1 5442 94 RENIN-ANGIOTENSIN BLOCKADE RESETS PODOCYTE EPIGENOME THROUGH KRUPPEL-LIKE FACTOR 4 AND ATTENUATES PROTEINURIA. PROTEINURIA IS A CENTRAL COMPONENT OF CHRONIC KIDNEY DISEASE AND AN INDEPENDENT RISK FACTOR FOR CARDIOVASCULAR DISEASE. KIDNEY PODOCYTES HAVE AN ESSENTIAL ROLE AS A FILTRATION BARRIER AGAINST PROTEINURIA. KRUPPEL-LIKE FACTOR 4 (KLF4) IS EXPRESSED IN PODOCYTES AND DECREASED IN GLOMERULAR DISEASES LEADING TO METHYLATION OF THE NEPHRIN PROMOTER, DECREASED NEPHRIN EXPRESSION AND PROTEINURIA. TREATMENT WITH AN ANGIOTENSIN RECEPTOR BLOCKER (ARB) REDUCED METHYLATION OF THE NEPHRIN PROMOTER IN MURINE GLOMERULI OF AN ADRIAMYCIN NEPHROPATHY MODEL WITH RECOVERY OF KLF4 EXPRESSION AND A DECREASE IN ALBUMINURIA. IN PODOCYTE-SPECIFIC KLF4 KNOCKOUT MICE, THE EFFECT OF ARB ON ALBUMINURIA AND THE NEPHRIN PROMOTER METHYLATION WAS ATTENUATED. IN CULTURED HUMAN PODOCYTES, ANGIOTENSIN II REDUCED KLF4 EXPRESSION AND CAUSED METHYLATION OF THE NEPHRIN PROMOTER WITH DECREASED NEPHRIN EXPRESSION. IN PATIENTS, NEPHRIN PROMOTER METHYLATION WAS INCREASED IN PROTEINURIC KIDNEY DISEASES WITH DECREASED KLF4 AND NEPHRIN EXPRESSION. KLF4 EXPRESSION IN ARB-TREATED PATIENTS WAS HIGHER IN PATIENTS WITH THAN WITHOUT ARB TREATMENT. THUS, ANGIOTENSIN II CAN MODULATE EPIGENETIC REGULATION IN PODOCYTES AND ARB INHIBITS THESE ACTIONS IN PART VIA KLF4 IN PROTEINURIC KIDNEY DISEASES. THIS STUDY PROVIDES A NEW CONCEPT THAT RENIN-ANGIOTENSIN SYSTEM BLOCKADE CAN EXERT THERAPEUTIC EFFECTS THROUGH EPIGENETIC MODULATION OF THE KIDNEY GENE EXPRESSION. 2015 2 2990 19 GENETIC FACTORS PREDISPOSING TO SYSTEMIC LUPUS ERYTHEMATOSUS AND LUPUS NEPHRITIS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC INFLAMMATORY DISEASE CHARACTERIZED BY A LOSS OF TOLERANCE TO SELF-ANTIGENS AND THE PRODUCTION OF HIGH TITERS OF SERUM AUTOANTIBODIES. LUPUS NEPHRITIS CAN AFFECT UP TO 74% OF SLE PATIENTS, PARTICULARLY THOSE OF HISPANIC AND AFRICAN ANCESTRIES, AND REMAINS A MAJOR CAUSE OF MORBIDITY AND MORTALITY. A GENETIC ETIOLOGY IN SLE IS NOW WELL SUBSTANTIATED. THANKS TO EXTENSIVE COLLABORATIONS, EXTRAORDINARY PROGRESS HAS BEEN MADE IN THE PAST FEW YEARS AND THE NUMBER OF CONFIRMED GENES PREDISPOSING TO SLE HAS CATAPULTED TO APPROXIMATELY 30. STUDIES OF OTHER FORMS OF GENETIC VARIATION, SUCH AS COPY NUMBER VARIANTS AND EPIGENETIC ALTERATIONS, ARE EMERGING AND PROMISE TO REVOLUTIONIZE OUR KNOWLEDGE ABOUT