1 2635 152 EPIGENOME-WIDE DNA METHYLATION REGULATES CARDINAL PATHOLOGICAL FEATURES OF PSORIASIS. BACKGROUND: PSORIASIS IS A CHRONIC INFLAMMATORY AUTOIMMUNE SKIN DISORDER. SEVERAL STUDIES SUGGESTED PSORIASIS TO BE A COMPLEX MULTIFACTORIAL DISEASE, BUT THE EXACT TRIGGERING FACTOR IS YET TO BE DETERMINED. EVIDENCES SUGGEST THAT IN ADDITION TO GENETIC FACTORS, EPIGENETIC REPROGRAMMING IS ALSO INVOLVED IN PSORIASIS DEVELOPMENT. MAJOR HISTOPATHOLOGICAL FEATURES, LIKE INCREASED PROLIFERATION AND ABNORMAL DIFFERENTIATION OF KERATINOCYTES, AND IMMUNE CELL INFILTRATIONS ARE CHARACTERISTIC MARKS OF PSORIATIC SKIN LESIONS. FOLLOWING THERAPY, HISTOPATHOLOGICAL FEATURES AS WELL AS ABERRANT DNA METHYLATION REVERSED TO NORMAL LEVELS. TO UNDERSTAND THE ROLE OF DNA METHYLATION IN REGULATING THESE CRUCIAL HISTOPATHOLOGIC FEATURES, WE INVESTIGATED THE GENOME-WIDE DNA METHYLATION PROFILE OF PSORIASIS PATIENTS WITH DIFFERENT HISTOPATHOLOGICAL FEATURES. RESULTS: GENOME-WIDE DNA METHYLATION PROFILING OF PSORIATIC AND ADJACENT NORMAL SKIN TISSUES IDENTIFIED SEVERAL NOVEL DIFFERENTIALLY METHYLATED REGIONS ASSOCIATED WITH PSORIASIS. DIFFERENTIALLY METHYLATED CPGS WERE SIGNIFICANTLY ENRICHED IN SEVERAL PSORIASIS SUSCEPTIBILITY (PSORS) REGIONS AND EPIGENETICALLY REGULATED THE EXPRESSION OF KEY PATHOGENIC GENES, EVEN WITH LOW-CPG PROMOTERS. TOP DIFFERENTIALLY METHYLATED GENES OVERLAPPED WITH PSORS REGIONS INCLUDING S100A9, SELENBP1, CARD14, KAZN AND PTPN22 SHOWED INVERSE CORRELATION BETWEEN METHYLATION AND GENE EXPRESSION. WE IDENTIFIED DIFFERENTIALLY METHYLATED GENES ASSOCIATED WITH CHARACTERISTIC HISTOPATHOLOGICAL FEATURES IN PSORIASIS. PSORIATIC SKIN WITH MUNRO'S MICROABSCESS, A DISTINCTIVE FEATURE IN PSORIASIS INCLUDING PARAKERATOSIS AND NEUTROPHIL ACCUMULATION AT THE STRATUM CORNEUM, WAS ENRICHED WITH DIFFERENTIALLY METHYLATED GENES INVOLVED IN NEUTROPHIL CHEMOTAXIS. RETE PEG ELONGATION AND FOCAL HYPERGRANULOSIS WERE ALSO ASSOCIATED WITH EPIGENETICALLY REGULATED GENES, SUPPORTING THE REVERSIBLE NATURE OF THESE CHARACTERISTIC FEATURES DURING REMISSION AND RELAPSE OF THE LESIONS. CONCLUSION: OUR STUDY, FOR THE FIRST TIME, INDICATED THE POSSIBLE INVOLVEMENT OF DNA METHYLATION IN REGULATING THE CARDINAL PATHOPHYSIOLOGICAL FEATURES IN PSORIASIS. COMMON GENES INVOLVED IN REGULATION OF THESE PATHOLOGIES MAY BE USED TO DEVELOP DRUGS FOR BETTER CLINICAL MANAGEMENT OF PSORIASIS. 2018 2 2553 40 EPIGENETICS IN PSORIASIS: PERSPECTIVE OF DNA METHYLATION. PSORIASIS IS A CHRONIC INFLAMMATORY SKIN DISEASE CHARACTERIZED BY EXCESSIVE PROLIFERATION OF KERATINOCYTES (KCS). ONSET OF PSORIASIS IS RELATED TO GENETIC, IMMUNE AND ENVIRONMENTAL FACTORS. THE ENVIRONMENT CAN INTERACT WITH THE GENOME THROUGH EPIGENETIC MODIFICATIONS, INCLUDING DNA METHYLATION, AND THIS MODIFICATION IS INVOLVED IN THE PATHOGENESIS OF PSORIASIS. IN ADDITION TO A SKIN DISEASE, PSORIASIS IS ALSO CONSIDERED A SYSTEMIC DISEASE. WE REVIEWED THE CURRENT LITERATURE OF PSORIATIC DNA METHYLATION FOR STUDIES FROM SEVERAL ASPECTS ON THE DNA METHYLATION DISTRIBUTION PATTERNS IN DIFFERENT TISSUES/CELLS, SINGLE-NUCLEOTIDE POLYMORPHISMS, AND CANDIDATE DISEASE GENES AND IDENTIFIED TARGET GENES REGULATED BY DNA METHYLATION THAT HAVE BEEN DIRECTLY/INDIRECTLY VALIDATED. THIS REVIEW CONTRIBUTES TO A COMPREHENSIVE UNDERSTANDING OF THE IMPORTANT A ROLE THAT DNA METHYLATION PLAYS IN PSORIASIS FROM A HOLISTIC PERSPECTIVE AND WILL PROMOTE THE IMPLEMENTATION OF DNA METHYLATION IN DIAGNOSTIC AND THERAPEUTIC STRATEGIES FOR PSORIATIC PATIENTS. 