1 1603 165 DNA METHYLATION STUDIES IN SALIVA OF PATIENTS WITH SJOGREN'S SYNDROME. SJOGREN'S SYNDROME (SS) IS A RELATIVELY COMMON SYSTEMIC AUTOIMMUNE DISEASE OF UNKNOWN AETIOLOGY, ALTHOUGH GENETIC, HORMONAL, IMMUNOLOGIC, AND ENVIRONMENTAL FACTORS ARE THOUGHT TO BE INVOLVED IN DISEASE PATHOGENESIS. IT IS ALSO TERMED "AUTOIMMUNE EPITHELITIS", AND AFFLICTS MAINLY THE EPITHELIAL STRUCTURES OF SALIVARY AND LACHRYMAL GLANDS, THROUGH PERIEPITHELIAL LYMPHOCYTIC INFILTRATION RESPONSIBLE FOR THE OCCURRENCE OF DRYNESS SYMPTOMS. SJOGREN'S SYNDROME (SS) IS ALSO CHARACTERISED BY B CELL HYPERACTIVITY AS REFLECTED BY THE PRESENCE OF HYPERGAMMAGLOBULINEMIA AND THE PRODUCTION OF AUTOANTIBODIES, WHICH SEEMS TO BE ASSOCIATED WITH THE PRESENCE OF ECTOPIC GERMINAL CENTRES WITHIN THE INFLAMED MINOR SALIVARY GLANDS. CHRONIC ANTIGENIC STIMULATION MAY LEAD TO EXPANSION OF B CELL AUTOREACTIVE CLONES WITH RHEUMATOID FACTOR ACTIVITY, AND ADDITIONAL MOLECULAR EVENTS MEDIATE MALIGNANT TRANSFORMATION INTO NON-HODGKIN'S LYMPHOMAS OF B CELL ORIGIN. THEREFORE, THE INTERACTION BETWEEN THE IMMUNE CELLS OF THE INFLAMMATORY INFILTRATE AND THE SALIVARY EPITHELIUM SEEMS TO HAVE AN IMPORTANT CONTRIBUTION IN DISEASE PROCESS. RECENT HISTOPATHOLOGIC AND MOLECULAR STUDIES HAVE SHOWN THAT DNA METHYLATION LEVELS OF SS PATIENTS COMPARED TO HEALTHY INDIVIDUALS DIFFER IN EPITHELIAL CELLS OF SALIVARY GLANDS AND PERIPHERAL BLOOD MONONUCLEAR CELLS. IN THE PRESENT STUDY, WE INTEND TO ANALYSE THE EPIGENETIC MODIFICATIONS OF DNA IN THE SALIVA OF SS PATIENTS COMPARED TO HEALTHY CONTROLS. MORE SPECIFICALLY, SALIVARY DNA METHYLATION LEVELS OF SELECTED GENETIC LOCI PREVIOUSLY FOUND TO DIFFER IN OTHER TISSUES, WILL BE COMPARED BETWEEN SS PATIENTS AND HEALTHY CONTROLS. THE STUDY INCLUDES SALIVA COLLECTION FROM SS PATIENTS AND HEALTHY INDIVIDUALS, EXTRACTION OF GENOMIC DNA AND METHYLATION ASSESSMENT. THE EPIGENETIC PROFILE OF EACH GENETIC LOCUS WILL BE CORRELATED WITH SS PATIENTS' CLINICAL CHARACTERISTICS AND THE POSSIBILITY OF GENETIC LOCI WITH DIFFERENTIAL DIFFERENCES IN METHYLATION TO BE USED AS POTENTIAL DIAGNOSTIC BIOMARKERS WILL BE EXPLORED. THE CURRENT STUDY IS ANTICIPATED TO REVEAL POTENTIAL BIOMARKERS FOR DIAGNOSTIC AND THERAPEUTIC PURPOSES, OFFERING THE ADVANTAGE TO UTILISE THE EASILY COLLECTED AND HANDLED SALIVA AS THE MAIN BIOLOGIC MATERIAL. 2021 2 6050 42 THE CONTRIBUTION OF EPIGENETICS IN SJOGREN'S SYNDROME. SJOGREN'S SYNDROME (SS) IS A CHRONIC AUTOIMMUNE EPITHELITIS THAT COMBINES EXOCRINE GLAND DYSFUNCTIONS AND LYMPHOCYTIC INFILTRATIONS. WHILE THE PATHOGENESIS OF SS REMAINS UNCLEAR, ITS ETIOLOGY IS MULTIFUNCTIONAL AND INCLUDES A COMBINATION OF GENETIC PREDISPOSITIONS, ENVIRONMENTAL FACTORS, AND EPIGENETIC FACTORS. RECENTLY, INTEREST HAS GROWN IN THE INVOLVEMENT OF EPIGENETICS IN AUTOIMMUNE DISEASES. EPIGENETICS IS DEFINED AS CHANGES IN GENE EXPRESSION, THAT ARE INHERITABLE AND THAT DO NOT ENTAIL CHANGES IN THE DNA SEQUENCE. IN SS, SEVERAL EPIGENETIC MECHANISMS ARE DEFECTIVE INCLUDING DNA DEMETHYLATION THAT PREDOMINATES IN EPITHELIAL CELLS, AN ABNORMAL EXPRESSION OF MICRORNAS, AND ABNORMAL CHROMATIN POSITIONING-ASSOCIATED WITH AUTOANTIBODY PRODUCTION. LAST BUT NOT LEAST, EPIGENETIC MODIFICATIONS ARE REVERSIBLE AS OBSERVED IN MINOR SALIVARY GLANDS FROM SS PATIENTS AFTER B CELL DEPLETION USING RITUXIMAB. THUS EPIGENETIC FINDINGS IN SS OPEN NEW PERSPECTIVES FOR THERAPEUTIC APPROACHES AS WELL AS THE POSSIBLE IDENTIFICATION OF NEW BIOMARKERS. 