATURE CHARACTERIZED BY HYPERMETHYLATED DNA REGIONS (HMR) AT IMMUNE RESPONSE GENES. H3K27AC AND TRANSCRIPTION FACTOR BINDING IS CONSISTENT WITH PRIMING OR MORE OPEN CHROMATIN AT BOTH HMR AND NON-HMR IN PROXIMITY TO IMMUNE GENES IN THESE CELLS, AND THIS SIGNATURE COINCIDES WITH INCREASED PATHOLOGICAL INFLAMMATION SIGNALS. HMR ARE ALSO ASSOCIATED WITH A SUBSET OF IMMUNE GENES THAT ARE DIRECT TARGETS OF TET2 AND REPRESSED IN TET2-DEFICIENT CELLS. REPRESSION OF THESE GENES RESULTS IN IMMUNE TOLERANCE TO ACUTE STIMULATION THAT CAN BE RESCUED WITH VITAMIN C TREATMENT OR REITERATED WITH A TET INHIBITOR. OVERALL, OUR DATA SUPPORT A MODEL WHERE TET2 PLAYS A DIRECT ROLE IN PREVENTING IMMUNE TOLERANCE IN CHRONICALLY ACTIVATED MAST CELLS, SUPPORTING TET2 AS A VIABLE TARGET TO REPROGRAM THE INNATE IMMUNE RESPONSE FOR INNOVATIVE THERAPIES. 2022 18 6057 26 THE DARK SIDE OF REGULATORY T CELLS IN PSORIASIS. PSORIASIS IS A HEREDITARY DISEASE ELICITED BY CHRONIC ACTIVATION OF CUTANEOUS T CELLS. DELINEATING THE MECHANISTIC INTERPLAY OF THE CELL SUBSETS INVOLVED IS KEY TO DEVELOPING THE NEXT GENERATION OF EFFECTIVE TREATMENTS. IN THIS ISSUE, BOVENSCHEN ET AL. REPORT THAT REGULATORY T CELLS MAINTAIN A FINE BALANCE BETWEEN THE TRANSCRIPTION FACTORS FOXP3 AND RORGAMMAT. IN PATIENTS WITH PSORIASIS, TREGS READILY TURN INTO IL-17-EXPRESSING CELLS, THUS POTENTIALLY PERPETUATING THE INFLAMMATORY PROCESS THAT CHARACTERIZES THE DISEASE. RESULTS DEMONSTRATING THAT THE HISTONE/PROTEIN DEACETYLATION INHIBITOR TRICHOSTATIN A CAN BLOCK THIS CONVERSION SUGGEST THAT AN EPIGENETIC MODIFICATION MAY UNDERLIE REGULATORY T-CELL PLASTICITY. 2011 19 5920 32 TARGETING CHROMATIN REMODELING IN INFLAMMATION AND FIBROSIS. MUCOSAL SURFACES OF THE HUMAN BODY ARE LINED BY A CONTIGUOUS EPITHELIAL CELL SURFACE THAT FORMS A BARRIER TO AEROSOLIZED PATHOGENS. SPECIALIZED PATTERN RECOGNITION RECEPTORS DETECT THE PRESENCE OF VIRAL PATHOGENS AND INITIATE PROTECTIVE HOST RESPONSES BY TRIGGERING ACTIVATION OF THE NUCLEAR FACTOR KAPPAB (NFKAPPAB)/RELA TRANSCRIPTION FACTOR AND FORMATION OF A COMPLEX WITH THE POSITIVE TRANSCRIPTION ELONGATION FACTOR (P-TEFB)/CYCLIN-DEPENDENT KINASE (CDK)9 AND BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) EPIGENETIC READER. THE RELA.BRD4.P-TEFB COMPLEX PRODUCES ACUTE INFLAMMATION BY REGULATING TRANSCRIPTIONAL ELONGATION, WHICH PRODUCES A RAPID GENOMIC RESPONSE BY INACTIVE GENES MAINTAINED IN AN OPEN CHROMATIN CONFIGURATION ENGAGED WITH HYPOPHOSPHORYLATED RNA POLYMERASE II. WE DESCRIBE RECENT STUDIES THAT HAVE LINKED PROLONGED ACTIVATION OF THE RELA-BRD4 PATHWAY WITH THE EPITHELIAL-MESENCHYMAL TRANSITION (EMT) BY INDUCING A CORE OF EMT COREPRESSORS, STIMULATING SECRETION OF GROWTH