1 841 101 CHEMOKINES FORM NANOPARTICLES WITH DNA AND CAN SUPERINDUCE TLR-DRIVEN IMMUNE INFLAMMATION. CHEMOKINES CONTROL THE MIGRATORY PATTERNS AND POSITIONING OF IMMUNE CELLS TO ORGANIZE IMMUNE RESPONSES TO PATHOGENS. HOWEVER, MANY CHEMOKINES HAVE BEEN ASSOCIATED WITH SYSTEMIC AUTOIMMUNE DISEASES THAT HAVE CHRONIC IFN SIGNATURES. WE REPORT THAT A SERIES OF CHEMOKINES, INCLUDING CXCL4, CXCL10, CXCL12, AND CCL5, CAN SUPERINDUCE TYPE I IFN (IFN-I) BY TLR9-ACTIVATED PLASMACYTOID DCS (PDCS), INDEPENDENTLY OF THEIR RESPECTIVE KNOWN CHEMOKINE RECEPTORS. MECHANISTICALLY, WE SHOW THAT CHEMOKINES SUCH AS CXCL4 MEDIATE TRANSCRIPTIONAL AND EPIGENETIC CHANGES IN PDCS, MOSTLY TARGETED TO THE IFN-I PATHWAYS. WE DESCRIBE THAT CHEMOKINES PHYSICALLY INTERACT WITH DNA TO FORM NANOPARTICLES THAT PROMOTE CLATHRIN-MEDIATED CELLULAR UPTAKE AND DELIVERY OF DNA IN THE EARLY ENDOSOMES OF PDCS. USING TWO SEPARATE MOUSE MODELS OF SKIN INFLAMMATION, WE OBSERVED THE PRESENCE OF CXCL4 ASSOCIATED WITH DNA IN VIVO. THESE DATA REVEAL A NONCANONICAL ROLE FOR CHEMOKINES TO SERVE AS NUCLEIC ACID DELIVERY VECTORS TO MODULATE TLR SIGNALING, WITH IMPLICATIONS FOR THE CHRONIC PRESENCE OF IFN-I BY PDCS IN AUTOIMMUNE DISEASES. 2022 2 730 31 CANCER CELLS RESISTANT TO IMMUNE CHECKPOINT BLOCKADE ACQUIRE INTERFERON-ASSOCIATED EPIGENETIC MEMORY TO SUSTAIN T CELL DYSFUNCTION. PROLONGED INTERFERON (IFN) SIGNALING IN CANCER CELLS CAN PROMOTE RESISTANCE TO IMMUNE CHECKPOINT BLOCKADE (ICB). HOW CANCER CELLS RETAIN EFFECTS OF PROLONGED IFN STIMULATION TO COORDINATE RESISTANCE IS UNCLEAR. WE SHOW THAT, ACROSS HUMAN AND/OR MOUSE TUMORS, IMMUNE DYSFUNCTION IS ASSOCIATED WITH CANCER CELLS ACQUIRING EPIGENETIC FEATURES OF INFLAMMATORY MEMORY. HERE, INFLAMMATORY MEMORY DOMAINS, MANY OF WHICH ARE INITIATED BY CHRONIC IFN-GAMMA, ARE MAINTAINED BY SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION (STAT)1 AND IFN REGULATORY FACTOR (IRF)3 AND LINK HISTONE 3 LYSINE 4 MONOMETHYLATION (H3K4ME1)-MARKED CHROMATIN ACCESSIBILITY TO INCREASED EXPRESSION OF A SUBSET OF IFN-STIMULATED GENES (ISGS). THESE ISGS INCLUDE THE RNA SENSOR OAS1 THAT AMPLIFIES TYPE I IFN (IFN-I) AND IMMUNE INHIBITORY GENES. ABROGATING CANCER CELL IFN-I SIGNALING RESTORES ANTI-PROGRAMMED CELL DEATH PROTEIN 1 (PD1) RESPONSE BY INCREASING IFN-GAMMA IN IMMUNE CELLS, PROMOTING DENDRITIC CELL AND CD8(+) T CELL INTERACTIONS, AND EXPANDING T CELLS TOWARD EFFECTOR-LIKE STATES RATHER THAN EXHAUSTED STATES. THUS, CANCER CELLS ACQUIRE INFLAMMATORY MEMORY TO AUGMENT A SUBSET OF ISGS THAT PROMOTE AND PREDICT IFN-DRIVEN IMMUNE DYSFUNCTION. 