1 6565 101 TRANSLATING EPIGENETICS INTO CLINIC: FOCUS ON LUPUS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC RELAPSING-REMITTING AUTOIMMUNE DISEASE WITH HIGHLY HETEROGENEOUS PHENOTYPES. BIOMARKERS WITH HIGH SENSITIVITY AND SPECIFICITY ARE USEFUL FOR EARLY DIAGNOSIS AS WELL AS MONITORING DISEASE ACTIVITY AND LONG-TERM COMPLICATIONS. EPIGENETICS POTENTIALLY PROVIDE NOVEL BIOMARKERS IN AUTOIMMUNE DISEASES. THESE MAY INCLUDE DNA METHYLATION CHANGES IN RELEVANT LUPUS-PRONE GENES OR HISTONE MODIFICATIONS AND MICRORNAS TO UPREGULATE AND DOWNREGULATE RELEVANT GENE EXPRESSION. THE TIMING AND NATURE OF EPIGENETIC MODIFICATION PROVIDE SUCH CHANGES. IN LUPUS, DNA METHYLATION ALTERATIONS IN CYTOKINE GENES, SUCH AS IFN-RELATED GENE AND RETROVIRUS GENE, HAVE BEEN FOUND TO OFFER BIOMARKERS FOR LUPUS DIAGNOSIS. HISTONE MODIFICATIONS SUCH AS HISTONE METHYLATION AND ACETYLATION LEAD TO TRANSCRIPTIONAL ALTERATIONS OF SEVERAL GENES SUCH AS PTPN22, LRP1B, AND TNFSF70. THERE ARE VARIETIES OF MICRORNAS APPLIED AS LUPUS BIOMARKERS, INCLUDING DNMT1-RELATED MICRORNAS, RENAL FUNCTION-ASSOCIATED MICRORNAS, MICRORNAS INVOLVED IN THE IMMUNE SYSTEM, AND MICRORNAS FOR PHENOTYPE CLASSIFICATION. THUS, WE CONCLUDE A WIDE RANGE OF PROMISING ROLES OF EPIGENETIC BIOMARKERS AIDING IN THE DIAGNOSING AND MONITORING OF LUPUS DISEASES AND THE RISK OF ORGAN DAMAGE. 2017 2 6800 38 [EPIGENETIC DISTURBANCES IN SYSTEMIC LUPUS ERYTHEMATOSUS]. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE THAT RESULTS IN UNCONTROLLED IMMUNE SYSTEM ACTIVATION AND OVERPRODUCTION OF AUTOANTIBODIES. THE PATHOGENESIS OF THE DISEASE IS COMPLEX AND NOT FULLY UNDERSTOOD, NEVERTHELESS, GENETIC AND ENVIRONMENTAL FACTORS PLAY AN IMPORTANT ROLE. SO FAR, ABOUT 30 GENES HAVE BEEN IDENTIFIED TO BE INVOLVED IN THE SLE PATHOMECHANISM. HOWEVER, NOT ALL GENETICALLY PREDISPOSED INDIVIDUALS DEVELOP THE DISEASE. THIS PHENOMENON CAN BE ASSOCIATED WITH EPIGENETIC CHANGES THAT OCCUR UNDER THE INFLUENCE OF ENVIRONMENTAL FACTORS. THEY CAN AFFECT GENE EXPRESSION AND ARE POTENTIALLY HEREDITARY, BUT DO NOT LEAD TO CHANGES IN THE NUCLEOTIDE SEQUENCE. EPIGENETIC DYSFUNCTIONS, IDENTIFIED IN THE COURSE OF THE DISEASE, LEAD TO CHANGES IN THE EXPRESSION OF GENES THAT PLAY A KEY ROLE IN MAINTAINING THE BODY'S IMMUNE TOLERANCE. MAJOR MECHANISMS OF EPIGENETIC VARIABILITY ARE: DNA METHYLATION, HISTONE PROTEIN MODIFICATION, NON-CODING RNA EXPRESSION, AS WELL AS GENE IMPRINTING. THE MAJOR EPIGENETIC DYSFUNCTIONS AFFECTING THE PATHOGENESIS OF THE DISEASE ARE GLOBAL HYPOMETHYLATION ON CD4+ T CELLS RESULTING FROM ERK SIGNALING PATHWAY REGULATION, HISTONE HYPOACETYLATION, HISTONE H3 LYSINE METHYLATION, AND REACTIVATION OF INACTIVE CHROMOSOME X. IN LUPUS PATIENTS, VARIOUS EPIGENETIC MECHANISMS INTERACT WITH EACH OTHER, ENHANCING THE EXPRESSION OR SILENCING OF GENES RESPONSIBLE FOR THE PRODUCTION OF PRO-INFLAMMATORY AND ANTI-INFLAMMATORY CYTOKINES AND ACTIVATION OF AUTOREACTIVE B-LYMPHOCYTES. 