2014 3 4268 52 MICROBIAL AGENTS AS PUTATIVE INDUCERS OF B CELL LYMPHOMA IN SJOGREN'S SYNDROME THROUGH AN IMPAIRED EPIGENETIC CONTROL: THE STATE-OF-THE-ART. INTRODUCTION: UNDERSTANDING THE MECHANISMS UNDERLYING THE PATHOGENESIS OF SJOGREN'S SYNDROME (SS) IS CRUCIALLY IMPORTANT IN ORDER TO BE ABLE TO DISCRIMINATE THE STEPS THAT LEAD TO B CELL TRANSFORMATION AND PROMPTLY IDENTIFY THE PATIENTS AT RISK OF LYMPHOMAGENESIS. THE AIM OF THIS NARRATIVE REVIEW IS TO DESCRIBE THE EVIDENCE CONCERNING THE ROLE THAT INFECTIONS OR DYSBIOSIS PLAYS IN THE EPIGENETIC CONTROL OF GENE EXPRESSION IN SS PATIENTS AND THEIR POSSIBLE INVOLVEMENT IN B CELL LYMPHOMAGENESIS. MATERIALS AND METHODS: WE SEARCHED THE PUBMED AND GOOGLE SCHOLAR DATABASES AND SELECTED A TOTAL OF 92 ARTICLES PUBLISHED DURING THE LAST 25 YEARS THAT DESCRIBE EXPERIMENTAL AND CLINICAL STUDIES OF THE POTENTIAL ASSOCIATIONS OF MICROBIOTA AND EPIGENETIC ABERRATIONS WITH THE RISK OF B CELL LYMPHOMA IN SS PATIENTS. RESULTS AND DISCUSSION: THE GENETIC BACKGROUND OF SS PATIENTS IS CHARACTERIZED BY THE HYPEREXPRESSION OF GENES THAT ARE MAINLY INVOLVED IN REGULATING THE INNATE AND ADAPTIVE IMMUNE RESPONSES AND ONCOGENESIS. IN ADDITION, SALIVARY GLAND EPITHELIAL CELLS AND LYMPHOCYTES BOTH HAVE AN ALTERED EPIGENETIC BACKGROUND THAT ENHANCES THE ACTIVATION OF PROINFLAMMATORY AND SURVIVAL PATHWAYS. DYSBIOSIS OR CHRONIC LATENT INFECTIONS MAY TUNE THE IMMUNE RESPONSE AND MODIFY THE CELL EPIGENETIC MACHINERY IN SUCH A WAY AS TO GIVE B LYMPHOCYTES AN ACTIVATED OR TRANSFORMED PHENOTYPE. IT IS ALSO WORTH NOTING THAT TRANSPOSABLE INTEGRATED RETROELEMENTS MAY PARTICIPATE IN THE PATHOGENESIS OF SS AND B CELL LYMPHOMAGENESIS BY INDUCING DNA BREAKS, MODULATING CELL GENE EXPRESSION, OR GENERATING ABERRANT TRANSCRIPTS THAT CHRONICALLY STIMULATE THE IMMUNE SYSTEM. CONCLUSIONS: MICROORGANISMS MAY EPIGENETICALLY MODIFY TARGET CELLS AND INDUCE THEIR TRANSCRIPTOME TO GENERATE AN ACTIVATED OR TRANSFORMED PHENOTYPE. THE OCCURRENCE OF LYMPHOMA IN MORE THAN 15% OF SS PATIENTS MAY BE THE END RESULT OF A COMBINATION OF GENETICS, EPIGENETICS, AND DYSBIOSIS OR LATENT INFECTIONS. 2019 4 1165 51 CONTRIBUTION OF DNA METHYLATION TO THE PATHOGENESIS OF SJOGREN'S SYNDROME: A REVIEW. SJOGREN'S SYNDROME (SS) IS A CHRONIC SYSTEMIC DISEASE CHARACTERISED BY SALIVARY AND LACRIMAL GLAND DYSFUNCTION WITH SEVERE IMPLICATIONS FOR THE WELL-BEING OF BEARING INDIVIDUALS. ALTHOUGH ITS ORIGIN HAS NOT YET BEEN FULLY ELUCIDATED, IT IS KNOWN THAT GENETIC, ENVIRONMENTAL, AND EPIGENETIC FACTORS ARE IMPORTANT CONTRIBUTORS TO THE PATHOGENESIS OF THIS SYNDROME. DNA METHYLATION IS A RELEVANT, WIDELY STUDIED EPIGENETIC FACTOR THAT IS POSSIBLY RELATED TO THE ESTABLISHMENT OF SS. THE AIM OF THE PRESENT STUDY WAS TO PERFORM A SYSTEMATIC REVIEW OF THE LITERATURE TO COMPILE STUDIES ON THE CONTRIBUTION OF DNA METHYLATION TO THE PATHOGENESIS OF SS. A LITERATURE SEARCH WAS PERFORMED IN 4 DATABASES (PUBMED, WEB OF SCIENCE, LILACS, AND SCOPUS) USING PREVIOUSLY SELECTED MEDICAL SUBJECT HEADINGS (MESH) DESCRIPTORS, AND ARTICLE SELECTION CONSIDERED OBSERVATIONAL STUDIES ONLY. AFTER A FULL-TEXT READING OF THE SELECTED ARTICLES, 15 STUDIES WERE IN ACCORDANCE WITH THE ELIGIBILITY CRITERIA FOR DATA EXTRACTION. METHYLATION DETECTION APPROACHES INCLUDED GLOBAL METHYLATION, GENOME-WIDE ASSESSMENT OF DIFFERENTIALLY METHYLATED REGIONS, AND SITE-SPECIFIC METHYLATION. FOURTEEN ARTICLES REPORTED ASSOCIATIONS OF DNA METHYLATION PROFILES IN SS PATIENTS, BOTH GLOBALLY AND IN SEVERAL GENES IN SALIVARY GLANDS AND BLOOD CELLS. THUS, DNA METHYLATION MAY CONTRIBUTE TO THE PATHOGENESIS OF SS. THE FINDINGS REINFORCE THE IMPORTANCE OF EPIGENETIC MARKERS IN THE DYNAMICS OF SS AND MAY DIRECT EFFORTS TOWARD THE DEVELOPMENT OF NEW DIAGNOSTIC AND THERAPEUTIC APPROACHES. 