2023 3 170 35 ABNORMALITIES OF THE TYPE I INTERFERON SIGNALING PATHWAY IN LUPUS AUTOIMMUNITY. TYPE I INTERFERONS (IFNS), MOSTLY IFNALPHA AND IFNBETA, AND THE TYPE I IFN SIGNATURE ARE IMPORTANT IN THE PATHOGENESIS OF SYSTEMIC LUPUS ERYTHEMATOSUS (SLE), AN AUTOIMMUNE CHRONIC CONDITION LINKED TO INFLAMMATION. BOTH IFNALPHA AND IFNBETA TRIGGER A SIGNALING CASCADE THAT, THROUGH THE ACTIVATION OF JAK1, TYK2, STAT1 AND STAT2, INITIATES GENE TRANSCRIPTION OF IFN STIMULATED GENES (ISGS). NOTEWORTHY, OTHER STAT FAMILY MEMBERS AND IFN RESPONSIVE FACTORS (IRFS) CAN ALSO CONTRIBUTE TO THE ACTIVATION OF THE IFN RESPONSE. ABERRANT TYPE I IFN SIGNALING, THEREFORE, CAN EXACERBATE SLE BY DEREGULATED HOMEOSTASIS LEADING TO UNNECESSARY PERSISTENCE OF THE BIOLOGICAL EFFECTS OF TYPE I IFNS. THE ETIOPATHOGENESIS OF SLE IS PARTIALLY KNOWN AND CONSIDERED MULTIFACTORIAL. FAMILY-BASED AND GENOME WIDE ASSOCIATION STUDIES (GWAS) HAVE IDENTIFIED GENETIC AND TRANSCRIPTIONAL ABNORMALITIES IN KEY MOLECULES DIRECTLY INVOLVED IN THE TYPE I IFN SIGNALING PATHWAY, NAMELY TYK2, STAT1 AND STAT4, AND IRF5. GAIN-OF-FUNCTION MUTATIONS THAT HEIGHTEN IFNALPHA/BETA PRODUCTION, WHICH IN TURN MAINTAINS TYPE I IFN SIGNALING, ARE FOUND IN OTHER PATHOLOGIES LIKE THE INTERFERONOPATHIES. HOWEVER, THE DISTINCTIVE CHARACTERISTICS HAVE YET TO BE DETERMINED. SIGNALING MOLECULES ACTIVATED IN RESPONSE TO TYPE I IFNS ARE UPREGULATED IN IMMUNE CELL SUBSETS AND AFFECTED TISSUES OF SLE PATIENTS. MOREOVER, TYPE I IFNS INDUCE CHROMATIN REMODELING LEADING TO A STATE PERMISSIVE TO TRANSCRIPTION, AND SLE PATIENTS HAVE INCREASED GLOBAL AND GENE-SPECIFIC EPIGENETIC MODIFICATIONS, SUCH AS HYPOMETHYLATION OF DNA AND HISTONE ACETYLATION. EPIGENOME WIDE ASSOCIATION STUDIES (EWAS) HIGHLIGHT IMPORTANT DIFFERENCES BETWEEN SLE PATIENTS AND HEALTHY CONTROLS IN INTERFERON STIMULATED GENES (ISGS). THE COMBINATION OF ENVIRONMENTAL AND GENETIC FACTORS MAY STIMULATE TYPE I IFN SIGNALING TRANSIENTLY AND PRODUCE LONG-LASTING DETRIMENTAL EFFECTS THROUGH EPIGENETIC ALTERATIONS. SUBSTANTIAL EVIDENCE FOR THE PATHOGENIC ROLE OF TYPE I IFNS IN SLE ADVOCATES THE CLINICAL USE OF NEUTRALIZING ANTI-TYPE I IFN RECEPTOR ANTIBODIES AS A THERAPEUTIC STRATEGY, WITH CLINICAL STUDIES ALREADY SHOWING PROMISING RESULTS. CURRENT AND FUTURE CLINICAL TRIALS WILL DETERMINE WHETHER DRUGS TARGETING MOLECULES OF THE TYPE I IFN SIGNALING PATHWAY, LIKE NON-SELECTIVE JAK INHIBITORS OR SPECIFIC TYK2 INHIBITORS, MAY BENEFIT PEOPLE LIVING WITH LUPUS. 