2018 3 398 30 AN UPDATE ON GENETIC SUSCEPTIBILITY IN LUPUS NEPHRITIS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC AUTOIMMUNE DISEASE CHARACTERIZED BY MULTIPLE SYSTEM INVOLVEMENT AND POSITIVE SERUM AUTOANTIBODIES. LUPUS NEPHRITIS (LN) IS THE MOST COMMON AND SERIOUS COMPLICATION OF SLE, AND IT IS THE MAIN CAUSE OF DEATH IN PATIENTS WITH SLE. ABNORMALITIES IN THE IMMUNE SYSTEM LEAD TO LN AND INVOLVE A VARIETY OF CELLS (T CELLS, B CELLS, MACROPHAGES, NK CELLS, ETC.), CYTOKINES (INTERLEUKIN, TUMOR NECROSIS FACTOR ALPHA, ETC.) AND THEIR RELATED PATHWAYS. PREVIOUS STUDIES HAVE SHOWN THAT THE INTERACTIONS OF GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS CONTRIBUTE TO THE PATHOGENESIS AND DEVELOPMENT OF LN. IN RECENT YEARS, ONE GENOME-WIDE ASSOCIATION STUDY (GWAS) AND A NUMBER OF GENE ASSOCIATION STUDIES HAVE EXPLORED THE SUSCEPTIBILITY GENES OF LN, INCLUDING IMMUNIZATION-, INFLAMMATION-, ADHESION- AND OTHER PATHWAY-RELATED GENES. THESE GENES PARTICIPATE IN OR SUGGEST THE PATHOGENESIS AND PROGRESSION OF LN. IN THIS REVIEW, WE SUMMARIZE THE GENETIC SUSCEPTIBILITY OF LN AND DISCUSS THE POSSIBLE MECHANISM UNDERLYING THE SUSCEPTIBILITY GENES OF LN. 2020 4 6194 36 THE IMPACT OF PROTEIN ACETYLATION/DEACETYLATION ON SYSTEMIC LUPUS ERYTHEMATOSUS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE IN WHICH THE BODY'S IMMUNE SYSTEM MISTAKENLY ATTACKS HEALTHY CELLS. ALTHOUGH THE EXACT CAUSE OF SLE HAS NOT BEEN IDENTIFIED, IT IS CLEAR THAT BOTH GENETICS AND ENVIRONMENTAL FACTORS TRIGGER THE DISEASE. IDENTICAL TWINS HAVE A 24% CHANCE OF GETTING LUPUS DISEASE IF THE OTHER ONE IS AFFECTED. INTERNAL FACTORS SUCH AS FEMALE GENDER AND SEX HORMONES, THE MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) LOCUS AND OTHER GENETIC POLYMORPHISMS HAVE BEEN SHOWN TO AFFECT SLE, AS WELL AS EXTERNAL, ENVIRONMENTAL INFLUENCES SUCH AS SUNLIGHT EXPOSURE, SMOKING, VITAMIN D DEFICIENCY, AND CERTAIN INFECTIONS. SEVERAL STUDIES HAVE REPORTED AND PROPOSED MULTIPLE ASSOCIATIONS BETWEEN THE ALTERATION OF THE EPIGENOME AND THE PATHOGENESIS OF AUTOIMMUNE DISEASE. EPIGENETIC FACTORS CONTRIBUTING TO SLE INCLUDE MICRORNAS, DNA METHYLATION STATUS, AND THE ACETYLATION/DEACETYLATION OF HISTONE PROTEINS. ADDITIONALLY, THE ACETYLATION OF NON-HISTONE PROTEINS CAN ALSO INFLUENCE CELLULAR FUNCTION. A BETTER UNDERSTANDING OF NON-GENOMIC FACTORS THAT REGULATE SLE WILL PROVIDE INSIGHT INTO THE MECHANISMS THAT INITIATE AND FACILITATE DISEASE AND ALSO CONTRIBUTE TO THE DEVELOPMENT OF NOVEL THERAPEUTICS THAT CAN SPECIFICALLY TARGET PATHOGENIC MOLECULAR PATHWAYS. 2018 5 2529 27 EPIGENETICS CHANGES ASSOCIATED TO ENVIRONMENTAL TRIGGERS IN AUTOIMMUNITY. AUTOIMMUNE DISEASES (AIDS) ARE CHRONIC CONDITIONS INITIATED BY THE LOSS OF IMMUNOLOGICAL TOLERANCE TO SELF-ANTIGENS AND REPRESENT A HETEROGENEOUS GROUP OF DISORDERS THAT AFFECT SPECIFIC TARGET ORGANS OR MULTIPLE ORGANS IN DIFFERENT SYSTEMS. WHILE THE PATHOGENESIS OF AID REMAINS UNCLEAR, ITS AETIOLOGY IS MULTIFUNCTIONAL AND INCLUDES A COMBINATION OF GENETIC, EPIGENETIC, IMMUNOLOGICAL AND ENVIRONMENTAL FACTORS. IN AIDS, SEVERAL EPIGENETIC MECHANISMS ARE DEFECTIVE INCLUDING DNA DEMETHYLATION, ABNORMAL CHROMATIN POSITIONING ASSOCIATED WITH AUTOANTIBODY PRODUCTION AND ABNORMALITIES IN THE EXPRESSION OF RNA INTERFERENCE (RNAI). IT IS KNOWN THAT ENVIRONMENTAL FACTORS MAY INTERFERE WITH DNA METHYLATION AND HISTONE MODIFICATIONS, HOWEVER, LITTLE IS KNOWN ABOUT EPIGENETIC CHANGES DERIVED OF REGULATION OF RNAI. AN APPROACH TO THE KNOWN ENVIRONMENTAL FACTORS AND THE MECHANISMS THAT ALTER THE EPIGENETIC REGULATION IN AIDS (WITH EMPHASIS IN SYSTEMIC LUPUS ERYTHEMATOSUS, THE PROTOTYPE OF SYSTEMIC AID) ARE SHOWED IN THIS REVIEW. 