2021 3 1584 33 DNA METHYLATION PROFILES OF SELECTED PRO-INFLAMMATORY CYTOKINES IN ALZHEIMER DISEASE. BY MEANS OF FUNCTIONAL GENOMICS ANALYSIS, WE RECENTLY DESCRIBED THE MRNA EXPRESSION PROFILES OF VARIOUS GENES INVOLVED IN THE NEUROINFLAMMATORY RESPONSE IN THE BRAINS OF SUBJECTS WITH LATE-ONSET ALZHEIMER DISEASE (LOAD). SOME OF THESE GENES, NAMELY INTERLEUKIN (IL)-1BETA AND IL-6, SHOWED DISTINCT EXPRESSION PROFILES WITH PEAK EXPRESSION DURING THE FIRST STAGES OF THE DISEASE AND CONTROL-LIKE LEVELS AT LATER STAGES. IL-1BETA AND IL-6 GENES ARE MODULATED BY DNA METHYLATION IN DIFFERENT CHRONIC AND DEGENERATIVE DISEASES; IT IS ALSO WELL KNOWN THAT LOAD MAY HAVE AN EPIGENETIC BASIS. INDEED, WE AND OTHERS HAVE PREVIOUSLY REPORTED GENE-SPECIFIC DNA METHYLATION ALTERATIONS IN LOAD AND IN RELATED ANIMAL MODELS. BASED ON THESE DATA, WE STUDIED THE DNA METHYLATION PROFILES, AT SINGLE CYTOSINE RESOLUTION, OF IL-1BETA AND IL-6 5'-FLANKING REGION BY BISULPHITE MODIFICATION IN THE CORTEX OF HEALTHY CONTROLS AND LOAD PATIENTS AT 2 DIFFERENT DISEASE STAGES: BRAAK I-II/A AND BRAAK V-VI/C. OUR ANALYSIS PROVIDES EVIDENCE THAT NEUROINFLAMMATION IN LOAD IS ASSOCIATED WITH (AND POSSIBLY MEDIATED BY) EPIGENETIC MODIFICATIONS. 2017 4 1508 49 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 5 51 45 A DISTINCT EPIGENETIC PROFILE DISTINGUISHES STENOTIC FROM NON-INFLAMED FIBROBLASTS IN THE ILEAL MUCOSA OF CROHN'S DISEASE PATIENTS. BACKGROUND: THE CHRONIC REMITTING AND RELAPSING INTESTINAL INFLAMMATION CHARACTERISTIC OF CROHN'S DISEASE FREQUENTLY LEADS TO FIBROSIS AND SUBSEQUENT STENOSIS OF THE INFLAMED REGION. APPROXIMATELY A THIRD OF ALL CROHN'S DISEASE PATIENTS REQUIRE RESECTION AT SOME STAGE IN THEIR DISEASE COURSE. AS THE PATHOGENESIS OF CROHN'S DISEASE ASSOCIATED FIBROSIS IS LARGELY UNKNOWN, A STRONG NECESSITY EXISTS TO BETTER UNDERSTAND THE PATHOPHYSIOLOGY THEREOF. METHODS: IN THIS STUDY, WE INVESTIGATED CHANGES OF THE DNA METHYLOME AND TRANSCRIPTOME OF ILEUM-DERIVED FIBROBLASTS ASSOCIATED TO THE OCCURRENCE OF CROHN'S DISEASE ASSOCIATED FIBROSIS. EIGHTEEN SAMPLES WERE INCLUDED IN A DNA METHYLATION ARRAY AND TWENTY-ONE SAMPLES WERE USED FOR RNA SEQUENCING. RESULTS: MOST DIFFERENTIALLY METHYLATED REGIONS AND DIFFERENTIALLY EXPRESSED GENES WERE OBSERVED WHEN COMPARING STENOTIC WITH NON-INFLAMED SAMPLES. BY CONTRAST, FEW DIFFERENCES WERE OBSERVED WHEN COMPARING CROHN'S DISEASE WITH NON-CROHN'S DISEASE, OR INFLAMED WITH NON-INFLAMED TISSUE. INTEGRATIVE METHYLATION AND GENE EXPRESSION ANALYSES REVEALED DYSREGULATION OF GENES ASSOCIATED TO THE PRKACA AND E2F1 NETWORK, WHICH IS INVOLVED IN CELL CYCLE PROGRESSION, ANGIOGENESIS, EPITHELIAL TO MESENCHYMAL TRANSITION, AND BILE METABOLISM. CONCLUSION: OUR RESEARCH PROVIDES EVIDENCE THAT THE METHYLOME AND THE TRANSCRIPTOME ARE SYSTEMATICALLY DYSREGULATED IN STENOSIS-ASSOCIATED FIBROBLASTS. 