2021 4 855 25 CHROMATIN ACCESSIBILITY LANDSCAPES OF IMMUNE CELLS IN RHEUMATOID ARTHRITIS NOMINATE MONOCYTES IN DISEASE PATHOGENESIS. BACKGROUND: RHEUMATOID ARTHRITIS (RA) IS A CHRONIC, SYSTEMIC AUTOIMMUNE DISEASE THAT INVOLVES A VARIETY OF CELL TYPES. HOWEVER, HOW THE EPIGENETIC DYSREGULATIONS OF PERIPHERAL IMMUNE CELLS CONTRIBUTE TO THE PATHOGENESIS OF RA STILL REMAINS LARGELY UNCLEAR. RESULTS: HERE, WE ANALYSED THE GENOME-WIDE ACTIVE DNA REGULATORY ELEMENTS OF FOUR MAJOR IMMUNE CELLS, NAMELY MONOCYTES, B CELLS, CD4(+) T CELLS AND CD8(+) T CELLS, IN PERIPHERAL BLOOD OF RA PATIENTS, OSTEOARTHRITIS (OA) PATIENTS AND HEALTHY DONORS USING ASSAY OF TRANSPOSASE ACCESSIBLE CHROMATIN WITH SEQUENCING (ATAC-SEQ). WE FOUND A STRONG RA-ASSOCIATED CHROMATIN DYSREGULATION SIGNATURE IN MONOCYTES, BUT NO OTHER EXAMINED CELL TYPES. MOREOVER, WE FOUND THAT SERUM C-REACTIVE PROTEIN (CRP) CAN INDUCE THE RA-ASSOCIATED CHROMATIN DYSREGULATION IN MONOCYTES VIA IN VITRO EXPERIMENTS. AND THE EXTENT OF THIS DYSREGULATION WAS REGULATED THROUGH THE TRANSCRIPTION FACTOR FRA2. CONCLUSIONS: TOGETHER, OUR STUDY REVEALED A CRP-INDUCED PATHOGENIC CHROMATIN DYSREGULATION SIGNATURE IN MONOCYTES FROM RA PATIENTS AND PREDICTED THE RESPONSIBLE SIGNALLING PATHWAY AS POTENTIAL THERAPEUTIC TARGETS FOR THE DISEASE. 2021 5 1479 22 DIVERSE TARGETS OF THE TRANSCRIPTION FACTOR STAT3 CONTRIBUTE TO T CELL PATHOGENICITY AND HOMEOSTASIS. STAT3, AN ESSENTIAL TRANSCRIPTION FACTOR WITH PLEIOTROPIC FUNCTIONS, PLAYS CRITICAL ROLES IN THE PATHOGENESIS OF AUTOIMMUNITY. DESPITE RECENT DATA LINKING STAT3 WITH INFLAMMATORY BOWEL DISEASE, EXACTLY HOW IT CONTRIBUTES TO CHRONIC INTESTINAL INFLAMMATION IS NOT KNOWN. USING A T CELL TRANSFER MODEL OF COLITIS, WE FOUND THAT STAT3 EXPRESSION IN T CELLS WAS ESSENTIAL FOR THE INDUCTION OF BOTH COLITIS AND SYSTEMIC INFLAMMATION. STAT3 WAS CRITICAL IN MODULATING THE BALANCE OF T HELPER 17 (TH17) AND REGULATORY T (TREG) CELLS, AS WELL AS IN PROMOTING CD4(+) T CELL PROLIFERATION. WE USED CHROMATIN IMMUNOPRECIPITATION AND MASSIVE PARALLEL SEQUENCING (CHIP-SEQ) TO DEFINE THE GENOME-WIDE TARGETS OF STAT3 IN CD4(+) T CELLS. WE FOUND THAT STAT3 BOUND TO MULTIPLE GENES INVOLVED IN TH17 CELL DIFFERENTIATION, CELL ACTIVATION, PROLIFERATION, AND SURVIVAL, REGULATING BOTH EXPRESSION AND EPIGENETIC MODIFICATIONS. THUS, STAT3 ORCHESTRATES MULTIPLE CRITICAL ASPECTS OF T CELL FUNCTION IN INFLAMMATION AND HOMEOSTASIS. 2010 6 2055 26 EPIGENETIC CONTROL DURING LYMPHOID DEVELOPMENT AND IMMUNE RESPONSES: ABERRANT REGULATION, VIRUSES, AND CANCER. METHYLATION OF CYTOSINES CONTROLS A NUMBER OF BIOLOGIC PROCESSES SUCH AS IMPRINTING AND X CHROMOSOMAL INACTIVATION. DNA HYPERMETHYLATION IS CLOSELY ASSOCIATED WITH TRANSCRIPTIONAL SILENCING, WHILE DNA HYPOMETHYLATION IS ASSOCIATED WITH TRANSCRIPTIONAL ACTIVATION. HYPOACETYLATION OF HISTONES LEADS TO COMPACT CHROMATIN WITH REDUCED ACCESSIBILITY TO THE TRANSCRIPTIONAL MACHINERY. METHYL-CPG BINDING PROTEINS CAN RECRUIT COREPRESSORS AND HISTONE DEACETYLASES; THUS, THE INTERPLAY BETWEEN THESE EPIGENETIC MECHANISMS REGULATES GENE