2022 5 2515 43 EPIGENETICS AND SJOGREN'S SYNDROME. THERE IS GROWING EVIDENCE THAT EPIGENETICS, THE STUDY OF HERITABLE CHANGES IN GENE EXPRESSION THAT DO NOT INVOLVE MUTATIONS IN THE DNA ITSELF, MAY PLAY AN ESSENTIAL ROLE IN AUTOIMMUNE DISEASES (AID). IN SJOGREN'S SYNDROME (SS), A CHRONIC AID CHARACTERIZED BY AN EPITHELIS OF THE EXOCRINE GLANDS, EPIGENETIC STUDIES HAVE FOCUSED ON THREE MECHANISMS: DNA METHYLATION AND ITS CONSEQUENCES INCLUDING HUMAN ENDOGENOUS RETROVIRUS (HERV) EXPRESSION; MICRORNA EXPRESSION; AND PROTEIN POST-TRANSLATIONAL MODIFICATIONS ASSOCIATED WITH AUTOANTIBODY PRODUCTION. ALTHOUGH IN ITS INFANCY, COMPREHENSION OF THE EPIGENETIC (DYS)REGULATION IN SS MAY HELP US TO UNDERSTAND: WHY SS AFFECTS PREDOMINANTLY MIDDLE-AGED WOMEN; WHY GENETICALLY PREDISPOSED INDIVIDUALS DEVELOP SS BUT NOT OTHERS; WHY FLARE-UPS OCCUR; WHY TREATMENT RESPONSES DIFFER BETWEEN PATIENTS; AND WHY SOME PATIENTS DEVELOP LYMPHOMA. FROM THESE STUDIES WILL ARISE A BETTER COMPREHENSION OF THE PATHOPHYSIOLOGY OF SS AS WELL AS DEVELOPMENT OF NEW DIAGNOSTIC AND PROGNOSTIC BIOMARKERS, AND NOVEL THERAPEUTICS FOR PREVENTION AND PERHAPS EARLY INTERVENTION. 2012 6 207 54 ACTIVATION OF THE TYPE I INTERFERON PATHWAY IN PRIMARY SJOGREN'S SYNDROME. SJOGREN'S SYNDROME (SS), A CHRONIC AUTOIMMUNE SYSTEMIC DISEASE AFFECTING MIDDLE AGED WOMEN, IS CHARACTERIZED BY LYMPHOCYTIC INFILTRATION OF THE SALIVARY AND LACHRYMAL GLANDS RESULTING IN DRY EYES AND DRY MOUTH. RECENT ADVANCES HAVE REVEALED A MAJOR ROLE FOR ACTIVATION OF THE TYPE I INTERFERON (IFN) PATHWAY IN THE PATHOGENESIS OF THE SYNDROME, AS EVIDENCED BY THE INCREASED CIRCULATING TYPE I IFN ACTIVITY AND AN IFN "SIGNATURE" IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC) AND MINOR SALIVARY GLAND (MSG) BIOPSIES FROM THESE PATIENTS. POLYMORPHISMS IN GENES INVOLVED IN THE IFNALPHA PATHWAY, SUCH AS IRF5 AND STAT4, HAVE BEEN FOUND TO BE ASSOCIATED WITH DISEASE SUSCEPTIBILITY. WHILE THE INITIAL TRIGGERS OF THE INNATE IMMUNE RESPONSE IN SS REMAIN ELUSIVE, PRELIMINARY EVIDENCE SUPPORTS THE ROLE OF INAPPROPRIATELY EXPRESSED ENDOGENOUS LINE-1 (L1) RETROELEMENTS AS POTENTIAL TRIGGERS OF TYPE I IFN ACTIVATION IN SS, POSSIBLY THROUGH TOLL-LIKE RECEPTOR (TLR) DEPENDENT OR INDEPENDENT PATHWAYS. PROTEINS OF THE METHYLATION MACHINERY AND THE APOBEC FAMILY OF CYTIDINE DEAMINASES ARE COORDINATELY OVEREXPRESSED, SUGGESTING THAT THOSE PROTEINS MIGHT CONTRIBUTE TO REGULATION OF THE INAPPROPRIATELY EXPRESSED L1 ENDOGENOUS RETROELEMENTS IN SS. GIVEN THE APPARENT CENTRAL ROLE OF IFNALPHA IN THE PATHOGENESIS OF SS, BLOCKADE OF THIS CYTOKINE MAY BE A RATIONAL THERAPEUTIC APPROACH. IN THE CURRENT REVIEW WE SUMMARIZE THE CURRENT EVIDENCE REGARDING THE POTENTIAL TRIGGERS OF TYPE I IFN ACTIVATION AS WELL AS THE DATA SUPPORTING GENETIC AND EPIGENETIC REGULATION OF THE TYPE I IFN SYSTEM IN SS. 2010 7 2552 41 EPIGENETICS IN PRIMARY SJOGREN'S SYNDROME. PRIMARY SJOGREN'S SYNDROME (SJS) IS A CHRONIC AND SYSTEMIC AUTOIMMUNE EPITHELITIS WITH PREDOMINANT FEMALE INCIDENCE, WHICH IS CHARACTERIZED BY EXOCRINE GLAND DYSFUNCTION. INCOMPLETELY UNDERSTOOD, THE ETIOLOGY OF SJS IS MULTI-FACTORIAL AND EVIDENCE IS GROWING TO CONSIDER THAT EPIGENETIC FACTORS ARE PLAYING A CRUCIAL ROLE IN ITS DEVELOPMENT. INDEPENDENT FROM DNA SEQUENCE MUTATIONS, EPIGENETICS IS DESCRIBED AS INHERITABLE AND REVERSIBLE PROCESSES THAT MODIFY GENE EXPRESSION. EPIGENETIC MODIFICATIONS REPORTED IN MINOR SALIVARY GLAND AND LYMPHOCYTES FROM SJS PATIENTS ARE RELATED TO (I) AN ABNORMAL DNA