2016 6 6178 31 THE HISTONE MODIFICATION CODE IN THE PATHOGENESIS OF AUTOIMMUNE DISEASES. AUTOIMMUNE DISEASES ARE CHRONIC INFLAMMATORY DISORDERS CAUSED BY A LOSS OF SELF-TOLERANCE, WHICH IS CHARACTERIZED BY THE APPEARANCE OF AUTOANTIBODIES AND/OR AUTOREACTIVE LYMPHOCYTES AND THE IMPAIRED SUPPRESSIVE FUNCTION OF REGULATORY T CELLS. THE PATHOGENESIS OF AUTOIMMUNE DISEASES IS EXTREMELY COMPLEX AND REMAINS LARGELY UNKNOWN. RECENT ADVANCES INDICATE THAT ENVIRONMENTAL FACTORS TRIGGER AUTOIMMUNE DISEASES IN GENETICALLY PREDISPOSED INDIVIDUALS. IN ADDITION, ACCUMULATING RESULTS HAVE INDICATED A POTENTIAL ROLE OF EPIGENETIC MECHANISMS, SUCH AS HISTONE MODIFICATIONS, IN THE DEVELOPMENT OF AUTOIMMUNE DISEASES. HISTONE MODIFICATIONS REGULATE THE CHROMATIN STATES AND GENE TRANSCRIPTION WITHOUT ANY CHANGE IN THE DNA SEQUENCE, POSSIBLY RESULTING IN PHENOTYPE ALTERATION IN SEVERAL DIFFERENT CELL TYPES. IN THIS PAPER, WE DISCUSS THE SIGNIFICANT ROLES OF HISTONE MODIFICATIONS INVOLVED IN THE PATHOGENESIS OF AUTOIMMUNE DISEASES, INCLUDING RHEUMATOID ARTHRITIS, SYSTEMIC LUPUS ERYTHEMATOSUS, SYSTEMIC SCLEROSIS, PRIMARY BILIARY CIRRHOSIS, AND TYPE 1 DIABETES. 2017 7 1508 42 DNA METHYLATION AND MRNA AND MICRORNA EXPRESSION OF SLE CD4+ T CELLS CORRELATE WITH DISEASE PHENOTYPE. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS AN AUTOIMMUNE DISEASE WELL KNOWN FOR ITS CLINICAL HETEROGENEITY, AND ITS ETIOLOGY SECONDARY TO A CROSS-TALK INVOLVING GENETIC PREDISPOSITION AND ENVIRONMENTAL STIMULI. ALTHOUGH GENOME-WIDE ANALYSIS HAS CONTRIBUTED GREATLY TO OUR UNDERSTANDING OF THE GENETIC BASIS OF SLE, THERE IS INCREASING EVIDENCE FOR A ROLE OF EPIGENETICS. INDEED, RECENT DATA HAVE DEMONSTRATED THAT IN PATIENTS WITH SLE, THERE ARE STRIKING ALTERATIONS OF DNA METHYLATION, HISTONE MODIFICATIONS, AND DEREGULATED MICRORNA EXPRESSION, THE SUM OF WHICH CONTRIBUTE TO OVER-EXPRESSION OF SELECT AUTOIMMUNE-RELATED GENES AND LOSS OF TOLERANCE. TO ADDRESS THIS ISSUE AT THE LEVEL OF CLINICAL PHENOTYPE, WE PERFORMED DNA METHYLATION, MRNA AND MICRORNA EXPRESSION SCREENING USING HIGH-THROUGHPUT SEQUENCING OF PURIFIED CD4+ T CELLS FROM PATIENTS WITH SLE, COMPARED TO AGE AND SEX MATCHED CONTROLS. IN PARTICULAR, WE STUDIED 42 PATIENTS WITH SLE AND DIVIDED THIS GROUP INTO THREE CLINICAL PHENOTYPES: A) THE PRESENCE OF SKIN LESIONS WITHOUT SIGNS OF SYSTEMIC PATHOLOGY; B) SKIN LESIONS BUT ALSO CHRONIC RENAL PATHOLOGY; AND C) SKIN LESIONS, CHRONIC RENAL PATHOLOGY AND POLYARTICULAR DISEASE. INTERESTINGLY, AND AS EXPECTED, SEQUENCING DATA REVEALED CHANGES IN DNA METHYLATION IN SLE COMPARED TO CONTROLS. HOWEVER, AND MORE IMPORTANTLY, ALTHOUGH THERE WERE COMMON METHYLATION CHANGES FOUND IN ALL GROUPS OF SLE COMPARED TO CONTROLS, THERE WAS SPECIFIC DNA METHYLATION CHANGES THAT CORRELATED WITH CLINICAL PHENOTYPE. THESE INCLUDED CHANGES IN THE NOVEL KEY TARGET GENES NLRP2, CD300LB AND S1PR3, AS WELL AS CHANGES IN THE CRITICAL PATHWAYS, INCLUDING THE ADHERENS JUNCTION AND LEUKOCYTE TRANSENDOTHELIAL MIGRATION. WE ALSO NOTED THAT A SIGNIFICANT PROPORTION OF GENES UNDERGOING DNA METHYLATION CHANGES WERE INVERSELY CORRELATED WITH GENE EXPRESSION AND THAT MIRNA SCREENING REVEALED THE EXISTENCE OF SUBSETS WITH CHANGES IN EXPRESSION. INTEGRATED ANALYSIS OF THIS DATA HIGHLIGHTS SPECIFIC SETS OF MIRNAS CONTROLLED BY DNA METHYLATION, AND GENES THAT ARE ALTERED BY METHYLATION AND TARGETED BY MIRNAS. IN CONCLUSION, OUR FINDINGS SUGGEST SELECT EPIGENETIC MECHANISMS THAT CONTRIBUTE TO CLINICAL PHENOTYPES AND FURTHER SHED LIGHT ON A NEW VENUE FOR BASIC SLE RESEARCH. 