ACTIVATION. METHYLATION HAS BEEN IMPLICATED AS AN IMPORTANT MECHANISM DURING IMMUNE DEVELOPMENT, CONTROLLING VDJ RECOMBINATION, LINEAGE-SPECIFIC EXPRESSION OF CELL SURFACE ANTIGENS, AND TRANSCRIPTIONAL REGULATION OF CYTOKINE GENES DURING IMMUNE RESPONSES. ABERRATIONS IN EPIGENETIC MACHINERY, EITHER BY GENETIC MUTATIONS OR BY SOMATIC CHANGES SUCH AS VIRAL INFECTIONS, ARE ASSOCIATED WITH EARLY ALTERATIONS IN CHRONIC DISEASES SUCH AS IMMUNODEFICIENCY AND CANCER. 2003 7 911 25 CHRONIC EXPOSURE TO TNF REPROGRAMS CELL SIGNALING PATHWAYS IN FIBROBLAST-LIKE SYNOVIOCYTES BY ESTABLISHING LONG-TERM INFLAMMATORY MEMORY. FIBROBLAST-LIKE SYNOVIOCYTES (FLS) PLAY A CRITICAL ROLE IN THE PATHOGENESIS OF RHEUMATOID ARTHRITIS (RA). CHRONIC INFLAMMATION INDUCES TRANSCRIPTOMIC AND EPIGENETIC MODIFICATIONS THAT IMPARTS A PERSISTENT CATABOLIC PHENOTYPE TO THE FLS, DESPITE THEIR DISSOCIATION FROM THE INFLAMMATORY ENVIRONMENT. WE ANALYZED HIGH THROUGHPUT GENE EXPRESSION AND CHROMATIN ACCESSIBILITY DATA FROM HUMAN AND MOUSE FLS FROM OUR AND OTHER STUDIES AVAILABLE ON PUBLIC REPOSITORIES, WITH THE GOAL OF IDENTIFYING THE PERSISTENTLY REPROGRAMMED SIGNALING PATHWAYS DRIVEN BY CHRONIC INFLAMMATION. WE FOUND THAT THE GENE EXPRESSION CHANGES INDUCED BY SHORT-TERM TUMOR NECROSIS FACTOR-ALPHA (TNF) TREATMENT WERE LARGELY SUSTAINED IN THE FLS EXPOSED TO CHRONIC INFLAMMATION. THESE CHANGES THAT INCLUDED BOTH ACTIVATION AND REPRESSION OF GENE EXPRESSION, WERE ACCOMPANIED BY THE REMODELING OF CHROMATIN ACCESSIBILITY. THE SUSTAINED ACTIVATED GENES (SAGS) INCLUDED ESTABLISHED PRO-INFLAMMATORY SIGNALING COMPONENTS KNOWN TO ACT AT MULTIPLE LEVELS OF NF-KAPPAB, STAT AND AP-1 SIGNALING CASCADES. INTERESTINGLY, THE SUSTAINED REPRESSED GENES (SRGS) INCLUDED CRITICAL MEDIATORS AND TARGETS OF THE BMP SIGNALING PATHWAY. WE THUS IDENTIFIED SUSTAINED REPRESSION OF BMP SIGNALING AS A UNIQUE CONSTITUENT OF THE LONG-TERM INFLAMMATORY MEMORY INDUCED BY CHRONIC INFLAMMATION. WE POSTULATE THAT SIMULTANEOUS TARGETING OF THESE ACTIVATED AND REPRESSED SIGNALING PATHWAYS MAY BE NECESSARY TO COMBAT RA PERSISTENCE. 2020 8 5872 20 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 9 3167 28 GROUP 1 METABOTROPIC GLUTAMATE RECEPTOR EXPRESSION DEFINES A T CELL MEMORY POPULATION DURING CHRONIC TOXOPLASMA INFECTION THAT ENHANCES IFN-GAMMA AND PERFORIN PRODUCTION IN THE CNS. WITHIN THE BRAIN, A PRO-INFLAMMATORY RESPONSE IS ESSENTIAL TO PREVENT CLINICAL DISEASE DUE TO TOXOPLASMA GONDII REACTIVATION. INFECTION IN THE IMMUNOCOMPROMISED LEADS TO LETHAL TOXOPLASMIC ENCEPHALITIS WHILE IN THE IMMUNOCOMPETENT, THERE IS PERSISTENT LOW-GRADE INFLAMMATION WHICH IS DEVOID OF CLINICAL SYMPTOMS. THIS SIGNIFIES THAT THERE IS A WELL-BALANCED AND REGULATED