1 1611 124 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 2 6136 51 THE EPIGENETICS OF MULTIPLE SCLEROSIS AND OTHER RELATED DISORDERS. MULTIPLE SCLEROSIS (MS) IS A DEMYELINATING DISEASE CHARACTERIZED BY CHRONIC INFLAMMATION OF THE CENTRAL NERVOUS SYSTEM (CNS) GRAY AND WHITE MATTER. ALTHOUGH THE CAUSE OF MS IS UNKNOWN, IT IS WIDELY APPRECIATED THAT INNATE AND ADAPTIVE IMMUNE PROCESSES CONTRIBUTE TO ITS PATHOGENESIS. THESE INCLUDE MICROGLIA/MACROPHAGE ACTIVATION, PRO-INFLAMMATORY T-CELL (TH1) RESPONSES AND HUMORAL RESPONSES. ADDITIONALLY, THERE IS EVIDENCE INDICATING THAT MS HAS A NEURODEGENERATIVE COMPONENT SINCE NEURONAL AND AXONAL LOSS OCCURS EVEN IN THE ABSENCE OF OVERT INFLAMMATION. THESE ASPECTS ALSO FORM THE RATIONALE FOR CLINICAL MANAGEMENT OF THE DISEASE. HOWEVER, THE CURRENTLY AVAILABLE THERAPIES TO CONTROL THE DISEASE ARE ONLY PARTIALLY EFFECTIVE AT BEST INDICATING THAT MORE EFFECTIVE THERAPEUTIC SOLUTIONS ARE URGENTLY NEEDED. IT IS APPRECIATED THAT IN THE IMMUNE-DRIVEN AND NEURODEGENERATIVE PROCESSES MS-SPECIFIC DEREGULATION OF GENE EXPRESSIONS AND RESULTING PROTEIN DYSFUNCTION ARE THOUGHT TO PLAY A CENTRAL ROLE. THESE DEVIATIONS IN GENE EXPRESSION PATTERNS CONTRIBUTE TO THE INFLAMMATORY RESPONSE IN THE CNS, AND TO NEURONAL OR AXONAL LOSS. EPIGENETIC MECHANISMS CONTROL TRANSCRIPTION OF MOST, IF NOT ALL GENES, IN NUCLEATED CELLS INCLUDING CELLS OF THE CNS AND IN HAEMATOPOIETIC CELLS. MS-SPECIFIC ALTERATIONS IN EPIGENETIC REGULATION OF GENE EXPRESSION MAY THEREFORE LIE AT THE HEART OF THE DEREGULATION OF GENE EXPRESSION IN MS. AS SUCH, EPIGENETIC MECHANISMS MOST LIKELY PLAY AN IMPORTANT ROLE IN DISEASE PATHOGENESIS. IN THIS REVIEW WE DISCUSS A ROLE FOR MS-SPECIFIC DEREGULATION OF EPIGENETIC FEATURES THAT CONTROL GENE EXPRESSION IN THE CNS AND IN THE PERIPHERY. FURTHERMORE, WE DISCUSS THE APPLICATION OF SMALL MOLECULE INHIBITORS THAT TARGET THE EPIGENETIC MACHINERY TO AMELIORATE DISEASE IN EXPERIMENTAL ANIMAL MODELS, INDICATING THAT SUCH APPROACHES MAY BE APPLICABLE TO MS PATIENTS. 2014 3 4439 46 MOLECULAR GENETIC AND EPIGENETIC BASIS OF MULTIPLE SCLEROSIS. MULTIPLE SCLEROSIS (MS) IS A CHRONIC IMMUNE-MEDIATED DISEASE OF SPINAL CORD AND BRAIN. THE INITIAL EVENT IN MS OCCURS WHEN ACTIVATED CD4(+) T CELLS IN PERIPHERY EXACERBATES IMMUNE RESPONSES BY STIMULATING IMMUNE CELLS SUCH AS B CELLS, CD8(+) CELLS, MAST CELLS, GRANULOCYTES AND MONOCYTES. THESE PROINFLAMMATORY CELLS PASS BLOOD BRAIN BARRIER BY SECRETING PROINFLAMMATORY CYTOKINES INCLUDING TNF-ALPHA AND INF-(GAMMA) WHICH