DISEASE MECHANISMS. HOWEVER, TO DATE LITTLE PROGRESS HAS BEEN MADE ON THE IDENTIFICATION OF GENETIC FACTORS SPECIFIC TO LUPUS NEPHRITIS. ON THE NEAR HORIZON, TWO LARGE-SCALE EFFORTS, A COLLABORATIVE META-ANALYSIS OF LUPUS NEPHRITIS BASED ON ALL GENOME-WIDE ASSOCIATION DATA IN CAUCASIANS AND PARALLEL SCANS IN FOUR OTHER ETHNICITIES, ARE POISED TO MAKE FUNDAMENTAL DISCOVERIES IN THE GENETICS OF LUPUS NEPHRITIS. COLLECTIVELY, THESE FINDINGS WILL SHOW THAT A BROAD ARRAY OF PATHWAYS UNDERLINES THE GENETIC HETEROGENEITY OF SLE AND LUPUS NEPHRITIS, AND PROVIDE POTENTIAL AVENUES FOR THE DEVELOPMENT OF NOVEL THERAPIES. 2010 3 3501 28 IDENTIFICATION OF POTENTIAL BIOMARKERS FOR SYSTEMIC LUPUS ERYTHEMATOSUS BY INTEGRATED ANALYSIS OF GENE EXPRESSION AND METHYLATION DATA. INTRODUCTION: SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A HETEROGENEOUS AND CHRONIC AUTOIMMUNE DISEASE. ABERRANT DNA METHYLATION OCCURS DURING VARIOUS PROCESSES OF SLE DEVELOPMENT REGULATING THE MRNA EXPRESSION OF INTERRELATED GENES. THIS STUDY AIMS TO SCREEN POTENTIAL DNA METHYLATION MARKERS FOR SLE. METHODS: GENE EXPRESSION AND METHYLATION DATASETS WERE DOWNLOADED FROM THE GENE EXPRESSION OMNIBUS (GEO) DATABASE. DIFFERENTIALLY EXPRESSED GENES (DEGS) BETWEEN SLE PATIENTS AND HEALTHY CONTROLS WERE SCREENED USING THE LIMMA R PACKAGE, AND DIFFERENTIALLY METHYLATED POSITIONS (DMPS) AND REGIONS (DMRS) WERE IDENTIFIED USING DMPFINDER AND BUMPHUNTER (MINFI). ADDITIONALLY, THE DNA METHYLATION MARKERS TO DISTINGUISH SLE PATIENTS FROM HEALTHY CONTROLS WERE EXPLORED THROUGH RECEIVER OPERATING CHARACTERISTIC (ROC) CURVES AND LOGISTIC REGRESSION ANALYSES. FINALLY, WE VALIDATED THE RESULTS OF THE BIOINFORMATIC ANALYSIS BY PYROSEQUENCING. RESULTS: IN TOTAL, 91 DEGS, 90,092 DMPS, 15 DMRS, AND 13 DMR-ASSOCIATED GENES WERE IDENTIFIED. THROUGH THE INTEGRATIVE ANALYSIS OF DEG- AND DMR-ASSOCIATED GENES, WE IDENTIFIED FIVE TYPE I INTERFERON (IFN)-RELATED GENES AS KEY EPIGENETIC-DRIVEN GENES IN SLE. GO ENRICHMENT ANALYSIS SHOWED THAT THE FIVE SLE-ASSOCIATED EPIGENETIC-DRIVEN GENES WERE MAINLY ENRICHED IN THE TYPE I IFN SIGNALING PATHWAY INVOLVED IN IMMUNE RESPONSE AND DEFENSE RESPONSE TO VIRUS. MOREOVER, WE IDENTIFIED TWO SLE-SPECIFIC DNA METHYLATION MARKERS, THREE SLE WITHOUT LUPUS NEPHRITIS (SLE-LN(-))-SPECIFIC DNA METHYLATION MARKERS, AND TWO SLE WITH LUPUS NEPHRITIS (SLE-LN(+))-SPECIFIC DNA METHYLATION MARKERS