2014 8 2516 41 EPIGENETICS AND SYSTEMIC LUPUS ERYTHEMATOSUS: UNMET NEEDS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC RELAPSING-REMITTING AUTOIMMUNE DISEASE AFFECTING SEVERAL ORGANS. ALTHOUGH THE MANAGEMENT OF LUPUS PATIENTS HAS IMPROVED IN THE LAST YEARS, SEVERAL ASPECTS STILL REMAIN CHALLENGING. MORE SENSITIVE AND SPECIFIC BIOMARKERS FOR AN EARLY DIAGNOSIS AS WELL AS FOR MONITORING DISEASE ACTIVITY AND TISSUE DAMAGE ARE NEEDED. GENOME-WIDE ASSOCIATION AND GENE MAPPING STUDIES HAVE SUPPORTED THE GENETIC BACKGROUND FOR SLE SUSCEPTIBILITY. HOWEVER, THE RELATIVELY MODEST RISK ASSOCIATION AND THE STUDIES IN TWINS HAVE SUGGESTED A ROLE FOR ENVIRONMENTAL AND EPIGENETIC FACTORS, AS WELL AS GENETIC-EPIGENETIC INTERACTION. ACCORDINGLY, THERE IS EVIDENCE THAT DIFFERENCES IN DNA METHYLATION, HISTONE MODIFICATIONS, AND MIRNA PROFILING CAN BE FOUND IN LUPUS PATIENTS VERSUS NORMAL SUBJECTS. MOREOVER, IMPAIRED DNA METHYLATION ON THE INACTIVE X-CHROMOSOME WAS SUGGESTED TO EXPLAIN, AT LEAST IN PART, THE FEMALE PREVALENCE OF THE DISEASE. EPIGENETIC MARKERS MAY BE HELP IN FULFILLING THE UNMET NEEDS FOR SLE BY OFFERING NEW DIAGNOSTIC TOOLS, NEW BIOMARKERS FOR MONITORING DISEASE ACTIVITY, OR TO BETTER CHARACTERIZE PATIENTS WITH A SILENT CLINICAL DISEASE BUT WITH AN ACTIVE SEROLOGY. ANTI-DNA, ANTI-PHOSPHOLIPID, AND ANTI-RO/SSA AUTOANTIBODIES ARE THOUGHT TO BE PATHOGENIC FOR GLOMERULONEPHRITIS, RECURRENT THROMBOSIS AND MISCARRIAGES, AND NEONATAL LUPUS, RESPECTIVELY. HOWEVER, TISSUE DAMAGE OCCURS OCCASIONALLY OR, IN SOME PATIENTS, ONLY IN SPITE OF THE PERSISTENT PRESENCE OF THE ANTIBODIES. PRELIMINARY STUDIES SUGGEST THAT EPIGENETIC MECHANISMS MAY EXPLAIN WHY THE DAMAGE TAKES PLACE IN SOME PATIENTS ONLY OR AT A GIVEN TIME. 2016 9 1463 34 DISSECTING COMPLEX EPIGENETIC ALTERATIONS IN HUMAN LUPUS. SYSTEMIC LUPUS ERYTHEMATOSUS IS A CHRONIC RELAPSING AUTOIMMUNE DISEASE THAT PRIMARILY AFFLICTS WOMEN, AND BOTH A GENETIC PREDISPOSITION AND APPROPRIATE ENVIRONMENTAL EXPOSURES ARE REQUIRED FOR LUPUS TO DEVELOP AND FLARE. THE GENETIC REQUIREMENT IS EVIDENCED BY AN INCREASED CONCORDANCE IN IDENTICAL TWINS AND BY THE VALIDATION OF AT LEAST 35 SINGLE-NUCLEOTIDE POLYMORPHISMS PREDISPOSING PATIENTS TO LUPUS. GENES ALONE, THOUGH, ARE NOT ENOUGH. THE CONCORDANCE OF LUPUS IN IDENTICAL TWINS IS OFTEN INCOMPLETE, AND WHEN CONCORDANT, THE AGE OF ONSET IS USUALLY DIFFERENT. LUPUS IS ALSO NOT PRESENT AT BIRTH, BUT ONCE THE DISEASE DEVELOPS, IT TYPICALLY FOLLOWS A CHRONIC RELAPSING COURSE. THUS, GENES ALONE ARE INSUFFICIENT TO CAUSE HUMAN LUPUS, AND ADDITIONAL FACTORS ENCOUNTERED IN THE ENVIRONMENT AND OVER TIME ARE REQUIRED TO INITIATE THE DISEASE AND SUBSEQUENT FLARES. THE NATURE OF THE ENVIRONMENTAL CONTRIBUTION, THOUGH, AND THE MECHANISMS BY WHICH ENVIRONMENTAL AGENTS MODIFY THE IMMUNE RESPONSE TO CAUSE LUPUS ONSET AND FLARES IN GENETICALLY PREDISPOSED PEOPLE HAVE BEEN CONTROVERSIAL. REPORTS THAT THE LUPUS-INDUCING DRUGS PROCAINAMIDE AND HYDRALAZINE ARE EPIGENETIC MODIFIERS, THAT EPIGENETICALLY MODIFIED T CELLS ARE SUFFICIENT TO CAUSE LUPUS-LIKE AUTOIMMUNITY IN ANIMAL MODELS, AND THAT PATIENTS WITH ACTIVE LUPUS HAVE EPIGENETIC CHANGES SIMILAR TO THOSE CAUSED BY PROCAINAMIDE AND HYDRALAZINE HAVE PROMPTED A GROWING INTEREST IN HOW EPIGENETIC ALTERATIONS CONTRIBUTE TO THIS DISEASE. UNDERSTANDING HOW EPIGENETIC MECHANISMS MODIFY T CELLS TO CONTRIBUTE TO LUPUS REQUIRES AN UNDERSTANDING OF HOW EPIGENETIC MECHANISMS REGULATE GENE EXPRESSION. THE ROLES OF DNA METHYLATION, HISTONE MODIFICATIONS, AND