ACTIVATE ADHESION FACTORS. APCS (ANTIGEN-PRESENTING CELLS) REACTIVATE CD4(+) T CELLS AFTER INFILTRATING THE CNS AND CD4(+) T CELLS PRODUCE CYTOKINES AND CHEMOKINES. THESE PROINFLAMMATORY CYTOKINES AGGRAVATE INFLAMMATION BY INDUCING MYELIN PHAGOCYTOSIS THROUGH MICROGLIA AND ASTROCYTES ACTIVATION. MS IS BELIEVED TO HAVE A MULTIFACTORIAL ORIGIN THAT INCLUDES A COMBINATION OF MULTIPLE GENETIC, ENVIRONMENTAL AND STOCHASTIC FACTORS. ALTHOUGH THE EXACT COMPONENT OF MS RISKS THAT CAN BE EXPLAINED BY THESE FACTORS IS DIFFICULT TO DETERMINE, ESTIMATES BASED ON GENETIC AND EPIDEMIOLOGICAL STUDIES SUGGEST THAT UP TO 60-70 % OF THE TOTAL RISK OF MS MAY BE CONTRIBUTE TO GENETIC FACTORS. IN CONTINUE, FIRSTLY WE PROVIDE AN OVERVIEW OF THE CURRENT UNDERSTANDING OF EPIGENETIC MECHANISMS, AND SO PRESENT EVIDENCE OF HOW THE EPIGENETIC MODIFICATIONS CONTRIBUTE TO INCREASED SUSCEPTIBILITY OF MS. WE ALSO EXPLAIN HOW SPECIFIED EPIGENETIC MODIFICATIONS MAY INFLUENCE THE PATHOPHYSIOLOGY AND KEY ASPECTS OF DISEASE IN MS (DEMYELINATION, REMYELINATION, INFLAMMATION, AND NEURODEGENERATION). FINALLY, WE TEND TO DISCUSS HOW ENVIRONMENTAL FACTORS AND EPIGENETIC MECHANISMS MAY INTERACT TO HAVE AN EFFECT ON MS RISK AND CLINICAL OUTCOME AND RECOMMEND NEW THERAPEUTIC INTERVENTIONS THAT MIGHT MODULATE PATIENTS' EPIGENETIC PROFILES. 2017 4 3069 46 GENOME-WIDE DNA METHYLATION PROFILING IDENTIFIES EPIGENETIC CHANGES IN CD4+ AND CD14+ CELLS OF MULTIPLE SCLEROSIS PATIENTS. MULTIPLE SCLEROSIS (MS) IS A CHRONIC AUTOIMMUNE AND DEGENERATIVE DISEASE OF THE CENTRAL NERVOUS SYSTEM, WHICH DEVELOPS IN GENETICALLY PREDISPOSED INDIVIDUALS UPON EXPOSURE TO ENVIRONMENTAL INFLUENCES. ENVIRONMENTAL TRIGGERS OF MS, SUCH AS VIRAL INFECTIONS OR SMOKING, WERE DEMONSTRATED TO AFFECT DNA METHYLATION, AND THUS TO INVOLVE THIS IMPORTANT EPIGENETIC MECHANISM IN THE DEVELOPMENT OF PATHOLOGICAL PROCESS. TO IDENTIFY MS-ASSOCIATED DNA METHYLATION HALLMARKS, WE PERFORMED GENOME-WIDE DNA METHYLATION PROFILING OF TWO CELL POPULATIONS (CD4+ T-LYMPHOCYTES AND CD14+ MONOCYTES), COLLECTED FROM THE SAME TREATMENT-NAIVE RELAPSING-REMITTING MS PATIENTS AND HEALTHY SUBJECTS, USING ILLUMINA 450 K METHYLATION ARRAYS. WE REVEALED SIGNIFICANT CHANGES IN DNA METHYLATION FOR BOTH CELL POPULATIONS IN MS. IN CD4+ CELLS OF MS PATIENTS THE MAJORITY OF DIFFERENTIALLY METHYLATED POSITIONS (DMPS) WERE SHOWN TO BE HYPOMETHYLATED, WHILE IN CD14+ CELLS - HYPERMETHYLATED. DIFFERENTIAL METHYLATION OF HLA-DRB1 GENE IN CD4+ AND CD14+ CELLS WAS ASSOCIATED WITH CARRIAGE OF