1 1989 108 EPIGENETIC ANALYSIS IN RHEUMATOID ARTHRITIS SYNOVIOCYTES. RHEUMATOID ARTHRITIS (RA) IS A COMPLEX CHRONIC SYSTEMATIC DISEASE WITH PROGRESSIVE DESTRUCTION OF THE JOINTS BY INVASIVE SYNOVIOCYTES. TO CHARACTERIZE THE KEY REGULATORS INVOLVED IN THE DEVELOPMENT OF RA, WE OBTAINED MULTILAYER EPIGENOMICS DATA INCLUDING DNA METHYLATION BY WHOLE-GENOME BISULFITE SEQUENCING, MIRNA PROFILES, GENETIC VARIATIONS BY WHOLE-EXOME SEQUENCING, AND MRNA PROFILES FROM SYNOVIOCYTES OF RA AND OSTEOARTHRITIS (OA) PATIENTS. THE OVERALL DNA METHYLATION PATTERNS WERE NOT MUCH DIFFERENT BETWEEN RA AND OA, BUT 523 LOW-METHYLATED REGIONS (LMRS) WERE SPECIFIC TO RA. THE LMRS WERE PREFERENTIALLY LOCALIZED AT THE 5' INTRONS AND OVERLAPPED WITH TRANSCRIPTION FACTOR BINDING MOTIFS FOR GLI1, RUNX2, AND TFAP2A/C. SINGLE BASE-SCALE DIFFERENTIALLY METHYLATED CPGS WERE LINKED WITH SEVERAL NETWORKS RELATED TO WOUND RESPONSE, TISSUE DEVELOPMENT, COLLAGEN FIBRIL ORGANIZATION, AND THE TGF-BETA RECEPTOR SIGNALING PATHWAY. FURTHER, THE DNA METHYLATION OF 201 CPGS WAS SIGNIFICANTLY CORRELATED WITH 27 EXPRESSED MIRNA GENES. OUR INTERPRETATION OF EPIGENOMIC DATA OF THE SYNOVIOCYTES FROM RA AND OA PATIENTS IS AN INFORMATIVE RESOURCE TO FURTHER INVESTIGATE REGULATORY ELEMENTS AND BIOMARKERS RESPONSIBLE FOR THE PATHOPHYSIOLOGY OF RA AND OA. 2019 2 855 31 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 3 3959 30 LONG NON-CODING RNAS TARGET PATHOGENETICALLY RELEVANT GENES AND PATHWAYS IN RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE DRIVEN BY GENETIC, ENVIRONMENTAL AND EPIGENETIC FACTORS. LONG NON-CODING RNAS (LNCRNAS) ARE A KEY COMPONENT OF THE EPIGENETIC MECHANISMS AND ARE KNOWN TO BE INVOLVED IN THE DEVELOPMENT OF AUTOIMMUNE DISEASES. IN THIS WORK WE AIMED TO IDENTIFY SIGNIFICANTLY DIFFERENTIALLY EXPRESSED LNCRNAS (DE-LNCRNAS) THAT ARE FUNCTIONALLY CONNECTED TO MODULATED GENES STRICTLY ASSOCIATED WITH RA. IN TOTAL, 542,500 TRANSCRIPTS HAVE BEEN PROFILED IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM FOUR PATIENTS WITH EARLY ONSET RA PRIOR ANY TREATMENT AND FOUR HEALTHY DONORS USING CLARIOM D ARRAYS. RESULTS WERE CONFIRMED BY REAL-TIME PCR IN 20 PATIENTS AND 20 CONTROLS. SIX DE-LNCRNAS TARGET EXPERIMENTALLY VALIDATED MIRNAS ABLE TO REGULATE DIFFERENTIALLY EXPRESSED GENES (DEGS) IN RA; AMONG THEM, ONLY FTX, HNRNPU-AS1 AND RP11-498C9.15 TARGETED A LARGE NUMBER OF DEGS. MOST IMPORTANTLY, RP11-498C9.15 TARGETED THE LARGEST NUMBER OF SIGNALLING PATHWAYS THAT WERE FOUND TO BE ENRICHED BY THE GLOBAL AMOUNT OF RA-DEGS AND THAT HAVE ALREADY BEEN ASSOCIATED WITH RA AND RA-SYNOVIOCYTES. MOREOVER, RP11-498C9.15 TARGETED THE MOST HIGHLY CONNECTED GENES IN THE RA INTERACTOME, THUS SUGGESTING ITS INVOLVEMENT IN CRUCIAL GENE REGULATION. THESE RESULTS INDICATE THAT, BY MODULATING BOTH MICRORNAS AND GENE EXPRESSION, RP11-498C9.15 MAY PLAY A PIVOTAL ROLE IN RA PATHOGENESIS. 