MICRORNAS IN LUPUS PATHOGENESIS WILL BE REVIEWED HERE. 2013 10 6107 32 THE EMERGING ROLE OF NONCODING RNAS IN SYSTEMIC LUPUS ERYTHEMATOSUS: NEW INSIGHTS INTO THE MASTER REGULATORS OF DISEASE PATHOGENESIS. AUTO-IMMUNE DISEASES ARE A FORM OF CHRONIC DISORDERS IN WHICH THE IMMUNE SYSTEM DESTROYS THE BODY'S CELLS DUE TO A LOSS OF TOLERANCE TO SELF-ANTIGENS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE), IDENTIFIED BY THE PRODUCTION OF AUTOANTIBODIES IN DIFFERENT BODY PARTS, IS ONE OF THE MOST WELL-KNOWN EXAMPLES OF THESE DISEASES. ALTHOUGH THE ETIOLOGY OF SLE IS UNCLEAR, THE DISEASE'S PROGRESSION MAY BE AFFECTED BY GENETIC AND ENVIRONMENTAL FACTORS. AS STUDIES IN TWINS PROVIDE ADEQUATE EVIDENCE FOR GENETIC INVOLVEMENT IN THE SLE, OTHER PHENOMENA SUCH AS METALLIZATION, HISTONE MODIFICATIONS, AND ALTERATIONS IN THE EXPRESSION OF NONCODING RNAS (NCRNAS) ALSO INDICATE THE INVOLVEMENT OF EPIGENETIC FACTORS IN THIS DISEASE. AMONG ALL THE EPIGENETIC ALTERATIONS, NCRNAS APPEAR TO HAVE THE MOST CRUCIAL CONTRIBUTION TO THE PATHOGENESIS OF SLE. THE NCRNAS' LENGTH AND SIZE ARE DIVIDED INTO THREE MAIN CLASSES: MICRO RNAS, LONG NONCODING RNAS (LNCRNA), AND CIRCULAR RNAS (CIRCRNAS). ACCUMULATING EVIDENCE SUGGESTS THAT DYSREGULATIONS IN THESE NCRNAS CONTRIBUTED TO THE PATHOGENESIS OF SLE. HENCE, CLARIFYING THE FUNCTION OF THESE GROUPS OF NCRNAS IN THE PATHOPHYSIOLOGY OF SLE PROVIDES A DEEPER UNDERSTANDING OF THE DISEASE. IT ALSO OPENS UP NEW OPPORTUNITIES TO DEVELOP TARGETED THERAPIES FOR THIS DISEASE. 2023 11 6262 37 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 2257 29 EPIGENETIC PERSPECTIVES IN SYSTEMIC LUPUS ERYTHEMATOSUS: PATHOGENESIS, BIOMARKERS, AND THERAPEUTIC POTENTIALS. SYSTEM LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC AUTOIMMUNE DISEASE CHARACTERIZED BY THE PRODUCTION OF AUTOANTIBODIES THAT CAUSE WIDESPREAD TISSUE DAMAGE. THE UNDERLYING ETIOLOGY REMAINS LARGELY UNKNOWN. ABERRANT EPIGENETICS PLAYS ESSENTIAL ROLES IN THE PATHOGENESIS OF SLE. THIS REVIEW EXPLORES THE LINKS BETWEEN DNA METHYLATION, HISTONE MODIFICATIONS, AND MIRNAS IN SLE AND HIGHLIGHTS HOW THESE FACTORS MAY INTERACT IN SLE PATHOGENESIS. WE ALSO DISCUSS HOW FURTHERING OUR KNOWLEDGE OF EPIGENETICS IN LUPUS PROVIDES HOPE FOR FINDING NEW DIAGNOSTIC AND PROGNOSTIC BIOMARKERS AND NOVEL THERAPEUTIC TARGETS AND STRATEGIES. 2010 13 4216 36 METHYL DONOR MICRONUTRIENTS: A POTENTIAL DIETARY EPIGENETIC TARGET IN SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC AUTOIMMUNE DISEASE CHARACTERIZED BY AN ABERRANT IMMUNE RESPONSE AND PERSISTENT INFLAMMATION. ITS PATHOGENESIS REMAINS UNKNOWN; HOWEVER, A COMPLEX INTERACTION BETWEEN ENVIRONMENTAL, GENETIC, AND EPIGENETIC FACTORS HAS BEEN SUGGESTED TO CAUSE DISEASE ONSET. SEVERAL STUDIES HAVE DEMONSTRATED THAT EPIGENETIC ALTERATIONS, SUCH AS DNA HYPOMETHYLATION, MIRNA OVEREXPRESSION, AND ALTERED HISTONE ACETYLATION, MAY CONTRIBUTE TO SLE ONSET AND THE DISEASE'S CLINICAL MANIFESTATIONS. EPIGENETIC CHANGES, ESPECIALLY METHYLATION PATTERNS, ARE MODIFIABLE AND SUSCEPTIBLE TO ENVIRONMENTAL FACTORS SUCH AS DIET. IT IS WELL KNOWN THAT METHYL DONOR NUTRIENTS, SUCH AS FOLATE, METHIONINE, CHOLINE, AND SOME B VITAMINS, PLAY A RELEVANT ROLE IN DNA METHYLATION BY PARTICIPATING AS METHYL DONORS OR COENZYMES IN ONE-CARBON METABOLISM. BASED ON THIS KNOWLEDGE, THIS CRITICAL LITERATURE REVIEW AIMED TO INTEGRATE THE EVIDENCE IN ANIMAL MODELS AND HUMANS REGARDING THE ROLE