2018 6 2533 47 EPIGENETICS IN AUTOIMMUNE CONNECTIVE TISSUE DISEASES. BACKGROUND. AUTOIMMUNE CONNECTIVE TISSUE DISEASES (ACTDS) ENCOMPASS A HETEROGENEOUS GROUP OF CHRONIC IMMUNE-MEDIATED INFLAMMATORY DISORDERS, PRIMARILY AFFECTING CONNECTIVE TISSUES AND CLINICALLY CHARACTERIZED BY VARIABLE MULTISYSTEM MANIFESTATIONS, FREQUENTLY OVERLAPPING. ENVIRONMENTAL FACTORS ARE THOUGHT TO PROMOTE ACTD DEVELOPMENT IN GENETIC PREDISPOSING/ENDOCRINE PERMISSIVE BACKGROUND THROUGH THE INDUCTION OF EPIGENETIC MODIFICATIONS, CONSISTING OF STABLE, HERITABLE, BUT POTENTIALLY REVERSIBLE CHANGES IN GENE EXPRESSION, OCCURRING WITHOUT ALTERATIONS OF THE DNA SEQUENCE. ACTUALLY, EPIGENETIC MECHANISMS (SUCH AS HISTONE MODIFICATIONS, DNA METHYLATION, NUCLEOSOME POSITIONING, AND RNA INTERFERENCE) LINK GENOTYPE UPSTREAM AND PHENOTYPE DOWNSTREAM, AND, IF PERSISTENTLY ABERRANT, MAY CAUSE A VARIETY OF HUMAN DISEASES, INCLUDING ACTDS. WE AIMED TO REVIEW THE RECENT ADVANCES IN THE KNOWLEDGE OF THE ACTD EPIGENETIC ALTERATIONS. METHODS: A DETAILED SEARCH OF THE AVAILABLE LITERATURE WAS PERFORMED IN THE PUBMED (U.S. NATIONAL LIBRARY OF MEDICINE) DATABASE. RESULTS: GROWING EVIDENCE UNDERLINES THE RELEVANT ROLE OF EPIGENETIC DEFECTS IN THE ACTD PATHOGENESIS, AND SPECIFIC EPIGENETIC PATTERNS CAN REPRESENT DISEASE BIOMARKERS. IN PATIENTS WITH RHEUMATOID ARTHRITIS (RA), EPIGENETIC VARIATIONS INTERACT DETERMINING THE TYPICAL "AGGRESSIVE" PHENOTYPE DISPLAYED BY RA SYNOVIAL FIBROBLASTS. EPIGENETIC MODIFICATIONS ARE INVOLVED IN THE PROFIBROTIC PROCESS THAT CHARACTERIZES SYSTEMIC SCLEROSIS. IN SYSTEMIC LUPUS ERYTHEMATOSUS AND SJOGREN'S SYNDROME, COMPLEX EPIGENETIC CHANGES ALTERING GENE EXPRESSION HAVE BEEN DEMONSTRATED. CONCLUSIONS: COMPREHENSIVE STUDIES WILL CONTRIBUTE TO FURTHER DEFINE THE ABERRANT EPIGENETIC MECHANISMS INVOLVED IN THE ACTDS ETIOPATHOGENESIS. MOREOVER, BEING EPIGENETIC CHANGES POTENTIALLY REVERSIBLE, THE IDENTIFICATION OF ACTDS EPIGENETIC BIOMARKERS WILL ALLOW THE DEVELOPMENT OF THERAPEUTIC STRATEGIES ADDRESSED TO TARGET DYSREGULATED GENES AND CORRECT ABERRANT EPIGENOMIC ALTERATIONS. 2014 7 4164 39 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 8 1567 46 DNA METHYLATION OF THE KLF14 GENE REGION IN WHOLE BLOOD CELLS PROVIDES PREDICTION FOR THE CHRONIC INFLAMMATION IN THE ADIPOSE TISSUE. KRUPPEL-LIKE FACTOR 14 (KLF14) GENE, WHICH APPEARS TO BE A MASTER REGULATOR OF GENE EXPRESSION IN THE ADIPOSE TISSUE AND HAVE PREVIOUSLY BEEN ASSOCIATED WITH BMI AND TYPE 2 DIABETES (T2D) BY LARGE GENOME-WIDE ASSOCIATION STUDIES. IN ORDER TO FIND PREDICTIVE BIOMARKERS FOR THE DEVELOPMENT OF T2D, IT IS NECESSARY TO TAKE EPIGENOMIC CHANGES AFFECTED BY ENVIRONMENTAL FACTORS INTO ACCOUNT. THIS STUDY FOCUSES ON AGEING AND OBESITY, WHICH ARE T2D RISK FACTORS, AND EXAMINES EPIGENETIC CHANGES AND INFLAMMATORY CHANGES. WE INVESTIGATED DNA METHYLATION CHANGES IN THE KLF14 PROMOTER REGION IN DIFFERENT ORGANS OF MICE FOR COMPARING AGING AND WEIGHT. WE FOUND THAT METHYLATION LEVELS OF THESE SITES WERE INCREASED WITH AGING AND WEIGHT IN THE SPLEEN, THE ADIPOSE TISSUE, THE KIDNEY, THE LUNG, THE COLON AND THE WHOLE BLOOD CELLS. IN ADDITION, IN THE SPLEEN, THE ADIPOSE TISSUE AND THE WHOLE BLOOD, THESE EPIGENETIC CHANGES WERE ALSO SIGNIFICANTLY ASSOCIATED WITH INFLAMMATORY LEVELS. MOREOVER, NOT ONLY KLF14, BUT ALSO EXPRESSION LEVELS OF SOME DOWNSTREAM GENES WERE DECREASED WITH METHYLATION IN THE SPLEEN, THE ADIPOSE TISSUE AND THE WHOLE BLOOD CELLS. TAKEN TOGETHER, OUR RESULTS SUGGEST THAT METHYLATION CHANGES OF KLF14 IN THOSE TISSUES MAY BE ASSOCIATED WITH CHANGES IN GENE EXPRESSION AND INFLAMMATION ON THE ADIPOSE TISSUE OF OBESITY