METHYLATION PROCESS INDUCING IN TURN DEFECTIVE CONTROL OF NORMALLY REPRESSED GENES INVOLVING SUCH MATTERS AS AUTOANTIGENS, RETROTRANSPOSONS, AND THE X CHROMOSOME IN WOMEN; (II) ALTERED NUCLEOSOME POSITIONING ASSOCIATED WITH AUTOANTIBODY PRODUCTION; AND (III) ALTERED CONTROL OF MICRORNA. RESULTS FROM EPIGENOME-WIDE ASSOCIATION STUDIES HAVE FURTHER REVEALED THE IMPORTANCE OF THE INTERFERON PATHWAY IN DISEASE PROGRESSION, THE CALCIUM SIGNALING PATHWAY FOR CONTROLLING FLUID SECRETIONS, AND A CELL-SPECIFIC CROSS TALK WITH RISK FACTORS ASSOCIATED WITH SJS. IMPORTANTLY, EPIGENETIC MODIFICATIONS ARE REVERSIBLE THUS OPENING OPPORTUNITIES FOR THERAPEUTIC PROCEDURES IN THIS CURRENTLY INCURABLE DISEASE. 2020 8 1508 46 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 2909 42 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 10 4228 38 METHYLATION OF INFLAMMATORY CELLS IN LUNG DISEASES. THIS CHAPTER OVERVIEWS ROLES OF DNA METHYLATION IN INFLAMMATORY CELL BIOLOGY WITH THE FOCUSES ON LYMPHOCYTES AND MACROPHAGES/MONOCYTES IN LUNG DISEASES, ALTHOUGH THE MOLECULAR MECHANISMS BY WHICH TARGET GENES ARE METHYLATED AND REGULATED IN LUNG DISEASES REMAIN UNCLEAR. MOST OF EPIGENETIC STUDIES ON DNA METHYLATION OF TARGET GENES IN LUNG DISEASES MAINLY DEMONSTRATED THE CORRELATION OF DNA METHYLATION OF TARGET GENES WITH THE LEVELS OF OTHER CORRESPONDING FACTORS, WITH THE SPECIFICITY OF CLINICAL PHENOMES, AND WITH THE SEVERITY OF LUNG DISEASES. THERE IS AN URGENT NEED TO IDENTIFY AND VALIDATE THE SPECIFICITY AND REGULATORY MECHANISMS OF INFLAMMATORY CELL EPIGENETICS IN DEPTH. THE EPIGENETIC HETEROGENEITY AMONG DIFFERENT SUBSETS OF T CELLS AND AMONG PROMOTERS OR NON-PROMOTERS OF TARGET GENES SHOULD BE FURTHERMORE CLARIFIED IN ACUTE OR CHRONIC LUNG DISEASES AND CANCERS. THE HYPER/HYPO-METHYLATION AND MODIFICATIONS OF CHROMOSOL AND EXTRACHROMOSOMAL DNA MAY RESULT IN ALTERNATIONS IN PROTEINS WITHIN INFLAMMATORY CELLS, WHICH CAN BE IDENTIFIED AS DISEASE-SPECIFIC BIOMARKERS AND THERAPEUTIC TARGETS. 2020 11 6262 48 THE MULTIFACETED FUNCTIONAL ROLE OF DNA METHYLATION IN IMMUNE-MEDIATED RHEUMATIC DISEASES. GENOMIC PREDISPOSITION CANNOT EXPLAIN THE ONSET OF COMPLEX DISEASES, AS WELL ILLUSTRATED BY THE LARGELY INCOMPLETE CONCORDANCE AMONG MONOZYGOTIC TWINS. EPIGENETIC MECHANISMS, INCLUDING DNA METHYLATION, CHROMATIN REMODELLING AND NON-CODING RNA, ARE CONSIDERED TO BE THE LINK BETWEEN ENVIRONMENTAL STIMULI AND DISEASE ONSET ON A PERMISSIVE GENETIC BACKGROUND IN AUTOIMMUNE AND CHRONIC INFLAMMATORY DISEASES. THE PARADIGMATIC CASES OF RHEUMATOID ARTHRITIS (RA), SYSTEMIC LUPUS ERYTHEMATOSUS (SLE), SYSTEMIC SCLEROSIS (SSC), SJOGREN'S SYNDROME (SJS) AND TYPE-1 DIABETES (T1D) SHARE THE LOSS OF IMMUNOLOGICAL TOLERANCE TO SELF-ANTIGEN INFLUENCED BY SEVERAL FACTORS, WITH A LARGELY INCOMPLETE ROLE OF INDIVIDUAL GENOMIC SUSCEPTIBILITY. THE MOST WIDELY INVESTIGATED EPIGENETIC MECHANISM IS DNA METHYLATION WHICH IS ASSOCIATED WITH GENE SILENCING AND IS DUE TO THE BINDING OF METHYL-CPG BINDING DOMAIN (MBD)-CONTAINING PROTEINS, SUCH AS MECP2, TO 5-METHYLCYTOSINE (5MC). INDEED, A CAUSAL RELATIONSHIP OCCURS BETWEEN DNA METHYLATION AND TRANSCRIPTION FACTORS OCCUPANCY AND RECRUITMENT AT SPECIFIC GENOMIC LOCUS. IN MOST CASES, THE RESULTS OBTAINED IN DIFFERENT STUDIES ARE CONTROVERSIAL IN TERMS OF DNA METHYLATION COMPARISON WHILE FASCINATING EVIDENCE COMES FROM THE COMPARISON OF THE EPIGENOME IN CLINICALLY DISCORDANT MONOZYGOTIC TWINS. IN THIS MANUSCRIPT, WE WILL REVIEW THE MECHANISMS OF EPIGENETICS AND DNA METHYLATION CHANGES IN SPECIFIC IMMUNE-MEDIATED RHEUMATIC