OF NUTRIENTS IN EPIGENETIC HOMEOSTASIS AND THEIR IMPACT ON IMMUNE SYSTEM REGULATION TO SUGGEST A POTENTIAL EPIGENETIC DIET THAT COULD SERVE AS ADJUVANT THERAPY IN SLE. 2023 14 549 27 AUTOANTIGENS: NOVEL FORMS AND PRESENTATION TO THE IMMUNE SYSTEM. IT IS CLEAR THAT LUPUS AUTOIMMUNITY IS MARKED BY A VARIETY OF ABNORMALITIES, INCLUDING THOSE FOUND AT A MACROSCOPIC SCALE, CELLS AND TISSUES, AS WELL AS MORE MICROENVIRONMENTAL INFLUENCES, ORIGINATING AT THE INDIVIDUAL CELL SURFACE THROUGH TO THE NUCLEUS. THE CONVERGENCE OF GENETIC, EPIGENETIC, AND PERHAPS ENVIRONMENTAL INFLUENCES ALL LEAD TO THE OVERT CLINICAL EXPRESSION OF DISEASE, REFLECTED BY THE PRESENCES OF AUTOANTIBODIES AND TISSUE PATHOLOGY. THIS REVIEW WILL ADDRESS SEVERAL SPECIFIC AREAS THAT FALL AMONG THE NON-GENETIC FACTORS THAT CONTRIBUTE TO LUPUS AUTOIMMUNITY AND RELATED SYNDROMES. IN PARTICULAR, WE WILL DISCUSS THE IMPORTANCE OF UNDERSTANDING VARIOUS PROTEIN POST-TRANSLATIONAL MODIFICATIONS (PTMS), MECHANISMS THAT MEDIATE THE ABILITY OF "MODIFIED SELF" TO TRIGGER AUTOIMMUNITY, AND HOW THESE PTMS INFLUENCE LUPUS DIAGNOSIS. FINALLY, WE WILL DISCUSS ALTERED PATHWAYS OF AUTOANTIGEN PRESENTATION THAT MAY CONTRIBUTE TO THE PERPETUATION OF CHRONIC AUTOIMMUNE DISEASE. 2014 15 6340 28 THE ROLE OF EPIGENETIC FACTORS IN PSORIASIS. PSORIASIS IS A CHRONIC, SYSTEMIC, IMMUNE-MEDIATED DISEASE WITH AN INCIDENCE OF APPROXIMATELY 2%. THE PATHOGENESIS OF THE DISEASE IS COMPLEX AND NOT YET FULLY UNDERSTOOD. GENETIC FACTORS PLAY A SIGNIFICANT ROLE IN THE PATHOGENESIS OF THE DISEASE. IN PREDISPOSED INDIVIDUALS, MULTIPLE TRIGGER FACTORS MAY CONTRIBUTE TO DISEASE ONSET AND EXACERBATIONS OF SYMPTOMS. ENVIRONMENTAL FACTORS (STRESS, INFECTIONS, CERTAIN MEDICATIONS, NICOTINISM, ALCOHOL, OBESITY) PLAY A SIGNIFICANT ROLE IN THE PATHOGENESIS OF PSORIASIS. IN ADDITION, EPIGENETIC MECHANISMS ARE CONSIDERED RESULT IN MODULATION OF INDIVIDUAL GENE EXPRESSION AND AN INCREASED LIKELIHOOD OF THE DISEASE. STUDIES HIGHLIGHT THE SIGNIFICANT ROLE OF EPIGENETIC FACTORS IN THE ETIOLOGY AND PATHOGENESIS OF PSORIASIS. EPIGENETIC MECHANISMS IN PSORIASIS INCLUDE DNA METHYLATION, HISTONE MODIFICATIONS AND NON-CODING RNAS. EPIGENETIC MECHANISMS INDUCE GENE EXPRESSION CHANGES UNDER THE INFLUENCE OF CHEMICAL MODIFICATIONS OF DNA AND HISTONES, WHICH ALTER CHROMATIN STRUCTURE AND ACTIVATE TRANSCRIPTION FACTORS OF SELECTED GENES, THUS LEADING TO TRANSLATION OF NEW MRNA WITHOUT AFFECTING THE DNA SEQUENCE. EPIGENETIC FACTORS CAN REGULATE GENE EXPRESSION AT THE TRANSCRIPTIONAL (VIA HISTONE MODIFICATION, DNA METHYLATION) AND POSTTRANSCRIPTIONAL LEVELS (VIA MICRORNAS AND LONG NON-CODING RNAS). THIS STUDY AIMS TO PRESENT AND DISCUSS THE DIFFERENT EPIGENETIC MECHANISMS IN PSORIASIS BASED ON A REVIEW OF THE AVAILABLE LITERATURE. 2021 16 6275 38 THE PATHOGENESIS OF SYSTEMIC LUPUS ERYTHEMATOSUS: HARNESSING BIG DATA TO UNDERSTAND THE MOLECULAR BASIS OF LUPUS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC, SYSTEMIC AUTOIMMUNE DISEASE THAT CAUSES DAMAGE TO MULTIPLE ORGAN SYSTEMS. DESPITE DECADES OF RESEARCH AND AVAILABLE MURINE MODELS THAT CAPTURE SOME ASPECTS OF THE HUMAN DISEASE, NEW TREATMENTS FOR SLE LAG BEHIND OTHER AUTOIMMUNE DISEASES SUCH AS RHEUMATOID ARTHRITIS AND CROHN'S DISEASE. BIG DATA GENOMIC ASSAYS HAVE TRANSFORMED OUR UNDERSTANDING OF SLE BY PROVIDING IMPORTANT INSIGHTS INTO THE MOLECULAR HETEROGENEITY OF THIS MULTIGENIC DISEASE. GENE WIDE ASSOCIATION