2019 4 3473 35 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 5 2635 43 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 6 3066 30 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 7 3045 33 GENOME-WIDE ANALYSIS OF ABERRANT METHYLATION OF ENHANCER DNA IN HUMAN OSTEOARTHRITIS. BACKGROUND: OSTEOARTHRITIS IS A CHRONIC MUSCULOSKELETAL DISEASE CHARACTERIZED BY AGE-RELATED GRADUAL THINNING AND A HIGH RISK IN FEMALES. RECENT STUDIES HAVE SHOWN THAT DNA METHYLATION PLAYS IMPORTANT ROLES IN OSTEOARTHRITIS. HOWEVER, THE GENOME-WIDE PATTERN OF METHYLATION IN ENHANCERS IN OSTEOARTHRITIS REMAINS UNCLEAR. METHODS: TO EXPLORE THE FUNCTION OF ENHANCERS IN OSTEOARTHRITIS, WE QUANTIFIED CPG METHYLATION IN HUMAN ENHANCERS BASED ON A PUBLIC DATASET THAT INCLUDED METHYLATION PROFILES OF 470,870 CPG PROBES IN 108 SAMPLES FROM PATIENTS WITH HIP AND KNEE OSTEOARTHRITIS AND HIP TISSUES FROM HEALTHY INDIVIDUALS. COMBINING VARIOUS BIOINFORMATICS ANALYSIS TOOLS, WE SYSTEMATICALLY ANALYZED ABERRANT DNA METHYLATION OF THE ENHANCERS THROUGHOUT THE GENOME IN KNEE OSTEOARTHRITIS AND HIP OSTEOARTHRITIS. RESULTS: WE IDENTIFIED 16,816 DIFFERENTIALLY METHYLATED CPGS, AND NEARLY HALF (8111) OF THEM WERE FROM ENHANCERS, SUGGESTING MAJOR DNA METHYLATION CHANGES IN BOTH TYPES OF OSTEOARTHRITIS IN THE ENHANCER REGIONS. A DETAILED ANALYSIS OF HIP OSTEOARTHRITIS IDENTIFIED 2426 DIFFERENTIALLY METHYLATED CPGS IN ENHANCERS BETWEEN MALE AND FEMALE PATIENTS, AND 84.5% OF THEM WERE HYPOMETHYLATED IN FEMALE PATIENTS AND ENRICHED IN PHENOTYPES RELATED TO HIP OSTEOARTHRITIS IN FEMALES. NEXT, WE EXPLORED THE ENHANCER METHYLATION DYNAMICS AMONG PATIENTS WITH KNEE OSTEOARTHRITIS AND IDENTIFIED 280 DIFFERENTIALLY METHYLATED ENHANCER CPGS THAT WERE ENRICHED IN THE HUMAN PHENOTYPES AND DISEASE ONTOLOGIES RELATED TO OSTEOARTHRITIS. FINALLY, A COMPARISON OF ENHANCER METHYLATION BETWEEN KNEE OSTEOARTHRITIS AND HIP OSTEOARTHRITIS REVEALED ORGAN SOURCE-DEPENDENT DIFFERENCES IN ENHANCER METHYLATION. CONCLUSION: OUR FINDINGS INDICATE THAT ABERRANT METHYLATION OF ENHANCERS IS RELATED TO OSTEOARTHRITIS PHENOTYPES, AND A COMPREHENSIVE ATLAS OF ENHANCER METHYLATION IS USEFUL FOR FURTHER ANALYSIS OF THE EPIGENETIC REGULATION OF OSTEOARTHRITIS AND THE DEVELOPMENT OF CLINICAL DRUGS FOR TREATMENT OF OSTEOARTHRITIS. 