DRB1*15 ALLELE INDEPENDENTLY FROM THE DISEASE STATUS. BESIDES, ABOUT 20% OF IDENTIFIED DMPS WERE SHARED BETWEEN TWO CELL POPULATIONS AND HAD THE SAME DIRECTION OF METHYLATION CHANGES; THEY MAY BE INVOLVED IN BASIC EPIGENETIC PROCESSES OCCURING IN MS. THESE FINDINGS SUGGEST THAT THE EPIGENETIC MECHANISM OF DNA METHYLATION IN IMMUNE CELLS CONTRIBUTES TO MS; FURTHER STUDIES ARE NOW REQUIRED TO VALIDATE THESE RESULTS AND UNDERSTAND THEIR FUNCTIONAL SIGNIFICANCE. 2022 5 4590 39 NANOPORE SEQUENCING IDENTIFIES DIFFERENTIALLY METHYLATED GENES IN THE CENTRAL NERVOUS SYSTEM IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS. MULTIPLE SCLEROSIS (MS) IS A CHRONIC AUTOIMMUNE-MEDIATED DEMYELINATING DISEASE OF THE CENTRAL NERVOUS SYSTEM (CNS) THAT MIGHT BE TRIGGERED BY ABERRANT EPIGENETIC CHANGES IN THE GENOME. DNA METHYLATION IS THE MOST STUDIED EPIGENETIC MECHANISM THAT PARTICIPATES IN MS PATHOGENESIS. HOWEVER, THE OVERALL METHYLATION LEVEL IN THE CNS OF MS PATIENTS REMAINS ELUSIVE. WE USED DIRECT LONG-READ NANOPORE DNA SEQUENCING AND CHARACTERIZED THE DIFFERENTIALLY METHYLATED GENES IN THE BRAIN FROM MICE WITH EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS (EAE), AN ANIMAL MODEL OF MS. WE IDENTIFIED 163 HYPOMETHYLATED PROMOTERS AND 327 HYPERMETHYLATED PROMOTERS. THESE GENOMIC ALTERATIONS WERE LINKED TO VARIOUS BIOLOGICAL PROCESSES INCLUDING METABOLISM, IMMUNE RESPONSES, NEURAL ACTIVITIES, AND MITOCHONDRIAL DYNAMICS, ALL OF WHICH ARE VITAL FOR EAE DEVELOPMENT. OUR RESULTS INDICATE A GREAT POTENTIAL OF NANOPORE SEQUENCING IN IDENTIFYING GENOMIC DNA METHYLATION IN EAE AND PROVIDE IMPORTANT GUIDANCE FOR FUTURE STUDIES INVESTIGATING THE MS/EAE PATHOLOGY. 2023 6 1994 44 EPIGENETIC AND GENE EXPRESSION ALTERATIONS OF FOXP3 IN THE T CELLS OF EAE MOUSE MODEL OF MULTIPLE SCLEROSIS. MULTIPLE SCLEROSIS (MS) IS A CHRONIC AUTOIMMUNE DISEASE WITH DEMYELINATION AND NEURODEGENERATION OF THE CENTRAL NERVOUS SYSTEM. IT HAS BEEN SHOWN THAT THE REGULATORY T (TREG) CELLS ARE RESPONSIBLE FOR MAINTAINING TOLERANCE TO SELF-ANTIGENS AND CAN SUPPRESS THE AUTOIMMUNE PROCESS IN SEVERAL ANIMAL MODELS SUCH AS EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS (EAE), A MOUSE MODEL OF MS. RECENT BASIC STUDIES HAVE DEMONSTRATED THAT FORKHEAD BOX P (FOXP3) AND BTB DOMAIN AND CNC HOMOLOG 2 (BACH2) ARE THE MASTER TRANSCRIPTION FACTORS OF THESE CELLS PLAYING A PIVOTAL ROLE IN THE POLARIZATION OF NAIVE T CELLS INTO TREG CELLS. IN THE CURRENT STUDY, THE EXPRESSION OF FOXP3 AND BACH2 GENES AND FOXP3 PROMOTER METHYLATION