STUDIES HAVE DEMONSTRATED MORE THAN 100 RISK LOCI, SUPPORTING A MODEL OF MULTIPLE GENETIC HITS INCREASING SLE RISK IN A NON-LINEAR FASHION, AND PROVIDING EVIDENCE OF ANCESTRAL DIVERSITY IN SUSCEPTIBILITY LOCI. EPIGENETIC STUDIES TO DETERMINE THE ROLE OF METHYLATION, ACETYLATION AND NON-CODING RNAS HAVE PROVIDED NEW UNDERSTANDING OF THE MODULATION OF GENE EXPRESSION IN SLE PATIENTS AND IDENTIFIED NEW DRUG TARGETS AND BIOMARKERS FOR SLE. GENE EXPRESSION PROFILING HAS LED TO A GREATER UNDERSTANDING OF THE ROLE OF MYELOID CELLS IN THE PATHOGENESIS OF SLE, CONFIRMED ROLES FOR T AND B CELLS IN SLE, PROMOTED CLINICAL TRIALS BASED ON THE PROMINENT INTERFERON SIGNATURE FOUND IN SLE PATIENTS, AND IDENTIFIED CANDIDATE BIOMARKERS AND CELLULAR SIGNATURES TO FURTHER DRUG DEVELOPMENT AND DRUG REPURPOSING. GENE EXPRESSION STUDIES ARE ADVANCING OUR UNDERSTANDING OF THE UNDERLYING MOLECULAR HETEROGENEITY IN SLE AND PROVIDING HOPE THAT PATIENT STRATIFICATION WILL EXPEDITE NEW THERAPIES BASED ON PERSONAL MOLECULAR SIGNATURES. ALTHOUGH BIG DATA ANALYSES PRESENT UNIQUE INTERPRETATION CHALLENGES, BOTH COMPUTATIONALLY AND BIOLOGICALLY, ADVANCES IN MACHINE LEARNING APPLICATIONS MAY FACILITATE THE ABILITY TO PREDICT CHANGES IN SLE DISEASE ACTIVITY AND OPTIMIZE THERAPEUTIC STRATEGIES. 2020 17 2017 37 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 18 4285 35 MICRORNA EPIGENETIC SIGNATURES IN HUMAN DISEASE. MICRORNAS (MIRNAS) ARE SHORT NON-CODING RNAS THAT ACT AS IMPORTANT REGULATORS OF GENE EXPRESSION AS PART OF THE EPIGENETIC MACHINERY. IN ADDITION TO POSTTRANSCRIPTIONAL GENE SILENCING BY MIRNAS, THE EPIGENETIC MECHANISMS ALSO INCLUDE DNA METHYLATION, HISTONE MODIFICATIONS AND THEIR CROSSTALK. EPIGENETIC MODIFICATIONS WERE REPORTED TO PLAY AN IMPORTANT ROLE IN MANY DISEASE ONSETS AND PROGRESSIONS AND CAN BE USED TO EXPLAIN SEVERAL FEATURES OF COMPLEX DISEASES, SUCH AS LATE ONSET AND FLUCTUATION OF SYMPTOMS. HOWEVER, MIRNAS NOT ONLY FUNCTION AS A PART OF EPIGENETIC MACHINERY, BUT ARE ALSO EPIGENETICALLY MODIFIED BY DNA METHYLATION AND HISTONE MODIFICATION LIKE ANY OTHER PROTEIN-CODING GENE. THERE IS A STRONG CONNECTION BETWEEN EPIGENOME AND MIRNOME, AND ANY DYSREGULATION OF THIS COMPLEX SYSTEM CAN RESULT IN VARIOUS PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS. IN ADDITION, MIRNAS PLAY AN IMPORTANT ROLE IN TOXICOGENOMICS AND MAY EXPLAIN THE RELATIONSHIP BETWEEN TOXICANT EXPOSURE AND TUMORIGENESIS. THE PRESENT REVIEW PROVIDES INFORMATION ON 63 MIRNA GENES SHOWN TO BE EPIGENETICALLY REGULATED IN ASSOCIATION WITH 21 DISEASES, INCLUDING 11 CANCER TYPES: CARDIAC FIBROSIS, CARDIOVASCULAR DISEASE, PREECLAMPSIA, HIRSCHSPRUNG'S DISEASE, RHEUMATOID ARTHRITIS, SYSTEMIC SCLEROSIS, SYSTEMIC LUPUS ERYTHEMATOSUS, TEMPORAL LOBE EPILEPSY, AUTISM, PULMONARY FIBROSIS, MELANOMA, ACUTE MYELOID LEUKEMIA, CHRONIC LYMPHOCYTIC LEUKEMIA, COLORECTAL, GASTRIC, CERVICAL, OVARIAN, PROSTATE, LUNG, BREAST, AND BLADDER CANCER. THE REVIEW REVEALED THAT HSA-MIR-34A, HSA-MIR-34B, AND HSA-MIR-34C ARE THE MOST FREQUENTLY REPORTED EPIGENETICALLY DYSREGULATED MIRNAS. THERE IS A NEED TO FURTHER STUDY MOLECULAR MECHANISMS OF VARIOUS DISEASES TO BETTER UNDERSTAND THE CROSSTALK BETWEEN EPIGENETICS AND GENE EXPRESSION AND TO DEVELOP NEW THERAPEUTIC OPTIONS AND BIOMARKERS. 