AND T2D. IN ADDITION, THE METHYLATION CHANGES IN THE WHOLE BLOOD CELLS MAY SERVE AS A PREDICTIVE EPIGENETIC BIOMARKER FOR THE DEVELOPMENT OF T2D. 2018 9 5269 44 PROMOTER DNA METHYLATION CONTRIBUTES TO HUMAN BETA-DEFENSIN-1 DEFICIENCY IN ATOPIC DERMATITIS. ATOPIC DERMATITIS (AD) IS A CHRONIC INFLAMMATORY SKIN DISEASE CAUSED BY EPIDERMAL BARRIER DYSFUNCTION AND DYSREGULATION OF INNATE AND ADAPTIVE IMMUNITY. EPIGENETIC REGULATION OF HUMAN BETA-DEFENSIN-1 (HBD-1) MIGHT BE ASSOCIATED WITH A VARIETY OF DEFECTS IN THE INNATE IMMUNE SYSTEM DURING AD PATHOGENESIS. WE INVESTIGATED THE POSSIBLE MECHANISM OF DECREASED HBD-1 GENE EXPRESSION IN AD AND DEMONSTRATED THE RESTORATION OF HBD-1 TRANSCRIPTION IN UNDIFFERENTIATED NORMAL HUMAN EPIDERMAL KERATINOCYTE CELLS AFTER TREATMENT WITH A DNA METHYLTRANSFERASE INHIBITOR. WE ALSO CONDUCTED AN IN VITRO METHYLATED REPORTER ASSAY USING A REPORTER CONTAINING 14 CPG SITES. METHYLATION OF THE 14 CPG SITES WITHIN THE HBD-1 5' REGION RESULTED IN AN APPROXIMATELY 86% REDUCTION IN PROMOTER ACTIVITY AND AFFECTED HBD-1 TRANSCRIPTIONAL REGULATION. WE THEN COMPARED METHYLATION FREQUENCIES AT CPG 3 AND CPG 4 BETWEEN NON-LESIONAL AND LESIONAL EPIDERMIS SAMPLES OF PATIENTS WITH SEVERE AD AND BETWEEN THESE PAIRED TISSUES AND HEALTHY CONTROL EPIDERMIS FROM NORMAL VOLUNTEERS WITHOUT AD HISTORY. BISULFITE PYROSEQUENCING DATA SHOWED SIGNIFICANTLY HIGHER METHYLATION FREQUENCIES AT THE CPG 3 AND 4 SITES IN AD LESIONAL SAMPLES THAN IN NON-LESIONAL AD SKIN AND NORMAL SKIN SAMPLES (P < 0.05). THESE RESULTS SUGGEST THAT THE DNA METHYLATION SIGNATURE OF HBD-1 IS A NOVEL DIAGNOSTIC/PROGNOSTIC MARKER AND A PROMISING THERAPEUTIC TARGET FOR THE COMPROMISED STRATUM CORNEUM BARRIER ATTRIBUTED TO HBD-1 DEFICIENCY. 2018 10 1594 41 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 11 6468 32 TISSUE-SPECIFIC ENRICHMENT OF LYMPHOMA RISK LOCI IN REGULATORY ELEMENTS. THOUGH NUMEROUS POLYMORPHISMS HAVE BEEN ASSOCIATED WITH RISK OF DEVELOPING LYMPHOMA, HOW THESE VARIANTS FUNCTION TO PROMOTE TUMORIGENESIS IS POORLY UNDERSTOOD. HERE, WE REPORT THAT LYMPHOMA RISK SNPS, ESPECIALLY IN THE NON-HODGKIN'S LYMPHOMA SUBTYPE CHRONIC LYMPHOCYTIC LEUKEMIA, ARE SIGNIFICANTLY ENRICHED FOR CO-LOCALIZATION WITH EPIGENETIC MARKS OF ACTIVE GENE REGULATION. THESE ENRICHMENTS WERE SEEN IN A LYMPHOID-SPECIFIC MANNER FOR NUMEROUS ENCODE DATASETS, INCLUDING DNASE-HYPERSENSITIVITY AS WELL AS MULTIPLE SEGMENTATION-DEFINED ENHANCER REGIONS. FURTHERMORE, WE IDENTIFY PUTATIVELY FUNCTIONAL SNPS THAT ARE BOTH IN REGULATORY ELEMENTS IN LYMPHOCYTES AND ARE ASSOCIATED WITH GENE EXPRESSION CHANGES IN BLOOD. WE DEVELOPED AN ALGORITHM, UES, THAT USES A MONTE CARLO SIMULATION APPROACH TO CALCULATE THE ENRICHMENT OF PREVIOUSLY IDENTIFIED RISK SNPS IN VARIOUS FUNCTIONAL ELEMENTS. THIS MULTISCALE APPROACH INTEGRATING MULTIPLE DATASETS HELPS DISENTANGLE THE UNDERLYING BIOLOGY OF LYMPHOMA, AND MORE BROADLY, IS GENERALLY APPLICABLE TO GWAS RESULTS FROM OTHER DISEASES AS WELL. 2015 12 3473 38 IDENTIFICATION OF A NOVEL, METHYLATION-DEPENDENT, RUNX2 REGULATORY REGION ASSOCIATED WITH OSTEOARTHRITIS RISK. OSTEOARTHRITIS (OA) IS A COMMON, MULTIFACTORIAL AND POLYGENIC SKELETAL DISEASE THAT, IN ITS SEVEREST FORM, REQUIRES JOINT REPLACEMENT SURGERY TO RESTORE MOBILITY AND TO RELIEVE CHRONIC PAIN. USING TISSUES FROM THE ARTICULATING