INFLAMMATORY RESPONSE TO T. GONDII IN THE BRAIN. T CELLS ARE THE DOMINANT IMMUNE CELLS THAT PREVENT CLINICAL DISEASE, AND THIS IS MEDIATED THROUGH THE SECRETION OF EFFECTOR MOLECULES SUCH AS PERFORINS AND IFN-GAMMA. THE PRESENCE OF COGNATE ANTIGEN, THE EXPRESSION OF SURVIVAL CYTOKINES, AND THE ALTERATION OF THE EPIGENETIC LANDSCAPE DRIVE THE DEVELOPMENT OF MEMORY T CELLS. HOWEVER, SPECIFIC EXTRINSIC SIGNALS THAT PROMOTE THE FORMATION AND MAINTENANCE OF MEMORY T CELLS WITHIN TISSUE ARE POORLY UNDERSTOOD. DURING CHRONIC INFECTION, THERE IS AN INCREASE IN EXTRACELLULAR GLUTAMATE THAT, DUE TO ITS FUNCTION AS AN EXCITATORY NEUROTRANSMITTER, IS NORMALLY TIGHTLY CONTROLLED IN THE CNS. HERE WE DEMONSTRATE THAT CD8(+) T CELLS FROM THE T. GONDII-INFECTED BRAIN PARENCHYMA ARE ENRICHED FOR METABOTROPIC GLUTAMATE RECEPTORS (MGLUR'S). CHARACTERIZATION STUDIES DETERMINED THAT MGLUR(+) EXPRESSION BY CD8(+) T CELLS DEFINES A DISTINCT MEMORY POPULATION AT THE TRANSCRIPTIONAL AND PROTEIN LEVEL. FINALLY, USING RECEPTOR ANTAGONISTS AND AGONISTS WE DEMONSTRATE MGLUR SIGNALING IS REQUIRED FOR OPTIMAL CD8(+) T CELL PRODUCTION OF THE EFFECTOR CYTOKINE IFNGAMMA. THIS WORK SUGGESTS THAT GLUTAMATE IS AN IMPORTANT ENVIRONMENTAL SIGNAL OF INFLAMMATION THAT PROMOTES T CELL FUNCTION. UNDERSTANDING GLUTAMATE'S INFLUENCE ON T CELLS IN THE BRAIN CAN PROVIDE INSIGHTS INTO THE MECHANISMS THAT GOVERN PROTECTIVE IMMUNITY AGAINST CNS-INFILTRATING PATHOGENS AND NEUROINFLAMMATION. 2023 10 5415 24 REGULATION OF CELLULAR IMMUNE RESPONSES IN SEPSIS BY HISTONE MODIFICATIONS. SEVERE SEPSIS, SEPTIC SHOCK, AND RELATED INFLAMMATORY SYNDROMES ARE DRIVEN BY THE ABERRANT EXPRESSION OF PROINFLAMMATORY MEDIATORS BY IMMUNE CELLS. DURING THE ACUTE PHASE OF SEPSIS, OVEREXPRESSION OF CHEMOKINES AND CYTOKINES DRIVES PHYSIOLOGICAL STRESS LEADING TO ORGAN FAILURE AND MORTALITY. FOLLOWING RECOVERY FROM SEPSIS, THE IMMUNE SYSTEM EXHIBITS PROFOUND IMMUNOSUPPRESSION, EVIDENCED BY AN INABILITY TO PRODUCE THE SAME PROINFLAMMATORY MEDIATORS THAT ARE REQUIRED FOR NORMAL RESPONSES TO INFECTIOUS MICROORGANISMS. GENE EXPRESSION IN INFLAMMATORY RESPONSES IS INFLUENCED BY THE TRANSCRIPTIONAL ACCESSIBILITY OF THE CHROMATIN, WITH HISTONE POSTTRANSLATIONAL MODIFICATIONS DETERMINING WHETHER INFLAMMATORY GENE LOCI ARE SET TO TRANSCRIPTIONALLY ACTIVE, REPRESSED, OR POISED STATES. EXPERIMENTAL EVIDENCE INDICATES THAT HISTONE MODIFICATIONS PLAY A CENTRAL ROLE IN GOVERNING THE CYTOKINE STORM OF SEVERE SEPSIS, AND THAT ABERRANT CHROMATIN MODIFICATIONS INDUCED DURING THE ACUTE PHASE OF SEPSIS MAY MEDIATE CHRONIC IMMUNOSUPPRESSION IN SEPSIS SURVIVORS. THIS REVIEW WILL FOCUS ON THE ROLE OF HISTONE MODIFICATIONS IN GOVERNING IMMUNE RESPONSES IN SEVERE