WERE EVALUATED IN T CELLS OF THE EAE-INDUCED MICE. THE RESULTS OF THIS STUDY SHOWED A PROMINENT AND SIGNIFICANT HYPERMETHYLATION OF THE FOXP3 GENE PROMOTER IN THE EAE-INDUCED MICE COMPARED TO THE SHAM AND CONTROL GROUPS. THE EXPRESSION OF FOXP3 AND BACH2 GENES WAS SIGNIFICANTLY DECREASED IN THE EAE GROUP IN COMPARISON WITH THE SHAM AND CONTROL GROUPS. THIS STUDY SUGGESTS THAT THE EPIGENETIC MODIFICATION OF FOXP3 GENE IS INVOLVED IN THE PATHOGENESIS OF EAE AND THIS COULD BE IMPORTANT IN THERAPY IN AN APPROPRIATE AND LOGICAL STATEMENT. 2017 7 1508 40 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 8 4261 43 MGMT-METHYLATION IN NON-NEOPLASTIC DISEASES OF THE CENTRAL NERVOUS SYSTEM. QUANTIFYING O(6)-METHYLGUANINE-DNA METHYLTRANSFERASE (MGMT) PROMOTER METHYLATION PLAYS AN ESSENTIAL ROLE IN ASSESSING THE POTENTIAL EFFICACY OF ALKYLATING AGENTS IN THE CHEMOTHERAPY OF MALIGNANT GLIOMAS. MGMT PROMOTER METHYLATION IS CONSIDERED TO BE A CHARACTERISTIC OF SUBGROUPS OF CERTAIN MALIGNANCIES BUT HAS ALSO BEEN DESCRIBED IN VARIOUS PERIPHERAL INFLAMMATORY DISEASES. HOWEVER, MGMT PROMOTER METHYLATION LEVELS HAVE NOT YET BEEN INVESTIGATED IN NON-NEOPLASTIC BRAIN DISEASES. THIS STUDY DEMONSTRATES FOR THE FIRST TIME THAT ONE CAN INDEED DETECT SLIGHTLY ENHANCED MGMT PROMOTER METHYLATION IN INDIVIDUAL CASES OF INFLAMMATORY DEMYELINATING CNS DISEASES SUCH AS MULTIPLE SCLEROSIS AND PROGRESSIVE MULTIFOCAL LEUCENCEPHALOPATHY (PML), AS WELL AS IN OTHER DEMYELINATING DISEASES SUCH AS CENTRAL PONTINE AND EXPTRAPONTINE MYELINOLYSIS, AND DISEASES WITH MYELIN DAMAGE SUCH AS WALLERIAN DEGENERATION. IN THIS CONTEXT, WE IDENTIFIED A REDUCTION IN THE EXPRESSION OF THE DEMETHYLASE TET1 AS A POSSIBLE CAUSE FOR THE ENHANCED MGMT PROMOTER METHYLATION. HENCE, WE SHOW FOR THE FIRST TIME THAT MGMT HYPERMETHYLATION OCCURS IN CHRONIC DISEASES THAT ARE NOT STRICTLY ASSOCIATED TO DISTINCT PATHOGENS, ONCOGENIC VIRUSES OR NEOPLASMS BUT THAT LEAD TO DAMAGE OF THE MYELIN SHEATH IN VARIOUS WAYS. WHILE THIS GIVES NEW INSIGHTS INTO EPIGENETIC AND PATHOPHYSIOLOGICAL PROCESSES INVOLVED IN DE- AND REMYELINATION, WHICH MIGHT OFFER NEW THERAPEUTIC OPPORTUNITIES FOR DEMYELINATING DISEASES IN THE FUTURE, IT ALSO REDUCES THE SPECIFICITY OF MGMT HYPERMETHYLATION AS A TUMOR BIOMARKER. 