FACTORS PROMOTING AIRWAY FIBROSIS. THE MESENCHYMAL STATE PRODUCES REWIRING OF THE KINOME AND REPROGRAMMING OF INNATE RESPONSES TOWARD INFLAMMATION. IN ADDITION, THE CORE REGULATOR ZINC FINGER E-BOX HOMEODOMAIN 1 (ZEB1) SILENCES THE EXPRESSION OF THE INTERFERON RESPONSE FACTOR 1 (IRF1), REQUIRED FOR TYPE III IFN EXPRESSION. THIS EPIGENETIC SILENCING IS MEDIATED BY THE ENHANCER OF ZESTE 2 (EZH2) HISTONE METHYLTRANSFERASE. BECAUSE OF THEIR POTENTIAL APPLICATIONS IN CANCER AND INFLAMMATION, SMALL-MOLECULE INHIBITORS OF NFKAPPAB/RELA, CDK9, BRD4, AND EZH2 HAVE BEEN THE TARGETS OF MEDICINAL CHEMISTRY EFFORTS. WE SUGGEST THAT DISRUPTION OF THE RELA.BRD4.P-TEFB PATHWAY AND EZH2 METHYLTRANSFERASE HAS IMPORTANT IMPLICATIONS FOR REVERSING FIBROSIS AND RESTORING NORMAL MUCOSAL IMMUNITY IN CHRONIC INFLAMMATORY DISEASES. 2017 20 1594 32 DNA METHYLATION PROFILING REVEALS DIFFERENCES IN THE 3 HUMAN MONOCYTE SUBSETS AND IDENTIFIES UREMIA TO INDUCE DNA METHYLATION CHANGES DURING DIFFERENTIATION. HUMAN MONOCYTES ARE A HETEROGENEOUS CELL POPULATION CONSISTING OF 3 SUBSETS: CLASSICAL CD14++CD16-, INTERMEDIATE CD14++CD16+ AND NONCLASSICAL CD14+CD16++ MONOCYTES. VIA POORLY CHARACTERIZED MECHANISMS, INTERMEDIATE MONOCYTE COUNTS RISE IN CHRONIC INFLAMMATORY DISEASES, AMONG WHICH CHRONIC KIDNEY DISEASE IS OF PARTICULAR EPIDEMIOLOGIC IMPORTANCE. DNA METHYLATION IS A CENTRAL EPIGENETIC FEATURE THAT CONTROLS HEMATOPOIESIS. BY APPLYING NEXT-GENERATION METHYL-SEQUENCING WE NOW TESTED HOW FAR THE 3 MONOCYTE SUBSETS DIFFER IN THEIR DNA METHYLOME AND WHETHER UREMIA INDUCES DNA METHYLATION CHANGES IN DIFFERENTIATING MONOCYTES. WE FOUND THAT EACH MONOCYTE SUBSET DISPLAYS A UNIQUE PHENOTYPE WITH REGARDS TO DNA METHYLATION. GENES WITH DIFFERENTIALLY METHYLATED PROMOTER REGIONS IN INTERMEDIATE MONOCYTES WERE LINKED TO DISTINCT IMMUNOLOGICAL PROCESSES, WHICH IS IN LINE WITH RESULTS FROM RECENT GENE EXPRESSION ANALYSES. IN VITRO, UREMIA INDUCED DYSREGULATION OF DNA METHYLATION IN DIFFERENTIATING MONOCYTES, WHICH AFFECTED SEVERAL TRANSCRIPTION REGULATORS IMPORTANT FOR MONOCYTE DIFFERENTIATION (E.G., FLT3, HDAC1, MNT) AND LED TO ENHANCED GENERATION OF INTERMEDIATE MONOCYTES. AS POTENTIAL MEDIATOR, THE UREMIC TOXIN AND METHYLATION INHIBITOR S-ADENOSYLHOMOCYSTEINE INDUCED SHIFTS IN MONOCYTE SUBSETS IN VITRO, AND ASSOCIATED WITH MONOCYTE SUBSET COUNTS IN VIVO. OUR DATA SUPPORT THE CONCEPT OF MONOCYTE TRICHOTOMY AND THE DISTINCT ROLE OF INTERMEDIATE MONOCYTES IN HUMAN IMMUNITY. THE SHIFT IN MONOCYTE SUBSETS THAT OCCURS IN CHRONIC KIDNEY DISEASE, A PROINFLAMMATORY CONDITION OF SUBSTANTIAL EPIDEMIOLOGICAL IMPACT, MAY BE INDUCED BY ACCUMULATION OF UREMIC TOXINS THAT MEDIATE EPIGENETIC DYSREGULATION. 2016