SEPSIS, WITH AN EMPHASIS ON SPECIFIC LEUKOCYTE SUBSETS AND THE HISTONE MODIFICATIONS OBSERVED IN THESE CELLS DURING CHRONIC STAGES OF SEPSIS. ADDITIONALLY, THE EXPRESSION AND FUNCTION OF CHROMATIN-MODIFYING ENZYMES (CMES) WILL BE DISCUSSED IN THE CONTEXT OF SEVERE SEPSIS, AS POTENTIAL MEDIATORS OF EPIGENETIC REGULATION OF GENE EXPRESSION IN SEPSIS RESPONSES. IN SUMMARY, THIS REVIEW WILL ARGUE FOR THE USE OF CHROMATIN MODIFICATIONS AND CME EXPRESSION IN LEUKOCYTES AS POTENTIAL BIOMARKERS OF IMMUNOSUPPRESSION IN PATIENTS WITH SEVERE SEPSIS. 2017 11 4164 25 MEDIATORS OF CAPILLARY-TO-VENULE CONVERSION IN THE CHRONIC INFLAMMATORY SKIN DISEASE PSORIASIS. PSORIASIS IS A CHRONIC INFLAMMATORY SKIN DISEASE CHARACTERIZED BY EPIDERMAL HYPERPLASIA AND HYPERKERATOSIS, IMMUNE CELL INFILTRATION AND VASCULAR REMODELING. DESPITE THE EMERGING RECOGNITION OF VASCULAR NORMALIZATION AS A POTENTIAL STRATEGY FOR MANAGING PSORIASIS, AN IN-DEPTH DELINEATION OF THE REMODELED DERMAL VASCULATURE HAS BEEN MISSING. IN THIS STUDY, WE EXPLOITED 5' SINGLE-CELL RNA SEQUENCING TO INVESTIGATE THE TRANSCRIPTOMIC ALTERATIONS IN DIFFERENT SUBPOPULATIONS OF BLOOD VASCULAR AND LYMPHATIC ENDOTHELIAL CELLS DIRECTLY ISOLATED FROM PSORIATIC AND HEALTHY HUMAN SKIN. INDIVIDUAL SUBTYPES OF ENDOTHELIAL CELLS UNDERWENT SPECIFIC MOLECULAR REPATTERNING ASSOCIATED WITH CELL ADHESION AND EXTRACELLULAR MATRIX ORGANIZATION. BLOOD CAPILLARIES, IN PARTICULAR, SHOWED UPREGULATION OF THE MELANOMA CELL ADHESION MOLECULE AS WELL AS ITS BINDING PARTNERS AND ADOPTED POSTCAPILLARY VENULE?LIKE CHARACTERISTICS DURING CHRONIC INFLAMMATION THAT ARE MORE PERMISSIVE TO LEUKOCYTE TRANSMIGRATION. WE ALSO IDENTIFIED PSORIASIS-SPECIFIC INTERACTIONS BETWEEN CIS-REGULATORY ENHANCERS AND PROMOTERS FOR EACH ENDOTHELIAL CELL SUBTYPE, REVEALING THE DYSREGULATED GENE REGULATORY NETWORKS IN PSORIASIS. TOGETHER, OUR RESULTS PROVIDE MORE INSIGHTS INTO THE SPECIFIC TRANSCRIPTIONAL RESPONSES AND EPIGENETIC SIGNATURES OF ENDOTHELIAL CELLS LINING DIFFERENT VESSEL COMPARTMENTS IN CHRONIC SKIN INFLAMMATION. 2022 12 2308 20 EPIGENETIC REGULATION OF CHEMOKINE (CC-MOTIF) LIGAND 2 IN INFLAMMATORY DISEASES. APPROPRIATE RESPONSES TO INFLAMMATION ARE CONDUCIVE TO PATHOGEN ELIMINATION AND TISSUE REPAIR, WHILE UNCONTROLLED INFLAMMATORY REACTIONS ARE LIKELY TO RESULT IN THE DAMAGE OF TISSUES. CHEMOKINE (CC-MOTIF) LIGAND 2 (CCL2) IS THE MAIN CHEMOKINE AND ACTIVATOR OF MONOCYTES, MACROPHAGES, AND NEUTROPHILS. CCL2 PLAYED A KEY ROLE IN AMPLIFYING AND ACCELERATING THE INFLAMMATORY CASCADE AND IS CLOSELY RELATED TO CHRONIC NON-CONTROLLABLE INFLAMMATION (CIRRHOSIS, NEUROPATHIC PAIN, INSULIN RESISTANCE, ATHEROSCLEROSIS, DEFORMING ARTHRITIS, ISCHEMIC INJURY, CANCER, ETC.). THE