2020 8 1508 38 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 9 1584 28 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 10 1587 38 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 11 51 35 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 12 4657 30 NEW ADVANCES OF DNA METHYLATION AND HISTONE MODIFICATIONS IN RHEUMATOID ARTHRITIS, WITH SPECIAL EMPHASIS ON MECP2. EPIGENETICS IS A STEADILY GROWING RESEARCH AREA IN MANY HUMAN DISEASES, ESPECIALLY IN AUTOIMMUNE DISEASES SUCH AS RHEUMATOID ARTHRITIS (RA). RA IS AN AUTOIMMUNE DISEASE WITH UNCLEAR ETIOLOGY CHARACTERIZED BY CHRONIC INFLAMMATION AND JOINT DESTRUCTION AND FIBROBLAST-LIKE SYNOVIOCYTES (FLS) DISPLAY A CRUCIAL ROLE IN THE PATHOGENESIS OF RA. EVEN THOUGH THE ETIOLOGY IS NOT YET FULLY UNDERSTOOD, RA IS GENERALLY CONSIDERED TO BE CAUSED BY A COMBINATION OF EPIGENETIC MODIFICATION, DEREGULATED IMMUNOMODULATION, AND ENVIRONMENTAL FACTORS. EPIGENETIC MODIFICATIONS, INCLUDING DNA METHYLATION AND POST-TRANSLATIONAL HISTONE MODIFICATIONS, SUCH AS HISTONE METHYLATION AND HISTONE (DE)ACETYLATION ARE IDENTIFIED AS REGULATORY MECHANISMS IN CONTROLLING AGGRESSIVE FLS ACTIVATION IN PATIENTS AND ANIMAL MODELS. IN THE LAST 3YEARS, THE FIELD OF EPIGENETICS IN RA HAS IMPRESSIVELY INCREASED. METHYL-CPG-BINDING PROTEIN 2 (MECP2) IS FIRST IDENTIFIED AS A TRANSCRIPTIONAL REPRESSOR THAT INHIBITS GENE EXPRESSION THROUGH THE INTERPRETATION OF TWO EPIGENETIC MARKERS, DNA METHYLATION AND HISTONE MODIFICATION. THE COOPERATIVE ACTION AMONG MECP2, DNA METHYLATION AND HISTONE MODIFICATIONS INDICATES THAT MECP2 SHOULD PARTICIPATE IN THE PATHOGENESIS OF RA THROUGH SILENCE OF CERTAIN GENE TRANSCRIPTION. IN THIS REVIEW, WE CONSIDER THE ROLE OF DNA METHYLATION AND HISTONE MODIFICATIONS IN THE DEVELOPMENT OF RA, WITH A SPECIAL FOCUS ON INCREASED MECP2 EXPRESSION IN RA ANIMAL MODELS. 2013 13 827 36 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 14 6826 32 [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 15 5505 28 RHEUMATOID ARTHRITIS AND ALZHEIMER'S DISEASE: GENETIC AND EPIGENETIC LINKS IN INFLAMMATORY REGULATION. CONTROVERSIAL DATA ARE AVAILABLE ABOUT THE RELATIONSHIP BETWEEN ALZHEIMER'S DISEASE (AD) AND RHEUMATOID ARTHRITIS (RA). AN INVERSE RELATIONSHIP BETWEEN AD AND RA, DUE TO DIFFERENT FACTORS, WAS PREVIOUSLY DESCRIBED. SIMILARLY TO RA, AD PATHOGENESIS IS MULTIFACTORIAL AND DIFFERENT FINDINGS SUPPORT THE INFLAMMATORY PATHOGENETIC HYPOTHESIS. SEVERAL INFLAMMATORY MEDIATORS ARE INVOLVED IN THE DISEASE ONSET AND PROGRESSION REGULATED BY GENETIC AND EPIGENETIC MECHANISMS. AMONG THEM, INTELEUKIN-6 (IL-6) AND INTERLEUKIN-1 (IL-1) AS PRO-INFLAMMATORY