JOINTS OF 260 PATIENTS WITH OA AND A RANGE OF IN VITRO EXPERIMENTS, INCLUDING CRISPR-CAS9, WE HAVE CHARACTERIZED AN INTERGENIC REGULATORY ELEMENT. HERE, GENOTYPE AT AN OA RISK LOCUS CORRELATES WITH DIFFERENTIAL DNA METHYLATION, WITH ALTERED GENE EXPRESSION OF BOTH A TRANSCRIPTIONAL REGULATOR (RUNX2), AND A CHROMATIN REMODELLING PROTEIN (SUPT3H). RUNX2 IS A STRONG CANDIDATE FOR OA SUSCEPTIBILITY, WITH ITS ENCODED PROTEIN BEING ESSENTIAL FOR SKELETOGENESIS AND HEALTHY JOINT FUNCTION. THE OA RISK LOCUS INCLUDES SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) LOCATED WITHIN AND FLANKING THE DIFFERENTIALLY METHYLATED REGION (DMR). THE OA ASSOCIATION SNP, RS10948172, DEMONSTRATES PARTICULARLY STRONG CORRELATION WITH METHYLATION, AND TWO INTERGENIC SNPS FALLING WITHIN THE DMR (RS62435998 AND RS62435999) DEMONSTRATE GENETIC AND EPIGENETIC EFFECTS ON THE REGULATORY ACTIVITY OF THIS REGION. WE THEREFORE POSIT THAT THE OA SIGNAL MEDIATES ITS EFFECT BY MODULATING THE METHYLATION OF THE REGULATORY ELEMENT, WHICH THEN IMPACTS ON GENE EXPRESSION, WITH RUNX2 BEING THE PRINCIPAL TARGET. OUR STUDY HIGHLIGHTS THE INTERPLAY BETWEEN DNA METHYLATION, OA GENETIC RISK AND THE DOWNSTREAM REGULATION OF GENES CRITICAL TO NORMAL JOINT FUNCTION. 2018 13 1545 44 DNA METHYLATION IN LIVER TUMORIGENESIS IN FISH FROM THE ENVIRONMENT. THE LINK BETWEEN ENVIRONMENT, ALTERATION IN DNA METHYLATION AND CANCER HAS BEEN WELL ESTABLISHED IN HUMANS; YET, IT IS UNDER-STUDIED IN UNSEQUENCED NON-MODEL ORGANISMS. THE OCCURRENCE OF LIVER TUMORS IN THE FLATFISH DAB COLLECTED AT CERTAIN UK SAMPLING SITES EXCEEDS 20%, YET THE CAUSATIVE AGENTS AND THE MOLECULAR MECHANISMS OF TUMOR FORMATION ARE NOT KNOWN, ESPECIALLY REGARDING THE BALANCE BETWEEN EPIGENETIC AND GENETIC FACTORS. METHYLATED DNA IMMUNOPRECIPITATION (MEDIP) COMBINED WITH DE NOVO HIGH-THROUGHPUT DNA SEQUENCING WERE USED TO INVESTIGATE DNA METHYLATION CHANGES IN DAB HEPATOCELLULAR ADENOMA TUMORS FOR THE FIRST TIME IN AN UNSEQUENCED SPECIES. NOVEL CUSTOM-MADE DAB GENE EXPRESSION ARRAYS WERE DESIGNED AND USED TO DETERMINE THE RELATIONSHIP BETWEEN DNA METHYLATION AND GENE EXPRESSION. IN ADDITION, THE CONFIRMATORY TECHNIQUES OF BISULFITE SEQUENCING PCR (BSP) AND RT-PCR WERE APPLIED. GENES INVOLVED IN PATHWAYS RELATED TO CANCER, INCLUDING APOPTOSIS, WNT/BETA-CATENIN SIGNALING AND GENOMIC AND NON-GENOMIC ESTROGEN RESPONSES, WERE ALTERED BOTH IN METHYLATION AND TRANSCRIPTION. GLOBAL METHYLATION WAS STATISTICALLY SIGNIFICANTLY 1.8-FOLD REDUCED IN HEPATOCELLULAR ADENOMA AND NON-CANCEROUS SURROUNDING TISSUES COMPARED WITH LIVER FROM NON-CANCER BEARING DAB. BASED ON THE IDENTIFIED CHANGES AND CHEMICAL EXPOSURE DATA, OUR STUDY SUPPORTS THE EPIGENETIC MODEL OF CANCER. WE HYPOTHESIZE THAT CHRONIC EXPOSURE TO A MIXTURE OF ENVIRONMENTAL CONTAMINANTS CONTRIBUTES TO A GLOBAL HYPOMETHYLATION FOLLOWED BY FURTHER EPIGENETIC AND GENOMIC CHANGES. THE FINDINGS SUGGEST A LINK BETWEEN ENVIRONMENT, EPIGENETICS AND CANCER IN FISH TUMORS IN THE WILD AND SHOW THE UTILITY OF THIS METHODOLOGY FOR STUDIES IN NON-MODEL ORGANISMS. 