2016 19 2559 41 EPIGENETICS IN SYSTEMIC LUPUS ERYTHEMATOSUS: LEADING THE WAY FOR SPECIFIC THERAPEUTIC AGENTS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC AUTOIMMUNE DISORDER OF AN UNCLEARLY DETERMINED ETIOLOGY. PAST STUDIES, BOTH EPIDEMIOLOGICAL AND BIOLOGICAL, HAVE IMPLICATED EPIGENETIC INFLUENCES IN DISEASE ETIOLOGY AND PATHOGENESIS. EPIGENETICS DESCRIBES CHANGES IN GENE EXPRESSION NOT LINKED TO ALTERATIONS IN THE UNDERLYING GENOMIC SEQUENCE, AND IS MOST OFTEN TYPIFIED BY THREE MODIFICATIONS: METHYLATION OF DNA, ADDITION OF VARIOUS SIDE CHAINS TO HISTONE GROUPS AND TRANSCRIPTIONAL REGULATION VIA SHORT NCRNA SEQUENCES. THE PURPOSE OF THIS ARTICLE IS TO REVIEW THE MOST IMPORTANT ADVANCES THAT LINK EPIGENETIC CHANGES TO LUPUS. THE CONTRIBUTION OF DNA METHYLATION CHANGES TO LUPUS PATHOGENESIS IS DISCUSSED. THESE INCLUDE THE ROLE OF APOPTOTIC DNA, ULTRAVIOLET RADIATION, ENDOGENOUS RETROVIRUSES, DIETARY CONTRIBUTIONS AND AGING. HYPOMETHYLATION OF SPECIFIC GENES OVEREXPRESSED IN LUPUS T CELLS SUCH AS ITGAL (CD11A), CD40LG (CD40L), TNFSF7 (CD70), KIR2DL4 AND PRF1 (PERFORIN), AND CD5 IN LUPUS B CELLS SEEM TO PLAY AN IMPORTANT ROLE. MOREOVER, HISTONE MODIFICATIONS SUCH AS INCREASED GLOBAL H4 ACETYLATION IN MONOCYTES ARE HIGHLY ASSOCIATED WITH SLE. NCRNAS, ESPECIALLY MIR-21, MIR-148A AND MIR-126, CONTROL OTHER ELEMENTS OF EPIGENETIC REGULATION; PARTICULARLY, TRANSCRIPTION OF THE MAINTENANCE DNA METHYLATION ENZYME DNMT1. EPIGENETIC CONTRIBUTIONS TO SLE ETIOLOGY HAVE BEEN WELL ESTABLISHED, BUT MUCH IS STILL UNKNOWN. EPIGENOME-WIDE STUDIES COUPLED WITH FUNCTIONAL ANALYSIS OF THE EPIGENOMIC CHANGES DISCOVERED WILL UNCOVER NOVEL PATHWAYS IMPORTANT IN DISEASE PATHOGENESIS. EPIGENETIC THERAPIES FOR SLE MAY BE FEASIBLE IN THE FUTURE, PARTICULARLY IF THEY ARE DESIGNED TO TARGET SPECIFIC REGIONS WITHIN THE GENOME. 2011 20 1719 36 DYSREGULATED MICRORNAS IN THE PATHOGENESIS OF SYSTEMIC LUPUS ERYTHEMATOSUS: A COMPREHENSIVE REVIEW. SYSTEMIC LUPUS ERYTHEMATOSUS IS A CHRONIC AUTOIMMUNE DISEASE OF WHICH CLINICAL PRESENTATION IS VASTLY HETEROGENEOUS, RANGING FROM MILD SKIN RASHES TO SEVERE RENAL DISEASES. TREATMENT GOAL OF THIS ILLNESS IS TO MINIMIZE DISEASE ACTIVITY AND PREVENT FURTHER ORGAN DAMAGE. IN RECENT YEARS, MUCH RESEARCH HAS BEEN DONE ON THE EPIGENETIC ASPECTS OF SLE PATHOGENESIS, FOR AMONG THE VARIOUS FACTORS KNOWN TO CONTRIBUTE TO THE PATHOGENIC PROCESS, EPIGENETIC FACTORS, ESPECIALLY MICRORNAS, BEAR THE MOST THERAPEUTIC POTENTIAL THAT CAN BE ALTERED UNLIKE CONGENITAL GENETIC FACTORS. THIS ARTICLE REVIEWS AND UPDATES WHAT HAS BEEN DISCOVERED SO FAR ABOUT THE PATHOGENESIS OF LUPUS, WHILE FOCUSING ON THE DYSREGULATION OF MICRORNAS IN LUPUS PATIENTS IN COMPARISON TO HEALTHY CONTROLS ALONG WITH THE POTENTIALLY PATHOGENIC ROLES OF THE MICRORNAS COMMONLY REPORTED TO BE EITHER UPREGULATED OR DOWNREGULATED. FURTHERMORE, THIS REVIEW INCLUDES MICRORNAS OF WHICH RESULTS ARE CONTROVERSIAL, SUGGESTING POSSIBLE EXPLANATIONS FOR SUCH DISCREPANCIES AND DIRECTIONS FOR FUTURE RESEARCH. MOREOVER, WE AIMED TO EMPHASIZE THE POINT THAT HAD BEEN OVERLOOKED SO FAR IN STUDIES REGARDING MICRORNA EXPRESSION LEVELS; THAT IS, WHICH SPECIMEN WAS USED TO ASSESS THE DYSREGULATION OF MICRORNAS. TO OUR SURPRISE, A VAST NUMBER OF STUDIES HAVE NOT CONSIDERED THIS FACTOR AND HAVE ANALYZED THE POTENTIAL ROLE OF MICRORNAS IN GENERAL. DESPITE EXTENSIVE INVESTIGATIONS DONE ON MICRORNA LEVELS, THEIR SIGNIFICANCE AND POTENTIAL ROLE REMAIN A MYSTERY, WHICH CALLS FOR FURTHER STUDIES ON THIS PARTICULAR SUBJECT IN REGARD OF WHICH SPECIMEN IS USED FOR ASSESSMENT. 2023