SOLUBLE FACTORS PRODUCED BY MONOCYTES-MACROPHAGES AND TUMOR NECROSIS FACTOR ALPHA (TNF-ALPHA) PRODUCED BY ACTIVATED MACROPHAGES AND MONONUCLEAR CELLS REPRESENT KEY MOLECULES IN THE INDUCTION AND MAINTENANCE OF CHRONIC INFLAMMATION IN RA. IN PARTICULAR A LINK WITH THE T ALLELE OF THE SNP 3953 T/C IN THE IL-1 GENE AND AN OVEREXPRESSION OF MIR-146A APPEARS TO BE COMMON TO BOTH RA AND AD. IN THIS REVIEW WE WILL DISCUSS THE GENETIC AND EPIGENETIC REGULATION OF THE INFLAMMATORY CASCADE IN RA AND AD TO FIND OUT THE POSSIBLE LINKS BETWEEN RA AND AD ONSET. 2012 16 2533 36 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 17 1739 33 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 18 2375 38 EPIGENETIC REGULATION OF TRANSCRIPTION FACTOR BINDING MOTIFS PROMOTES TH1 RESPONSE IN CHAGAS DISEASE CARDIOMYOPATHY. CHAGAS DISEASE, CAUSED BY THE PROTOZOAN TRYPANOSOMA CRUZI, IS AN ENDEMIC PARASITIC DISEASE OF LATIN AMERICA, AFFECTING 7 MILLION PEOPLE. ALTHOUGH MOST PATIENTS ARE ASYMPTOMATIC, 30% DEVELOP COMPLICATIONS, INCLUDING THE OFTEN-FATAL CHRONIC CHAGASIC CARDIOMYOPATHY (CCC). ALTHOUGH PREVIOUS STUDIES HAVE DEMONSTRATED SOME GENETIC DEREGULATIONS ASSOCIATED WITH CCCS, THE CAUSES OF THEIR DEREGULATIONS REMAIN POORLY DESCRIBED. BASED ON BULK RNA-SEQ AND WHOLE GENOME DNA METHYLATION DATA, WE INVESTIGATED THE GENETIC AND EPIGENETIC DEREGULATIONS PRESENT IN THE MODERATE AND SEVERE STAGES OF CCC. ANALYSIS OF HEART TISSUE GENE EXPRESSION PROFILE ALLOWED US TO IDENTIFY 1407 DIFFERENTIALLY EXPRESSED TRANSCRIPTS (DEGS) SPECIFIC FROM CCC PATIENTS. A TISSUE DNA METHYLATION ANALYSIS DONE ON THE SAME TISSUE HAS PERMITTED THE IDENTIFICATION OF 92 REGULATORY DIFFERENTIALLY METHYLATED REGIONS (DMR) LOCALIZED IN THE PROMOTER OF DEGS. AN IN-DEPTH STUDY OF THE TRANSCRIPTION FACTORS BINDING SITES (TFBS) IN THE DMRS CORROBORATED THE IMPORTANCE OF TFBS'S DNA METHYLATION FOR GENE EXPRESSION IN CCC MYOCARDIUM. TBX21, RUNX3 AND EBF1 ARE THE TRANSCRIPTION FACTORS WHOSE BINDING MOTIF APPEARS TO BE AFFECTED BY DNA METHYLATION IN THE LARGEST NUMBER OF GENES. BY COMBINING BOTH TRANSCRIPTOMIC AND METHYLOMIC ANALYSIS ON HEART TISSUE, AND METHYLOMIC ANALYSIS ON BLOOD, 4 BIOLOGICAL PROCESSES AFFECTED BY SEVERE CCC HAVE BEEN IDENTIFIED, INCLUDING IMMUNE RESPONSE, ION TRANSPORT, CARDIAC MUSCLE PROCESSES AND NERVOUS SYSTEM. AN ADDITIONAL STUDY ON BLOOD METHYLATION OF MODERATE CCC SAMPLES PUT FORWARD THE IMPORTANCE OF ION TRANSPORT AND NERVOUS SYSTEM IN THE DEVELOPMENT OF THE DISEASE. 2022 19 2909 32 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 20 6468 22 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