2011 14 1587 43 DNA METHYLATION PROFILING IDENTIFIES NOVEL MARKERS OF PROGRESSION IN HEPATITIS B-RELATED CHRONIC LIVER DISEASE. BACKGROUND: CHRONIC HEPATITIS B INFECTION IS CHARACTERIZED BY HEPATIC IMMUNE AND INFLAMMATORY RESPONSE WITH CONSIDERABLE VARIATION IN THE RATES OF PROGRESSION TO CIRRHOSIS. GENETIC VARIANTS AND ENVIRONMENTAL CUES INFLUENCE PREDISPOSITION TO THE DEVELOPMENT OF CHRONIC LIVER DISEASE; HOWEVER, IT REMAINS UNKNOWN IF ABERRANT DNA METHYLATION IS ASSOCIATED WITH FIBROSIS PROGRESSION IN CHRONIC HEPATITIS B. RESULTS: TO IDENTIFY EPIGENETIC MARKS ASSOCIATED WITH INFLAMMATORY AND FIBROTIC PROCESSES OF THE HEPATITIS B-INDUCED CHRONIC LIVER DISEASE, WE CARRIED OUT HEPATIC GENOME-WIDE METHYLATION PROFILING USING ILLUMINA INFINIUM BEADARRAYS COMPARING MILD AND SEVERE FIBROTIC DISEASE IN A DISCOVERY COHORT OF 29 PATIENTS. WE OBTAINED 310 DIFFERENTIALLY METHYLATED REGIONS AND SELECTED FOUR LOCI COMPRISING THREE GENES FROM THE TOP DIFFERENTIALLY METHYLATED REGIONS: HYPERMETHYLATION OF HOXA2 AND HDAC4 ALONG WITH HYPOMETHYLATION OF PPP1R18 WERE SIGNIFICANTLY LINKED TO SEVERE FIBROSIS. WE REPLICATED THE PROMINENT METHYLATION MARKS IN AN INDEPENDENT COHORT OF 102 PATIENTS BY BISULFITE MODIFICATION AND PYROSEQUENCING. THE TIMING AND CAUSAL RELATIONSHIP OF EPIGENETIC MODIFICATIONS WITH DISEASE SEVERITY WAS FURTHER INVESTIGATED USING A COHORT OF PATIENTS WITH SERIAL BIOPSIES. CONCLUSIONS: OUR FINDINGS SUGGEST A LINKAGE OF WIDESPREAD EPIGENETIC DYSREGULATION WITH DISEASE PROGRESSION IN CHRONIC HEPATITIS B INFECTION. CPG METHYLATION AT NOVEL GENES SHEDS LIGHT ON NEW MOLECULAR PATHWAYS, WHICH CAN BE POTENTIALLY EXPLOITED AS A BIOMARKER OR TARGETED TO ATTENUATE INFLAMMATION AND FIBROSIS. 2016 15 276 38 AGE-RELATED DIFFERENCES IN MONOCYTE DNA METHYLATION AND IMMUNE FUNCTION IN HEALTHY KENYAN ADULTS AND CHILDREN. BACKGROUND: AGE-RELATED CHANGES IN ADAPTIVE AND INNATE IMMUNE CELLS HAVE BEEN ASSOCIATED WITH A DECLINE IN EFFECTIVE IMMUNITY AND CHRONIC, LOW-GRADE INFLAMMATION. EPIGENETIC, TRANSCRIPTIONAL, AND FUNCTIONAL CHANGES IN MONOCYTES OCCUR WITH AGING, THOUGH MOST STUDIES TO DATE HAVE FOCUSED ON DIFFERENCES BETWEEN YOUNG ADULTS AND THE ELDERLY IN POPULATIONS WITH EUROPEAN ANCESTRY; FEW DATA EXIST REGARDING CHANGES THAT OCCUR IN CIRCULATING MONOCYTES DURING THE FIRST FEW DECADES OF LIFE OR IN AFRICAN POPULATIONS. WE ANALYZED DNA METHYLATION PROFILES, CYTOKINE PRODUCTION, AND INFLAMMATORY GENE EXPRESSION PROFILES IN MONOCYTES FROM YOUNG ADULTS AND CHILDREN FROM WESTERN KENYA. RESULTS: WE IDENTIFIED SEVERAL HYPO- AND HYPER-METHYLATED CPG SITES IN MONOCYTES FROM KENYAN YOUNG ADULTS VS. CHILDREN THAT REPLICATED FINDINGS IN THE CURRENT LITERATURE OF DIFFERENTIAL DNA METHYLATION IN MONOCYTES FROM ELDERLY PERSONS VS. YOUNG ADULTS ACROSS DIVERSE POPULATIONS. DIFFERENTIALLY METHYLATED CPG SITES WERE ALSO NOTED IN GENE REGIONS IMPORTANT TO INFLAMMATION AND INNATE IMMUNE RESPONSES. MONOCYTES FROM KENYAN YOUNG ADULTS VS. CHILDREN DISPLAYED INCREASED PRODUCTION OF IL-8, IL-10, AND IL-12P70 IN RESPONSE TO TLR4 AND TLR2/1 STIMULATION AS WELL AS DISTINCT INFLAMMATORY GENE EXPRESSION PROFILES. CONCLUSIONS: THESE FINDINGS COMPLEMENT PREVIOUS REPORTS OF AGE-RELATED METHYLATION CHANGES IN ISOLATED MONOCYTES AND PROVIDE NOVEL INSIGHTS INTO THE ROLE OF AGE-ASSOCIATED CHANGES IN INNATE IMMUNE FUNCTIONS. 