2021 9 1526 41 DNA METHYLATION CHANGES IN GLIAL CELLS OF THE NORMAL-APPEARING WHITE MATTER IN MULTIPLE SCLEROSIS PATIENTS. MULTIPLE SCLEROSIS (MS), THE LEADING CAUSE OF NON-TRAUMATIC NEUROLOGICAL DISABILITY IN YOUNG ADULTS, IS A CHRONIC INFLAMMATORY AND NEURODEGENERATIVE DISEASE OF THE CENTRAL NERVOUS SYSTEM (CNS). DUE TO THE POOR ACCESSIBILITY TO THE TARGET ORGAN, CNS-CONFINED PROCESSES UNDERPINNING THE LATER PROGRESSIVE FORM OF MS REMAIN ELUSIVE THEREBY LIMITING TREATMENT OPTIONS. WE AIMED TO EXAMINE DNA METHYLATION, A STABLE EPIGENETIC MARK OF GENOME ACTIVITY, IN GLIAL CELLS TO CAPTURE RELEVANT MOLECULAR CHANGES UNDERLYING MS NEUROPATHOLOGY. WE PROFILED DNA METHYLATION IN NUCLEI OF NON-NEURONAL CELLS, ISOLATED FROM 38 POST-MORTEM NORMAL-APPEARING WHITE MATTER (NAWM) SPECIMENS OF MS PATIENTS (N = 8) IN COMPARISON TO WHITE MATTER OF CONTROL INDIVIDUALS (N = 14), USING INFINIUM METHYLATIONEPIC BEADCHIP. WE IDENTIFIED 1,226 SIGNIFICANT (GENOME-WIDE ADJUSTED P-VALUE < 0.05) DIFFERENTIALLY METHYLATED POSITIONS (DMPS) BETWEEN MS PATIENTS AND CONTROLS. FUNCTIONAL ANNOTATION OF THE ALTERED DMP-GENES UNCOVERED ALTERATIONS OF PROCESSES RELATED TO CELLULAR MOTILITY, CYTOSKELETON DYNAMICS, METABOLIC PROCESSES, SYNAPTIC SUPPORT, NEUROINFLAMMATION AND SIGNALING, SUCH AS WNT AND TGF-BETA PATHWAYS. A FRACTION OF THE AFFECTED GENES DISPLAYED TRANSCRIPTIONAL DIFFERENCES IN THE BRAIN OF MS PATIENTS, AS REPORTED BY PUBLICALLY AVAILABLE TRANSCRIPTOMIC DATA. CELL TYPE-RESTRICTED ANNOTATION OF DMP-GENES ATTRIBUTED ALTERATIONS OF CYTOSKELETON REARRANGEMENT AND EXTRACELLULAR MATRIX REMODELLING TO ALL GLIAL CELL TYPES, WHILE SOME PROCESSES, INCLUDING ION TRANSPORT, WNT/TGF-BETA SIGNALING AND IMMUNE PROCESSES WERE MORE SPECIFICALLY LINKED TO OLIGODENDROCYTES, ASTROCYTES AND MICROGLIAL CELLS, RESPECTIVELY. OUR FINDINGS STRONGLY SUGGEST THAT NAWM GLIAL CELLS ARE HIGHLY ALTERED, EVEN IN THE ABSENCE OF LESIONAL INSULT, COLLECTIVELY EXHIBITING A MULTICELLULAR REACTION IN RESPONSE TO DIFFUSE INFLAMMATION. 2022 10 2389 32 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 11 4164 30 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 5699 41 SIMULTANEOUS DETECTION OF DNA VARIATION AND METHYLATION AT HLA CLASS II LOCUS AND IMMUNE GENE PROMOTERS USING TARGETED SURESELECT METHYL-SEQUENCING. THE HUMAN LEUKOCYTE ANTIGEN (HLA) LOCUS ASSOCIATES WITH A VARIETY OF COMPLEX DISEASES, PARTICULARLY AUTOIMMUNE AND INFLAMMATORY CONDITIONS. THE HLA-DR15 HAPLOTYPE, FOR EXAMPLE, CONFERS THE MAJOR RISK FOR DEVELOPING MULTIPLE SCLEROSIS IN CAUCASIANS, PINPOINTING AN IMPORTANT ROLE IN THE ETIOLOGY OF THIS CHRONIC INFLAMMATORY DISEASE OF THE CENTRAL NERVOUS SYSTEM. IN ADDITION TO THE PROTEIN-CODING VARIANTS THAT SHAPE THE FUNCTIONAL HLA-ANTIGEN-T CELL INTERACTION, RECENT STUDIES