DISEASES TO HIGHLIGHT REMAINING UNMET NEEDS AND TO IDENTIFY POSSIBLE SHARED MECHANISMS BEYOND DIFFERENT TISSUE INVOLVEMENTS WITH COMMON THERAPEUTIC OPPORTUNITIES. KEY POINTS * DNA METHYLATION HAS A CRUCIAL ROLE IN REGULATING AND TUNING THE IMMUNE SYSTEM. * EVIDENCES SUGGEST THAT DYSREGULATION OF DNA METHYLATION IS PIVOTAL IN THE CONTEXT OF IMMUNE-MEDIATED RHEUMATIC DISEASES. * DNA METHYLATION DYSREGULATION IN FOXP3 AND INTERFERONS-RELATED GENES IS SHARED WITHIN SEVERAL AUTOIMMUNE DISEASES. * DNA METHYLATION IS AN ATTRACTIVE MARKER FOR DIAGNOSIS AND THERAPY. 2021 12 822 41 CHARACTERIZATION OF BLOOD SURROGATE IMMUNE-METHYLATION BIOMARKERS FOR IMMUNE CELL INFILTRATION IN CHRONIC INFLAMMAGING DISORDERS. ALZHEIMER'S DISEASE (AD) AND ATHEROSCLEROSIS ARE BOTH CHRONIC AGE- AND INFLAMMATION-DEPENDENT DISEASES. IN ADDITION, ATHEROSCLEROSIS IS FREQUENTLY OBSERVED IN AD PATIENTS INDICATING COMMON INVOLVEMENT OF VASCULAR COMPONENTS IN BOTH DISEASE ETIOLOGIES. RECENTLY, EPIGENOME-WIDE ASSOCIATION STUDIES HAVE IDENTIFIED EPIGENETIC ALTERATIONS, AND IN PARTICULARLY DNA METHYLATION CHANGES FOR BOTH DISORDERS. WE HYPOTHESIZED THE EXISTENCE OF A COMMON DNA METHYLATION PROFILE IN ATHEROSCLEROSIS AND AD WHICH MAY BE VALUABLE AS A BLOOD-BASED DNA METHYLATION INFLAMMAGING BIOMARKER. USING PUBLICLY AVAILABLE 450K ILLUMINA METHYLATION DATASETS, WE IDENTIFIED A CO-METHYLATION NETWORK ASSOCIATED WITH BOTH ATHEROSCLEROSIS AND AD IN WHOLE BLOOD SAMPLES. THIS METHYLATION PROFILE APPEARED TO INDICATE SHIFTS IN BLOOD IMMUNE CELL TYPE DISTRIBUTION. REMARKABLY, SIMILAR METHYLATION CHANGES WERE ALSO DETECTED IN DISEASE TISSUES, INCLUDING AD BRAIN TISSUES, ATHEROSCLEROTIC PLAQUES, AND TUMORS AND WERE FOUND TO CORRELATE WITH IMMUNE CELL INFILTRATION. IN ADDITION, THIS IMMUNE-RELATED METHYLATION PROFILE COULD ALSO BE DETECTED IN OTHER INFLAMMAGING DISEASES, INCLUDING PARKINSON'S DISEASE AND OBESITY, BUT NOT IN MULTIPLE SCLEROSIS, SCHIZOPHRENIA, AND OSTEOPOROSIS. IN CONCLUSION, WE IDENTIFIED A BLOOD-BASED IMMUNE-RELATED DNA METHYLATION SIGNATURE IN MULTIPLE INFLAMMAGING DISEASES ASSOCIATED WITH CHANGES IN BLOOD IMMUNE CELL COUNTS AND PREDICTIVE FOR IMMUNE CELL INFILTRATION IN DISEASED TISSUES. IN ADDITION TO EPIGENETIC CLOCK MEASUREMENTS, THIS IMMUNE-METHYLATION SIGNATURE MAY BECOME A VALUABLE BLOOD-BASED BIOMARKER TO PREVENT CHRONIC INFLAMMATORY DISEASE DEVELOPMENT OR MONITOR LIFESTYLE INTERVENTION STRATEGIES WHICH PROMOTE HEALTHY AGING. 2019 13 2294 49 EPIGENETIC REGULATION IN THE PATHOGENESIS OF SJOGREN SYNDROME AND RHEUMATOID ARTHRITIS. AUTOIMMUNE RHEUMATIC DISEASES, SUCH AS SJOGREN SYNDROME (SS) AND RHEUMATOID ARTHRITIS (RA), ARE CHARACTERIZED BY CHRONIC INFLAMMATION AND AUTOIMMUNITY, WHICH CAUSE JOINT TISSUE DAMAGE AND DESTRUCTION BY TRIGGERING REDUCED MOBILITY AND DEBILITATION IN PATIENTS WITH THESE DISEASES. INITIATION AND MAINTENANCE OF CHRONIC INFLAMMATORY STAGES ACCOUNT FOR SEVERAL MECHANISMS THAT INVOLVE IMMUNE CELLS AS KEY PLAYERS AND THE INTERACTION OF THE IMMUNE CELLS WITH OTHER TISSUES. INDEED, THE OVERLAPPING OF CERTAIN CLINICAL AND SEROLOGIC MANIFESTATIONS BETWEEN SS AND RA MAY INDICATE THAT NUMEROUS IMMUNOLOGIC-RELATED MECHANISMS ARE INVOLVED IN THE PHYSIOPATHOLOGY OF BOTH THESE DISEASES. IT IS WIDELY ACCEPTED THAT EPIGENETIC PATHWAYS PLAY AN ESSENTIAL ROLE IN THE DEVELOPMENT AND FUNCTION OF THE IMMUNE SYSTEM. ALTHOUGH MANY PUBLISHED STUDIES HAVE ATTEMPTED TO ELUCIDATE THE RELATION BETWEEN EPIGENETIC MODIFICATIONS (E.G. DNA METHYLATION, HISTONE POST-TRANSLATIONAL MODIFICATIONS, MIRNAS) AND AUTOIMMUNE DISORDERS, THE CONTRIBUTION OF