BY STEPWISE LOGISTIC REGRESSION. CONCLUSIONS: OVERALL, OUR STUDY DEMONSTRATES POTENTIAL DNA METHYLATION MARKERS OF SLE, SLE-LN(-), AND SLE-LN(+), WHICH MAY HELP THE DIAGNOSIS, BOOST THE DEVELOPMENT OF NEW EPIGENETIC THERAPY, AND CONTRIBUTE TO INDIVIDUALIZED TREATMENT. KEY POINTS * THIS STUDY IDENTIFIED FIVE TYPE I IFN-RELATED GENES AS KEY EPIGENETIC-DRIVEN GENES IN SLE, WHICH SUPPORT THE IMPORTANCE OF THE TYPE I IFN PATHWAY IN THE PATHOGENESIS OF SLE * WE IDENTIFIED NOVEL DNA METHYLATION BIOMARKERS IN SLE, SLE-LN-, AND SLE-LN+ BY A COMPREHENSIVE ANALYSIS OF BIOINFORMATICS METHODS AND EXECUTED EXPERIMENTAL VALIDATION, AND BINARY LOGISTIC REGRESSION ANALYSIS SHOWED THAT THEY HAVE EXCELLENT POTENTIAL * THESE RESULTS MAY PROVIDE NEW INSIGHTS INTO THE BIOLOGICAL MECHANISMS OF SLE, AND IDENTIFY RELIABLE BIOMARKERS FOR SLE, SLE-LN-, AND SLE-LN+, WHICH MAY CONTRIBUTE TO DIAGNOSIS AND INDIVIDUALIZED TREATMENT. 2023 4 3056 27 GENOME-WIDE DNA METHYLATION ANALYSIS IMPLICATES ENRICHMENT OF INTERFERON PATHWAY IN AFRICAN AMERICAN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS AND EUROPEAN AMERICANS WITH LUPUS NEPHRITIS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC, MULTISYSTEM, INFLAMMATORY AUTOIMMUNE DISEASE THAT DISPROPORTIONATELY AFFECTS WOMEN. TRENDS IN SLE PREVALENCE AND CLINICAL COURSE DIFFER BY ANCESTRY, WITH THOSE OF AFRICAN AMERICAN ANCESTRY PRESENTING WITH MORE ACTIVE, SEVERE AND RAPIDLY PROGRESSIVE DISEASE THAN EUROPEAN AMERICANS. PREVIOUS RESEARCH ESTABLISHED ALTERED EPIGENETIC SIGNATURES IN SLE PATIENTS COMPARED TO CONTROLS. HOWEVER, THE CONTRIBUTION OF ABERRANT DNA METHYLATION (DNAM) TO THE RISK OF SLE BY ANCESTRY AND DIFFERENCES AMONG PATIENTS WITH SLE-ASSOCIATED LUPUS NEPHRITIS (LN) HAS NOT BEEN WELL DESCRIBED. WE EVALUATED THE DNA METHYLOMES OF 87 INDIVIDUALS INCLUDING 41 SLE PATIENTS, WITH AND WITHOUT LN, AND 46 CONTROLS ENROLLED IN AN ANCESTRY DIVERSE, WELL-CHARACTERIZED COHORT STUDY OF ESTABLISHED SLE (41 SLE PATIENTS [20 SLE-LN+, 21 SLE-LN-] AND 46 SEX-, RACE- AND AGE-MATCHED CONTROLS; 55% AFRICAN AMERICAN, 45% EUROPEAN AMERICAN). PARTICIPANTS WERE GENOTYPED USING THE INFINIUM GLOBAL DIVERSITY ARRAY (GDA), AND GENETIC ANCESTRY WAS ESTIMATED USING PRINCIPAL COMPONENTS. GENOME-WIDE DNA METHYLATION WAS INITIALLY MEASURED USING THE ILLUMINA METHYLATIONEPIC 850K BEADCHIP ARRAY FOLLOWED BY METHYLATION-SPECIFIC QPCR TO VALIDATE THE METHYLATION