2021 16 6826 50 [GENOME-WIDE ANALYSIS OF DNA METHYLATION IN CD4+ T LYMPHOCYTES OF PATIENTS WITH PRIMARY PROGRESSIVE MULTIPLE SCLEROSIS INDICATES INVOLVEMENT OF THIS EPIGENETIC PROCESS IN THE DISEASE IMMUNOPATHOGENESIS]. THE PATHOGENESIS OF MULTIPLE SCLEROSIS (MS), A CHRONIC DISEASE OF THE CNS, INCLUDES AUTOIMMUNE AND NEURODEGENERATIVE COMPONENTS. IN MOST CASES, PATIENTS DEVELOP RELAPSING-REMITTING MS (RRMS), WHILE 10-15% OF PATIENTS DEVELOP PRIMARY PROGRESSIVE MS (PPMS), WHICH DIFFERS FROM RRMS IN THE MECHANISMS OF THE PATHOLOGICAL PROCESS, SOME DEMOGRAPHIC, AND SOME CLINICAL CHARACTERISTICS. THESE DIFFERENCES MAY BE EXPLAINED BY THE EPIGENETIC REGULATION OF GENE EXPRESSION IN PPMS INCLUDING DNA METHYLATION AS ONE OF THE KEY EPIGENETIC PROCESSES. THE FEATURES OF DNA METHYLATION IN VARIOUS CELL POPULATIONS IN PPMS PATIENTS REMAIN UNDERSTUDIED. THE GOAL OF THIS STUDY IS TO IDENTIFY DIFFERENTIALLY METHYLATED CPG SITES (DMSS) OF THE GENOME OF CD4+ T LYMPHOCYTES, WHICH CHARACTERIZE PPMS. THE STUDY INCLUDED EIGHT TREATMENT-NAIVE PPMS PATIENTS AND EIGHT HEALTHY CONTROLS. GENOME-WIDE ANALYSIS OF DNA METHYLATION OF CD4+ T LYMPHOCYTES WAS PERFORMED USING HIGH-DENSITY DNA MICROARRAYS. WE HAVE IDENTIFIED 108 DMSS, WHICH DISTINGUISH PPMS PATIENTS FROM HEALTHY CONTROLS. IN PPMS PATIENTS 81% OF THE DMSS ARE HYPERMETHYLATED. MORE THAN A HALF OF THE IDENTIFIED DMSS ARE LOCATED IN KNOWN GENES IN CPG ISLANDS AND ADJACENT REGIONS, WHICH INDICATES A HIGH FUNCTIONAL SIGNIFICANCE OF THESE DMSS IN PPMS DEVELOPMENT. ANALYSIS OF THE OVERREPRESENTATION OF DMS-CONTAINING GENES IN THE MAIN BIOLOGICAL PROCESSES DEMONSTRATES THEIR INVOLVEMENT IN THE REGULATION OF CELL ADHESION TO THE EXTRACELLULAR MATRIX AND THE DEVELOPMENT OF THE IMMUNE RESPONSE, I.E., ANTIGEN PROCESSING AND PRESENTATION, AND DEVELOPMENT OF THE IMMUNE SYSTEM. GENOME-WIDE ANALYSIS OF DNA METHYLATION IN CD4+ T LYMPHOCYTES OF PPMS PATIENTS INDICATES THE INVOLVEMENT OF THIS EPIGENETIC PROCESS IN THE IMMUNOPATHOGENESIS OF THE DISEASE. THESE RESULTS MAY HELP BETTER UNDERSTAND THE PATHOGENESIS OF THIS SEVERE FORM OF MS. 2022 17 3066 43 GENOME-WIDE DNA METHYLATION PATTERNS IN CD4+ T CELLS FROM PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS. SYSTEMIC LUPUS ERYTHEMATOSUS IS A CHRONIC-RELAPSING AUTOIMMUNE DISEASE OF INCOMPLETELY UNDERSTOOD ETIOLOGY. RECENT EVIDENCE STRONGLY SUPPORTS AN EPIGENETIC CONTRIBUTION TO THE PATHOGENESIS OF LUPUS. TO UNDERSTAND THE EXTENT AND NATURE OF DYSREGULATED DNA METHYLATION IN LUPUS T CELLS, WE PERFORMED A GENOME-WIDE DNA METHYLATION STUDY IN CD4 (+) T CELLS IN LUPUS PATIENTS COMPARED TO NORMAL HEALTHY CONTROLS. CYTOSINE METHYLATION WAS QUANTIFIED IN 27,578 CG SITES LOCATED WITHIN THE PROMOTER REGIONS OF 14,495 GENES. WE IDENTIFIED 236 HYPOMETHYLATED AND 105 HYPERMETHYLATED CG SITES IN LUPUS CD4 (+) T CELLS COMPARED TO NORMAL CONTROLS, CONSISTENT WITH WIDESPREAD DNA METHYLATION CHANGES IN LUPUS T CELLS. OF INTEREST, HYPOMETHYLATED GENES IN LUPUS T CELLS INCLUDE CD9, WHICH IS KNOWN TO PROVIDE POTENT T-CELL CO-STIMULATION SIGNALS. OTHER GENES WITH KNOWN INVOLVEMENT IN AUTOIMMUNITY SUCH AS MMP9 AND PDGFRA WERE ALSO HYPOMETHYLATED. THE BST2 GENE, AN INTERFERON-INDUCIBLE MEMBRANE-BOUND PROTEIN THAT HELPS RESTRICT THE RELEASE OF RETROVIRAL PARTICLES WAS ALSO HYPOMETHYLATED IN LUPUS PATIENTS. GENES INVOLVED IN FOLATE BIOSYNTHESIS, WHICH PLAYS A ROLE IN DNA METHYLATION, WERE OVERREPRESENTED AMONG HYPERMETHYLATED GENES. IN ADDITION, THE TRANSCRIPTION FACTOR RUNX3 WAS HYPERMETHYLATED IN PATIENTS, SUGGESTING AN IMPACT ON T-CELL MATURATION. PROTEIN-PROTEIN INTERACTION MAPS IDENTIFIED A TRANSCRIPTION FACTOR, HNF4A, AS A REGULATORY HUB AFFECTING A NUMBER OF DIFFERENTIALLY METHYLATED GENES. APOPTOSIS WAS ALSO AN OVERREPRESENTED ONTOLOGY IN THESE INTERACTION MAPS. FURTHER, OUR DATA SUGGEST THAT THE METHYLATION STATUS OF RAB22A, STX1B2, LGALS3BP, DNASE1L1 AND PREX1 CORRELATES WITH DISEASE ACTIVITY IN LUPUS PATIENTS. 