SUGGEST THAT THE LEVELS OF HLA MOLECULE EXPRESSION, THAT ARE EPIGENETICALLY CONTROLLED, ALSO PLAY A ROLE IN DISEASE DEVELOPMENT. HOWEVER, DECIPHERING THE EXACT MOLECULAR MECHANISMS OF THE HLA ASSOCIATION HAS BEEN HAMPERED BY THE TREMENDOUS GENETIC COMPLEXITY OF THE LOCUS AND A LACK OF ROBUST APPROACHES TO INVESTIGATE IT. HERE, WE DEVELOPED A METHOD TO SPECIFICALLY ENRICH THE GENOMIC DNA FROM THE HLA CLASS II LOCUS (CHR6:32,426,802-34,167,129) AND PROXIMAL PROMOTERS OF 2,157 IMMUNE-RELEVANT GENES, UTILIZING THE AGILENT RNA-BASED SURESELECT METHYL-SEQ CAPTURE RELATED METHOD, FOLLOWED BY SEQUENCING TO DETECT GENETIC AND EPIGENETIC VARIATION. WE DEMONSTRATED SUCCESSFUL SIMULTANEOUS DETECTION OF THE GENETIC VARIATION AND QUANTIFICATION OF DNA METHYLATION LEVELS IN HLA LOCUS. MOREOVER, BY THE DETECTION OF DIFFERENTIALLY METHYLATED POSITIONS IN PROMOTERS OF IMMUNE-RELATED GENES, WE IDENTIFIED RELEVANT PATHWAYS FOLLOWING STIMULATION OF CELLS. TAKEN TOGETHER, WE PRESENT A METHOD THAT CAN BE UTILIZED TO STUDY THE INTERPLAY BETWEEN GENETIC VARIANCE AND EPIGENETIC REGULATION IN THE HLA CLASS II REGION, POTENTIALLY, IN A WIDE DISEASE CONTEXT. 2023 13 1518 33 DNA METHYLATION AS AN EPIGENETIC MECHANISM IN THE DEVELOPMENT OF MULTIPLE SCLEROSIS. THE EPIGENETIC MECHANISMS OF GENE EXPRESSION REGULATION ARE A GROUP OF THE KEY CELLULAR AND MOLECULAR PATHWAYS THAT LEAD TO INHERITED ALTERATIONS IN GENES' ACTIVITY WITHOUT CHANGING THEIR CODING SEQUENCE. DNA METHYLATION AT THE C5 POSITION OF CYTOSINE IN CPG DINUCLEOTIDES IS AMONGST THE CENTRAL EPIGENETIC MECHANISMS. CURRENTLY, THE NUMBER OF STUDIES THAT ARE DEVOTED TO THE IDENTIFICATION OF METHYLATION PATTERNS SPECIFIC TO MULTIPLE SCLEROSIS (MS), A SEVERE CHRONIC AUTOIMMUNE DISEASE OF THE CENTRAL NERVOUS SYSTEM, IS ON A RAPID RISE. HOWEVER, THE ISSUE OF THE CONTRIBUTION OF DNA METHYLATION TO THE DEVELOPMENT OF THE DIFFERENT CLINICAL PHENOTYPES OF THIS HIGHLY HETEROGENEOUS DISEASE HAS ONLY BEGUN TO ATTRACT THE ATTENTION OF RESEARCHERS. THIS REVIEW SUMMARIZES THE DATA ON THE MOLECULAR MECHANISMS UNDERLYING DNA METHYLATION AND THE MS RISK FACTORS THAT CAN AFFECT THE DNA METHYLATION PROFILE AND, THEREBY, MODULATE THE EXPRESSION OF THE GENES INVOLVED IN THE DISEASE'S PATHOGENESIS. THE FOCUS OF OUR ATTENTION IS CENTERED ON THE ANALYSIS OF THE PUBLISHED DATA ON THE DIFFERENTIAL METHYLATION OF DNA FROM VARIOUS BIOLOGICAL SAMPLES OF MS PATIENTS OBTAINED USING BOTH THE CANDIDATE GENE APPROACH AND HIGH-THROUGHPUT METHODS. 