CRUCIAL REGULATORY ROLES OF CCL2 MAY PROVIDE POTENTIAL TARGETS FOR THE TREATMENT OF INFLAMMATORY DISEASES. THEREFORE, WE PRESENTED A REVIEW OF THE REGULATORY MECHANISMS OF CCL2. GENE EXPRESSION IS LARGELY AFFECTED BY THE STATE OF CHROMATIN. DIFFERENT EPIGENETIC MODIFICATIONS, INCLUDING DNA METHYLATION, POST-TRANSLATIONAL MODIFICATION OF HISTONES, HISTONE VARIANTS, ATP-DEPENDENT CHROMATIN REMODELLING, AND NON-CODING RNA, COULD AFFECT THE 'OPEN' OR 'CLOSED' STATE OF DNA, AND THEN SIGNIFICANTLY AFFECT THE EXPRESSION OF TARGET GENES. SINCE MOST EPIGENETIC MODIFICATIONS ARE PROVEN TO BE REVERSIBLE, TARGETING THE EPIGENETIC MECHANISMS OF CCL2 IS EXPECTED TO BE A PROMISING THERAPEUTIC STRATEGY FOR INFLAMMATORY DISEASES. THIS REVIEW FOCUSES ON THE EPIGENETIC REGULATION OF CCL2 IN INFLAMMATORY DISEASES. 2023 13 6535 29 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 14 5429 19 REGULATION OF TYPE I INTERFERON RESPONSES. TYPE I INTERFERONS (IFNS) ACTIVATE INTRACELLULAR ANTIMICROBIAL PROGRAMMES AND INFLUENCE THE DEVELOPMENT OF INNATE AND ADAPTIVE IMMUNE RESPONSES. CANONICAL TYPE I IFN SIGNALLING ACTIVATES THE JANUS KINASE (JAK)-SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION (STAT) PATHWAY, LEADING TO TRANSCRIPTION OF IFN-STIMULATED GENES (ISGS). HOST, PATHOGEN AND ENVIRONMENTAL FACTORS REGULATE THE RESPONSES OF CELLS TO THIS SIGNALLING PATHWAY AND THUS CALIBRATE HOST DEFENCES WHILE LIMITING TISSUE DAMAGE AND PREVENTING AUTOIMMUNITY. HERE, WE SUMMARIZE THE SIGNALLING AND EPIGENETIC MECHANISMS THAT REGULATE TYPE I IFN-INDUCED STAT ACTIVATION AND ISG TRANSCRIPTION AND TRANSLATION. THESE REGULATORY MECHANISMS DETERMINE THE BIOLOGICAL OUTCOMES OF TYPE I IFN RESPONSES AND WHETHER PATHOGENS ARE CLEARED EFFECTIVELY OR CHRONIC INFECTION OR AUTOIMMUNE DISEASE ENSUES. 2014 15 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 16 5223 28 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 17 1594 26 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 18 827 32 CHARACTERIZATION OF LONG NON-CODING RNAS IN SYSTEMIC SCLEROSIS MONOCYTES: A POTENTIAL ROLE FOR PSMB8-AS1 IN ALTERED CYTOKINE SECRETION. SYSTEMIC SCLEROSIS (SSC) IS A CHRONIC AUTOIMMUNE DISEASE MAINLY AFFECTING THE CONNECTIVE TISSUE. IN SSC PATIENTS, MONOCYTES ARE INCREASED IN CIRCULATION, INFILTRATE AFFECTED TISSUES, AND SHOW A PRO-INFLAMMATORY ACTIVATION STATUS, INCLUDING THE SO-CALLED INTERFERON (IFN) SIGNATURE. WE PREVIOUSLY DEMONSTRATED THAT THE DYSREGULATION OF THE IFN RESPONSE IN SSC MONOCYTES IS SUSTAINED BY ALTERED EPIGENETIC FACTORS AS WELL AS BY UPREGULATION OF THE LONG NON-CODING RNA (LNCRNA) NRIR. CONSIDERING THE ENORMOUSLY DIVERSE MOLECULAR FUNCTIONS OF LNCRNAS IN IMMUNE REGULATION, THE PRESENT STUDY