EPIGENETIC REGULATION TO THE PATHOGENESIS OF SS AND RA IS AT PRESENT POORLY UNDERSTOOD. THIS REVIEW ATTEMPTS TO SHED LIGHT FROM A CRITICAL POINT OF VIEW ON THE IDENTIFICATION OF THE MOST RELEVANT EPIGENETIC MECHANISMS RELATED TO RA AND SS BY EXPLAINING INTRICATE REGULATORY PROCESSES AND PHENOTYPIC FEATURES OF BOTH AUTOIMMUNE DISEASES. MOREOVER, WE POINT OUT SOME EPIGENETIC MARKERS WHICH CAN BE USED TO MONITOR THE INFLAMMATION STATUS AND THE DYSREGULATED IMMUNITY IN SS AND RA. FINALLY, WE DISCUSS THE INCONVENIENCE OF USING EPIGENETIC DATA OBTAINED FROM BULK IMMUNE CELL POPULATIONS INSTEAD SPECIFIC IMMUNE CELL SUBPOPULATIONS. 2019 14 2017 49 EPIGENETIC BIOMARKERS IN RHEUMATOLOGY - THE FUTURE? EPIGENETIC CHANGES ARE STABLE MODIFICATIONS OF DNA OR HISTONES THAT PROFOUNDLY ALTER GENE EXPRESSION. THEY CAN BE CHANGED BY ENVIRONMENTAL INFLUENCES AND CAN THEN BE PASSED ON TO DAUGHTER CELLS OR VIA THE GERM LINE TO OFFSPRING. A VARIETY OF CHANGES IN EPIGENETIC MARKS AND IN THE EXPRESSION OF NONCODING RNA HAS BEEN FOUND IN CANCER AS WELL AS IN CHRONIC INFLAMMATORY DISEASES. INTERESTINGLY, IN BOTH DISEASES SIMILAR MECHANISMS AND PATHWAYS ARE AFFECTED ALBEIT OFTEN TO A DIFFERENT EXTENT. DNA METHYLATION IS OFTEN LOST IN REPETITIVE SEQUENCES, WHILE IN PROMOTER REGIONS HYPO- AS WELL AS HYPERMETHYLATION IS FOUND. CHANGES IN MICRORNA LEVELS TYPICALLY AFFECT MICRORNAS THAT ARE CHANGED BY AN INFLAMMATORY ENVIRONMENT, BUT DISEASE SPECIFIC CHANGES HAVE ALSO BEEN FOUND IN THE BLOOD AND VARIOUS CELL TYPES OF PATIENTS WITH RHEUMATOID ARTHRITIS, SYSTEMIC LUPUS ERYTHEMATOSUS AND OTHER RHEUMATIC DISEASES. THEREFORE, CHANGES IN THE EXPRESSION OF MICRORNA IN PARTICULAR, BUT ALSO DEMETHYLATED GENE LOCI, HAVE BEEN PROPOSED AS POTENTIAL BIOMARKERS IN CHRONIC INFLAMMATORY DISEASES AND IN CANCER. POTENTIALLY, THESE CHANGES COULD BE USED FOR EARLY DIAGNOSIS AND ALSO TO PREDICT TREATMENT RESPONSE. UNFORTUNATELY MOST STUDIES IN RHEUMATOLOGY UP TO NOW WERE NOT DESIGNED TO VALIDATE THESE EPIGENETIC CHANGES AS BIOMARKERS. SINCE THE CANCER FIELD IS MUCH MORE ADVANCED IN THE USAGE OF BIOMARKERS FOR DISEASE SUBCLASSIFICATIONS AND SUBSEQUENT THERAPEUTIC DECISIONS, IT IS WORTHWHILE TO TAKE A CLOSER LOOK AT THE BIOMARKERS, METHODS AND PROCEDURES USED IN ONCOLOGY AND TO SEE WHICH OF THESE COULD ALSO BE APPLIED TO PREDICTING DISEASE SEVERITY AND THERAPEUTIC RESPONSE IN RHEUMATIC DISEASES. THIS ARTICLE WILL HIGHLIGHT COMMON EPIGENETIC PATHWAYS ACTIVATED IN CANCER AND VARIOUS RHEUMATIC DISEASES AND SUMMARISE EPIGENETIC CHANGES THAT HAVE THE POTENTIAL TO BECOME BIOMARKERS IN RHEUMATIC DISEASES. 2016 15 6013 51 THE APPLICATIONS OF DNA METHYLATION AS A BIOMARKER IN KIDNEY TRANSPLANTATION: A SYSTEMATIC REVIEW. BACKGROUND: ALTHOUGH KIDNEY TRANSPLANTATION IMPROVES PATIENT SURVIVAL AND QUALITY OF LIFE, LONG-TERM RESULTS ARE HAMPERED BY BOTH IMMUNE- AND NON-IMMUNE-MEDIATED COMPLICATIONS. CURRENT BIOMARKERS OF POST-TRANSPLANT COMPLICATIONS, SUCH AS ALLOGRAFT REJECTION, CHRONIC RENAL ALLOGRAFT DYSFUNCTION, AND CUTANEOUS SQUAMOUS CELL CARCINOMA, HAVE A SUBOPTIMAL PREDICTIVE VALUE. DNA METHYLATION IS AN EPIGENETIC MODIFICATION THAT DIRECTLY AFFECTS GENE EXPRESSION AND PLAYS AN IMPORTANT ROLE IN PROCESSES SUCH AS ISCHEMIA/REPERFUSION INJURY, FIBROSIS, AND ALLOREACTIVE IMMUNE RESPONSE. NOVEL TECHNIQUES CAN QUICKLY ASSESS THE DNA METHYLATION STATUS OF MULTIPLE LOCI IN DIFFERENT CELL TYPES, ALLOWING A DEEP AND INTERESTING STUDY OF CELLS' ACTIVITY AND FUNCTION. THEREFORE, DNA METHYLATION HAS THE POTENTIAL TO BECOME AN IMPORTANT BIOMARKER FOR PREDICTION AND MONITORING IN KIDNEY