2021 14 2909 37 GENE EXPRESSION PROFILING IN FIBROMYALGIA INDICATES AN AUTOIMMUNE ORIGIN OF THE DISEASE AND OPENS NEW AVENUES FOR TARGETED THERAPY. FIBROMYALGIA IS A CHRONIC DISORDER CHARACTERIZED BY WIDESPREAD PAIN AND BY SEVERAL NON-PAIN SYMPTOMS. AUTOIMMUNITY, SMALL FIBER NEUROPATHY AND NEUROINFLAMMATION HAVE BEEN SUGGESTED TO BE INVOLVED IN THE PATHOGENESIS OF THE DISEASE. WE HAVE INVESTIGATED THE GENE EXPRESSION PROFILE IN PERIPHERAL BLOOD MONONUCLEAR CELLS OBTAINED FROM TEN PATIENTS AND TEN HEALTHY SUBJECTS. OF THE 545,500 TRANSCRIPTS ANALYZED, 1673 RESULTED MODULATED IN FIBROMYALGIC PATIENTS. THE MAJORITY OF THESE GENES ARE INVOLVED IN BIOLOGICAL PROCESSES AND PATHWAYS LINKED TO THE CLINICAL MANIFESTATIONS OF THE DISEASE. MOREOVER, GENES INVOLVED IN IMMUNOLOGICAL PATHWAYS CONNECTED TO INTERLEUKIN-17 AND TO TYPE I INTERFERON SIGNATURES WERE ALSO MODULATED, SUGGESTING THAT AUTOIMMUNITY PLAYS A ROLE IN THE DISEASE. WE THEN AIMED AT IDENTIFYING DIFFERENTIALLY EXPRESSED LONG NON-CODING RNAS (LNCRNAS) FUNCTIONALLY CONNECTED TO MODULATED GENES BOTH DIRECTLY AND VIA MICRORNA TARGETING. ONLY TWO LNCRNAS OF THE 298 FOUND MODULATED IN PATIENTS, WERE ABLE TO TARGET THE MOST HIGHLY CONNECTED GENES IN THE FIBROMYALGIA INTERACTOME, SUGGESTING THEIR INVOLVEMENT IN CRUCIAL GENE REGULATION. OUR GENE EXPRESSION DATA WERE CONFIRMED BY REAL TIME PCR, BY AUTOANTIBODY TESTING, DETECTION OF SOLUBLE MEDIATORS AND TH-17 POLARIZATION IN A VALIDATION COHORT OF 50 PATIENTS. OUR RESULTS INDICATE THAT GENETIC AND EPIGENETIC MECHANISMS AS WELL AS AUTOIMMUNITY PLAY A PIVOTAL ROLE IN THE PATHOGENESIS OF FIBROMYALGIA. 2020 15 2022 41 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 16 2139 50 EPIGENETIC INSIGHTS INTO MULTIPLE SCLEROSIS DISEASE PROGRESSION. MULTIPLE SCLEROSIS (MS), A CHRONIC INFLAMMATORY DEMYELINATING AND NEURODEGENERATIVE DISEASE OF THE CENTRAL NERVOUS SYSTEM, IS TODAY A LEADING CAUSE OF UNPREDICTABLE LIFELONG DISABILITY IN YOUNG ADULTS. THE TREATMENT OF PATIENTS IN PROGRESSIVE STAGES REMAINS HIGHLY CHALLENGING, ALLUDING TO OUR LIMITED UNDERSTANDING OF THE UNDERLYING PATHOLOGICAL PROCESSES. IN THIS REVIEW, WE PROVIDE INSIGHTS INTO THE MECHANISMS UNDERPINNING MS PROGRESSION FROM A PERSPECTIVE OF EPIGENETICS, THAT REFERS TO STABLE AND MITOTICALLY HERITABLE, YET REVERSIBLE, CHANGES IN THE GENOME ACTIVITY AND GENE EXPRESSION. WE FIRST RECAPITULATE FINDINGS FROM EPIGENETIC STUDIES EXAMINING THE BRAIN TISSUE OF PROGRESSIVE MS PATIENTS, WHICH SUPPORT A CONTRIBUTION OF DNA AND HISTONE MODIFICATIONS IN IMPAIRED OLIGODENDROCYTE