2011 18 5998 33 THE ABERRANT EPIGENETIC MODIFICATIONS IN THE PATHOGENESIS OF PSORIASIS. PSORIASIS IS A CHRONIC AND RECURRENT INFLAMMATORY SKIN DISEASE THAT IS CHARACTERIZED BY ABNORMAL KERATINOCYTE PROLIFERATION, VASCULAR HYPERPLASIA, AND INFILTRATION OF INFLAMMATORY CELLS INTO THE DERMIS AND EPIDERMIS. IT IS GENERALLY ACCEPTED THAT THE CENTRAL PATHOGENESIS OF PSORIASIS IS DYSFUNCTION OF T LYMPHOCYTES, WHICH ARE AFFECTED BY THE COMPLEX INTERPLAY BETWEEN GENETIC AND ENVIRONMENTAL FACTORS, INCLUDING TRAUMA, INFECTIONS, STRESS, DRUGS, SMOKING, AND ALCOHOL CONSUMPTION (NESTLE ET AL., 2009). THE ENVIRONMENTALLY INDUCED EPIGENETIC CHANGES, INCLUDING DNA METHYLATION, HISTONE MODIFICATION, AND MICRORNAS, HAVE BEEN SHOWN TO BE INVOLVED IN THE PATHOGENESIS OF THIS DISEASE (ZHANG ET AL., 2012). 2018 19 827 46 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 20 1739 49 EARLY DNA METHYLATION CHANGES IN CHILDREN DEVELOPING BETA CELL AUTOIMMUNITY AT A YOUNG AGE. AIMS/HYPOTHESIS: TYPE 1 DIABETES IS A CHRONIC AUTOIMMUNE DISEASE OF COMPLEX AETIOLOGY, INCLUDING A POTENTIAL ROLE FOR EPIGENETIC REGULATION. PREVIOUS EPIGENOMIC STUDIES FOCUSED MAINLY ON CLINICALLY DIAGNOSED INDIVIDUALS. THE AIM OF THE STUDY WAS TO ASSESS EARLY DNA METHYLATION CHANGES ASSOCIATED WITH TYPE 1 DIABETES ALREADY BEFORE THE DIAGNOSIS OR EVEN BEFORE THE APPEARANCE OF AUTOANTIBODIES. METHODS: REDUCED REPRESENTATION BISULPHITE SEQUENCING (RRBS) WAS APPLIED TO STUDY DNA METHYLATION IN PURIFIED CD4(+) T CELL, CD8(+) T CELL AND CD4(-)CD8(-) CELL FRACTIONS OF 226 PERIPHERAL BLOOD MONONUCLEAR CELL SAMPLES LONGITUDINALLY COLLECTED FROM SEVEN TYPE 1 DIABETES-SPECIFIC AUTOANTIBODY-POSITIVE INDIVIDUALS AND CONTROL INDIVIDUALS MATCHED FOR AGE, SEX, HLA RISK AND PLACE OF BIRTH. WE ALSO EXPLORED CORRELATIONS BETWEEN DNA METHYLATION AND GENE EXPRESSION USING RNA SEQUENCING DATA FROM THE SAME SAMPLES. TECHNICAL VALIDATION OF RRBS RESULTS WAS PERFORMED USING PYROSEQUENCING. RESULTS: WE IDENTIFIED 79, 56 AND 45 DIFFERENTIALLY METHYLATED REGIONS IN CD4(+) T CELLS, CD8(+) T CELLS AND CD4(-)CD8(-) CELL FRACTIONS, RESPECTIVELY, BETWEEN TYPE 1 DIABETES-SPECIFIC AUTOANTIBODY-POSITIVE INDIVIDUALS AND CONTROL PARTICIPANTS. THE ANALYSIS OF PRE-SEROCONVERSION SAMPLES IDENTIFIED DNA METHYLATION SIGNATURES AT THE VERY EARLY STAGE OF DISEASE, INCLUDING DIFFERENTIAL METHYLATION AT THE PROMOTER OF IRF5 IN CD4(+) T CELLS. FURTHER, WE VALIDATED RRBS RESULTS USING PYROSEQUENCING AT THE FOLLOWING CPG SITES: CHR19:18118304 IN THE PROMOTER OF ARRDC2; CHR21:47307815 IN THE INTRON OF PCBP3; AND CHR14:81128398 IN THE INTERGENIC REGION NEAR TRAF3 IN CD4(+) T CELLS. CONCLUSIONS/INTERPRETATION: THESE PRELIMINARY RESULTS PROVIDE NOVEL INSIGHTS INTO CELL TYPE-SPECIFIC DIFFERENTIAL EPIGENETIC REGULATION OF GENES, WHICH MAY CONTRIBUTE TO TYPE 1 DIABETES PATHOGENESIS AT THE VERY EARLY STAGE OF DISEASE DEVELOPMENT. SHOULD THESE FINDINGS BE VALIDATED, THEY MAY SERVE AS A POTENTIAL SIGNATURE USEFUL FOR DISEASE PREDICTION AND MANAGEMENT. 2022