TRANSPLANTATION. PURPOSE OF THE STUDY: THE AIM OF THIS STUDY WAS TO EVALUATE THE ROLE OF DNA METHYLATION AS A POTENTIAL BIOMARKER OF GRAFT SURVIVAL AND COMPLICATIONS DEVELOPMENT IN KIDNEY TRANSPLANTATION. MATERIAL AND METHODS: A SYSTEMATIC REVIEW OF SEVERAL DATABASES HAS BEEN CONDUCTED. THE NEWCASTLE-OTTAWA SCALE AND THE JADAD SCALE HAVE BEEN USED TO ASSESS THE RISK OF BIAS FOR OBSERVATIONAL AND RANDOMIZED STUDIES, RESPECTIVELY. RESULTS: TWENTY ARTICLES REPORTING ON DNA METHYLATION AS A BIOMARKER FOR KIDNEY TRANSPLANTATION WERE INCLUDED, ALL USING DNA METHYLATION FOR PREDICTION AND MONITORING. DNA METHYLATION PATTERN ALTERATIONS IN CELLS ISOLATED FROM DIFFERENT TISSUES, SUCH AS KIDNEY BIOPSIES, URINE, AND BLOOD, HAVE BEEN ASSOCIATED WITH ISCHEMIA-REPERFUSION INJURY AND CHRONIC RENAL ALLOGRAFT DYSFUNCTION. THESE ALTERATIONS OCCURRED IN DIFFERENT AND SPECIFIC LOCI. DNA METHYLATION STATUS HAS ALSO PROVED TO BE IMPORTANT FOR IMMUNE RESPONSE MODULATION, HAVING A CRUCIAL ROLE IN REGULATORY T CELL DEFINITION AND ACTIVITY. RESEARCH ALSO FOCUSED ON A BETTER UNDERSTANDING OF THE ROLE OF THIS EPIGENETIC MODIFICATION ASSESSMENT FOR REGULATORY T CELLS ISOLATION AND EXPANSION FOR FUTURE TOLERANCE INDUCTION-ORIENTED THERAPIES. CONCLUSIONS: STUDIES INCLUDED IN THIS REVIEW ARE HETEROGENEOUS IN STUDY DESIGN, BIOLOGICAL SAMPLES, AND OUTCOME. MORE COORDINATED INVESTIGATIONS ARE NEEDED TO AFFIRM DNA METHYLATION AS A CLINICALLY RELEVANT BIOMARKER IMPORTANT FOR PREVENTION, MONITORING, AND INTERVENTION. 2022 16 1518 31 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 17 1844 44 EFFECTS OF THE LIFESTYLE HABITS IN BREAST CANCER TRANSCRIPTIONAL REGULATION. THROUGH RESEARCH CARRIED OUT IN THE LAST 25 YEARS ABOUT THE BREAST CANCER ETIOLOGY, IT HAS BEEN POSSIBLE TO ESTIMATE THAT LESS THAN 10 % OF PATIENTS WHO ARE DIAGNOSED WITH THE CONDITION ARE CARRIERS OF SOME GERMLINE OR SOMATIC MUTATION. THE CLINICAL REPORTS OF BREAST CANCER PATIENTS WITH HEALTHY TWINS AND THE DEVELOPMENT OF DISEASE IN WOMEN WITHOUT HIGH PENETRANCE MUTATIONS DETECTED, WARN THE PARTICIPATION MORE FACTORS IN THE TRANSFORMATION PROCESS. THE HIGH INCIDENCE OF MAMMARY ADENOCARCINOMA IN THE MODERN WOMAN AND THE URGENT NEED FOR NEW METHODS OF PREVENTION AND EARLY DETECTION HAVE DEMANDED MORE INFORMATION ABOUT THE ROLE THAT ENVIRONMENT AND LIFESTYLE HAVE ON THE TRANSFORMATION OF MAMMARY GLAND EPITHELIAL CELLS. OBESITY, ALCOHOLISM AND SMOKING ARE FACTORS THAT HAVE SHOWN A CLOSE CORRELATION WITH THE RISK OF DEVELOPING BREAST CANCER. AND ALTHOUGH THESE CONDITIONS AFFECT DIFFERENT CELL REGULATION LEVELS, THE STUDY OF ITS EFFECTS IN THE MECHANISMS OF TRANSCRIPTIONAL AND EPIGENETIC REGULATION IS CONSIDERED CRITICAL FOR A BETTER UNDERSTANDING OF THE LOSS OF IDENTITY OF EPITHELIAL CELLS DURING CARCINOGENESIS OF THIS TISSUE. THE MAIN OBJECTIVE OF THIS REVIEW WAS TO ESTABLISH THE IMPORTANCE OF CHANGES OCCURRING TO TRANSCRIPTIONAL LEVEL IN THE MAMMARY GLAND AS A CONSEQUENCE OF ACUTE OR CHRONIC EXPOSURE TO HARMFUL PRODUCTS SUCH AS OBESITY-CAUSING FOODS, ETHANOL AND CIGARETTE SMOKE COMPONENTS. AT ANALYZE THE MAIN STUDIES RELATED TO TOPIC, IT HAS CONCLUDED THAT THE UNDERSTANDING OF EFFECTS CAUSED BY THE LIFESTYLE FACTORS IN PERFORMANCE OF THE TRANSCRIPTIONAL MECHANISMS THAT DETERMINE GENE EXPRESSION OF THE MAMMARY GLAND EPITHELIAL CELLS, MAY HELP EXPLAIN THE DEVELOPMENT OF THIS DISEASE IN WOMEN WITHOUT GENETIC PROPENSITY AND DIFFERENT PHENOTYPIC MANIFESTATIONS OF THIS CANCER TYPE. 2016 18 3503 27 IDENTIFICATION OF POTENTIAL DIFFERENTIALLY METHYLATED GENE-RELATED BIOMARKERS IN ENDOMETRIOSIS. AIM: TO IDENTIFY EPIGENETIC ALTERATIONS OF DIFFERENTIALLY EXPRESSED GENES AND SCREEN OUT TARGETED THERAPEUTIC DRUGS IN ENDOMETRIOSIS. METHODS: BASED ON THE GENE EXPRESSION OMNIBUS DATABASE AND A SERIES OF BIOLOGICAL INFORMATION ANALYSIS TOOLS, SUPPLEMENTED BY VALIDATION OF CLINICAL SAMPLES, ABERRANT DNA METHYLATION-DRIVEN GENES AND THEIR FUNCTIONS WERE EXPLORED, AS WELL AS POSSIBLE TARGETED DRUGS. RESULTS: THIS STUDY SCREENED OUT A RANGE OF DNA METHYLATION-DRIVEN GENES THAT WERE ASSOCIATED WITH POWERFUL PROPERTIES AND CORRESPONDING PATHWAYS. AMONG THEM, BDNF AND CCL2 WERE KEY GENES IN THE DEVELOPMENT OF ENDOMETRIOSIS. FOUR CHEMICAL AGENTS HAVE BEEN FLAGGED AS POTENTIAL TREATMENTS FOR ENDOMETRIOSIS. CONCLUSION: THESE CANDIDATE GENES AND SMALL-MOLECULE AGENTS MAY BE FURTHER EXPLORED AS POTENTIAL TARGETS AND DRUGS FOR ENDOMETRIOSIS DIAGNOSIS AND THERAPY, RESPECTIVELY. 2022 19 1873 43 EMERGING ROLE OF MICRORNAS AND LONG NON-CODING RNAS IN SJOGREN'S SYNDROME. SJOGREN'S SYNDROME (SS) IS A CHRONIC AUTOIMMUNE INFLAMMATORY DISEASE. IT IS CONSIDERED A MULTIFACTORIAL PATHOLOGY, IN WHICH UNDERLYING GENETIC PREDISPOSITION, EPIGENETIC MECHANISMS AND ENVIRONMENTAL FACTORS CONTRIBUTE TO DEVELOPMENT. THE EPIGENETIC REGULATIONS REPRESENT A LINK BETWEEN GENETIC PREDISPOSITION AND ENVIRONMENTAL FACTORS. RECENT STUDIES SUGGESTED A REGULATORY ROLE FOR NON-CODING RNAS IN CRITICAL BIOLOGICAL AND DISEASE PROCESSES. AMONG NON-CODING RNAS, MICRORNAS (MIRNAS) AND LONG NON-CODING RNAS (LNCRNAS) PLAY A CRITICAL ROLE IN THE POST-TRANSCRIPTIONAL MRNA EXPRESSION, FORMING A COMPLEX NETWORK OF GENE EXPRESSION REGULATION. THIS REVIEW AIMS TO GIVE AN OVERVIEW OF THE LATEST STUDIES THAT HAVE INVESTIGATED THE ROLE OF MIRNAS AND LNCRNAS IN THE SS. WE INCLUDED PAPERS THAT INVESTIGATED THE EXPRESSION OF NON-CODING RNAS ON DIFFERENT TISSUES, IN PARTICULAR ON PERIPHERAL BLOOD MONONUCLEAR CELLS AND SALIVARY GLANDS. HOWEVER, REGARDING THE INVOLVEMENT OF NON-CODING RNAS GENETIC VARIABILITY IN SS SUSCEPTIBILITY VERY FEW DATA ARE AVAILABLE. FURTHER RESEARCH COULD HELP TO ELUCIDATE UNDERLYING PATHOGENIC PROCESSES OF SS AND PROVIDE NEW OPPORTUNITIES FOR THE DEVELOPMENT OF TARGETED THERAPIES. 2021 20 2483 33 EPIGENETIC VARIATION AND HUMAN DISEASE. CYTOSINE GUANINE DINUCLEOTIDE (CPG) ISLAND METHYLATION IS A KNOWN MECHANISM OF EPIGENETIC INHERITANCE IN POSTMEIOTIC CELLS. THROUGH ASSOCIATED CHROMATIN CHANGES AND SILENCING, SUCH EPIGENETIC STATES CAN INFLUENCE CELLULAR PHYSIOLOGY AND AFFECT DISEASE RISK AND SEVERITY. OUR STUDIES OF CPG ISLAND METHYLATION IN NORMAL COLORECTAL MUCOSA REVEALED PROGRESSIVE AGE-RELATED INCREASES AT MULTIPLE GENE LOCI, SUGGESTING GENOME-WIDE MOLECULAR ALTERATIONS WITH POTENTIAL TO SILENCE GENE EXPRESSION. HOWEVER, THERE WAS CONSIDERABLE VARIATION IN THE DEGREE OF METHYLATION AMONG INDIVIDUALS OF COMPARABLE AGES. SUCH VARIATION COULD BE RELATED TO GENETIC FACTORS, LIFESTYLE, OR ENVIRONMENTAL EXPOSURES. STUDIES IN ULCERATIVE COLITIS AND HEPATOCELLULAR CIRRHOSIS AND NEOPLASIA REVEALED THAT CHRONIC INFLAMMATORY STATES ARE ACCOMPANIED BY MARKED INCREASES IN CPG ISLAND METHYLATION IN NORMAL-APPEARING TISSUES, CONFIRMING THE HYPOTHESIS THAT PROINFLAMMATORY EXPOSURES COULD ACCOUNT FOR PART OF THE EPIGENETIC VARIATION IN HUMAN POPULATIONS. PRELIMINARY DATA ALSO SUGGEST POTENTIAL INFLUENCES OF LIFESTYLE AND EXPOSURE FACTORS ON CPG ISLAND METHYLATION. IT IS SUGGESTED THAT EPIGENETIC VARIATION RELATED TO AGING, LIFESTYLE, EXPOSURES AND POSSIBLY GENETIC FACTORS, IS ONE OF THE MODULATORS OF ACQUIRED, AGE-RELATED HUMAN DISEASES, INCLUDING NEOPLASIA. 2002