DIFFERENTIATION, DEFECTIVE MYELINATION/REMYELINATION AND SUSTAINED NEURO-AXONAL VULNERABILITY. WE NEXT EXPLORE POSSIBILITIES FOR IDENTIFYING FACTORS AFFECTING PROGRESSION USING EASILY ACCESSIBLE TISSUES SUCH AS BLOOD BY COMPARING EPIGENETIC SIGNATURES IN PERIPHERAL IMMUNE CELLS AND BRAIN TISSUE. DESPITE MINOR OVERLAP AT INDIVIDUAL METHYLATION SITES, NEARLY 30% OF ALTERED GENES REPORTED IN PERIPHERAL IMMUNE CELLS OF PROGRESSIVE MS PATIENTS WERE FOUND IN BRAIN TISSUE, JOINTLY CONVERGING ON ALTERATIONS OF NEURONAL FUNCTIONS. WE FURTHER SPECULATE ABOUT THE MECHANISMS UNDERLYING SHARED EPIGENETIC PATTERNS BETWEEN BLOOD AND BRAIN, WHICH LIKELY IMPLY THE INFLUENCE OF INTERNAL (GENETIC CONTROL) AND/OR EXTERNAL (E.G. SMOKING AND AGEING) FACTORS IMPRINTING A COMMON SIGNATURE IN BOTH COMPARTMENTS. OVERALL, WE PROPOSE THAT EPIGENETICS MIGHT SHED LIGHT ON CLINICALLY RELEVANT MECHANISMS INVOLVED IN DISEASE PROGRESSION AND OPEN NEW AVENUES FOR THE TREATMENT OF PROGRESSIVE MS PATIENTS IN THE FUTURE. 2020 17 1594 34 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 18 855 34 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 19 2055 30 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 20 810 42 CHANGES IN DNA METHYLATION IN APOE AND ACKR3 GENES IN MULTIPLE SCLEROSIS PATIENTS AND THE RELATIONSHIP WITH THEIR HEAVY METAL BLOOD LEVELS. MULTIPLE SCLEROSIS (MS) IS A CHRONIC INFLAMMATORY DISEASE WITH DEMYELINATED LESIONS IN THE CENTRAL NERVOUS SYSTEM CAUSED BY GENETIC AND ENVIRONMENTAL FACTORS. DNA METHYLATION AS AN EPIGENETIC CHANGE INFLUENCED BY ENVIRONMENTAL FACTORS, INCLUDING HEAVY METALS HAS BEEN IMPLEMENTED IN MS DISEASE. WE INVESTIGATED THE CORRELATION OF DNA METHYLATION CHANGES IN APOE AND ACKR3 GENES IN MS PATIENTS AND THE POSSIBLE ASSOCIATION WITH BLOOD CONCENTRATION OF ARSENIC (AS), CADMIUM (CD) AND LEAD (PB) AS MAJOR HEAVY METAL POLLUTANTS. THIS STUDY INCLUDED 69 RELAPSING-REMITTING MULTIPLE SCLEROSIS (RR-MS) PATIENTS AND 69 AGE/GENDER-MATCHED HEALTHY SUBJECTS. THE HRM REAL-TIME PCR METHOD WAS USED TO INVESTIGATE THE CHANGES IN DNA METHYLATION AND HEAVY METAL CONCENTRATIONS WERE MEASURED BY ELECTROTHERMAL ATOMIC ABSORPTION SPECTROMETRY. OUR RESULTS SHOWED THAT THE METHYLATION PATTERN IN THE ACKR3 GENE OF THE PATIENT GROUP WAS MORE HYPOMETHYLATED, WHILE IN THE CASE OF THE APOE GENE, THIS PATTERN WAS MORE TOWARDS HYPERMETHYLATION COMPARED TO HEALTHY SUBJECTS. MOREOVER, THE BLOOD LEVELS OF AS AND CD METALS, BUT NOT PB, WERE SIGNIFICANTLY HIGHER IN THE PATIENT GROUP COMPARE TO THE CONTROL GROUP (P