INVESTIGATED THE GENOME-WIDE PROFILE OF LNCRNAS IN SSC MONOCYTES, WITH THE AIM TO FURTHER UNRAVEL THEIR POSSIBLE ROLE IN MONOCYTE DYSREGULATION AND DISEASE PATHOGENESIS. TRANSCRIPTOMIC DATA FROM TWO INDEPENDENT COHORTS OF SSC PATIENTS IDENTIFIED 886 LNCRNAS WITH AN ALTERED EXPRESSION IN SSC MONOCYTES. DIFFERENTIALLY EXPRESSED LNCRNAS WERE CORRELATED WITH NEIGHBORING PROTEIN CODING GENES IMPLICATED IN THE REGULATION OF IFN RESPONSES AND APOPTOTIC SIGNALING IN SSC MONOCYTES. IN PARALLEL, GENE CO-EXPRESSION NETWORK ANALYSIS IDENTIFIED THE LNCRNA PSMB8-AS1 AS A TOP-RANKING HUB GENE IN CO-EXPRESSION MODULES IMPLICATED IN CELL ACTIVATION AND RESPONSE TO VIRAL AND EXTERNAL STIMULI. FUNCTIONAL CHARACTERIZATION OF PSMB8-AS1 IN MONOCYTES DEMONSTRATED THAT THIS LNCRNA IS INVOLVED IN THE SECRETION OF IL-6 AND TNFALPHA, TWO PIVOTAL PRO-INFLAMMATORY CYTOKINES ALTERED IN THE CIRCULATION OF SSC PATIENTS AND ASSOCIATED WITH FIBROSIS AND DISEASE SEVERITY. COLLECTIVELY, OUR DATA SHOWED THAT LNCRNAS ARE LINKED TO MONOCYTE DYSREGULATION IN SSC, AND HIGHLIGHT THEIR POTENTIAL CONTRIBUTION TO DISEASE PATHOGENESIS. 2021 19 2389 25 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 20 1611 26 DNA METHYLATION: A NEW PLAYER IN MULTIPLE SCLEROSIS. MULTIPLE SCLEROSIS (MS) IS A NEUROLOGICAL AND CHRONIC INFLAMMATORY DISEASE THAT IS MEDIATED BY DEMYELINATION AND AXONAL DEGENERATION IN THE CENTRAL NERVOUS SYSTEM (CNS). STUDIES HAVE SHOWN THAT IMMUNE SYSTEM COMPONENTS SUCH AS CD4+, CD8+, CD44+ T CELLS, B LYMPHATIC CELLS, AND INFLAMMATORY CYTOKINES PLAY A CRITICAL ROLE IN INFLAMMATORY PROCESSES AND MYELIN DAMAGE ASSOCIATED WITH MS. NEVERTHELESS, THE PATHOGENESIS OF MS REMAINS POORLY DEFINED. DNA METHYLATION, A SIGNIFICANT EPIGENETIC MODIFICATION, IS REPORTED TO BE EXTENSIVELY INVOLVED IN MS PATHOGENESIS THROUGH THE REGULATION OF GENE EXPRESSION. THIS REVIEW FOCUSES ON DNA METHYLATION INVOLVED IN MS PATHOGENESIS. EVIDENCE SHOWED THE HYPERMETHYLATION OF HUMAN LEUKOCYTE ANTIGEN-DRB1 (HLA-DRB1) IN CD4+ T CELLS, THE GENOME-WIDE DNA METHYLATION IN CD8+ T CELLS, THE HYPERMETHYLATION OF INTERLEUKIN-4 (IL-4)/FORKHEAD WINGED HELIX TRANSCRIPTION FACTOR 3 (FOXP3), AND THE DEMETHYLATION OF INTERFERON-GAMMA (IFN-GAMMA)/IL-17A IN CD44+ ENCEPHALITOGENIC T CELLS. STUDIES ALSO SHOWED THE HYPERMETHYLATION OF SH2-CONTAINING PROTEIN TYROSINE PHOSPHATASE-1 (SHP-1) IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) AND METHYLATED CHANGES OF GENES REGULATING OLIGODENDROCYTE AND NEURONAL FUNCTION IN NORMAL-APPEARING WHITE MATTER. CLARIFYING THE MECHANISM OF ABERRANT METHYLATION ON MS MAY EXPLAIN PART OF THE PATHOLOGY AND WILL LEAD TO THE DEVELOPMENT OF A NEW THERAPEUTIC TARGET FOR THE TREATMENT OF MS IN THE FUTURE. 2017