STATUS AT PUTATIVE LOCI. DIFFERENTIALLY METHYLATED POSITIONS (DMP) WERE IDENTIFIED USING A CASE-CONTROL APPROACH ADJUSTED FOR ANCESTRY. WE IDENTIFIED A TOTAL OF 51 DMPS IN CPGS AMONG SLE PATIENTS COMPARED TO CONTROLS. GENES PROXIMAL TO THESE CPGS WERE HIGHLY ENRICHED FOR INVOLVEMENT IN TYPE I INTERFERON SIGNALING. DMPS AMONG EUROPEAN AMERICAN SLE PATIENTS WITH LN WERE SIMILAR TO AFRICAN AMERICAN SLE PATIENTS WITH AND WITHOUT LN. OUR FINDINGS WERE VALIDATED USING AN ORTHOGONAL, METHYL-SPECIFIC PCR FOR THREE SLE-ASSOCIATED DMPS NEAR OR PROXIMAL TO MX1, USP18, AND IFITM1. OUR STUDY CONFIRMS PREVIOUS REPORTS THAT DMPS IN CPGS ASSOCIATED WITH SLE ARE ENRICHED IN TYPE I INTERFERON GENES. HOWEVER, WE SHOW THAT EUROPEAN AMERICAN SLE PATIENTS WITH LN HAVE SIMILAR DNAM PATTERNS TO AFRICAN AMERICAN SLE PATIENTS IRRESPECTIVE OF LN, SUGGESTING THAT ABERRANT DNAM ALTERS ACTIVITY OF TYPE I INTERFERON PATHWAY LEADING TO MORE SEVERE DISEASE INDEPENDENT OF ANCESTRY. 2023 5 6544 25 TRANSCRIPTOMIC AND EPIGENETIC ALTERATIONS IN DENDRITIC CELLS CORRESPOND WITH CHRONIC KIDNEY DISEASE IN LUPUS NEPHRITIS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A SERIOUS AUTOIMMUNE DISEASE WITH VARIETY OF ORGAN MANIFESTATIONS. THE MOST DREADFUL ONE, AFFECTING THE MAJORITY OF SLE PATIENTS, IS KIDNEY MANIFESTATION-LUPUS NEPHRITIS (LN). DENDRITIC CELLS (DC) ARE BELIEVED TO BE ONE OF THE CULPRITS OF IMMUNE DYSREGULATION IN LN. FLOW CYTOMETRY ANALYSIS WAS APPLIED TO IDENTIFY THE FREQUENCY AND ACTIVITY OF PERIPHERAL BLOOD DCS SUBPOPULATIONS: MYELOID AND PLASMACYTOID, IN LN PATIENTS. MAGNETICALLY ISOLATED MDCS AND PDCS WERE SUBJECTED TO MOLECULAR ANALYSIS OF GENES EXPRESSION, EVALUATION OF GLOBAL DNA METHYLATION AND HISTONE H3 METHYLATION. WE OBSERVED DISTINCTIVE FEATURES OF DCS ASSOCIATED WITH THE STAGES OF NEPHRITIS IN LN PATIENTS. LOWER NUMBERS OF PDCS WERE OBSERVED IN PATIENTS WITH SEVERE LN, WHILE INCREASED CO-STIMULATORY POTENTIAL OF MDCS WAS CONNECTED WITH THE EARLY, MILD STAGE OF THIS DISEASE. IRF1 TRANSCRIPT UPREGULATION WAS SPECIFIC FOR MDCS FROM TOTAL LN PATIENTS, WHILE EXCEPTIONAL AMOUNT OF IRF1 MRNA WAS DETECTED IN MDCS FROM SEVERE LN PATIENTS. DCS DNA HYPERMETHYLATION SEEMED CHARACTERISTIC FOR SEVERE LN, WHEREAS A DECREASE IN H3K4ME3 AND H3K27ME3 MARKS WAS SIGNIFICANT FOR THE EARLY STAGES OF LN. THESE FINDINGS PRESENT DENDRITIC CELL ALTERATIONS THAT MAY REFLECT RENAL INVOLVEMENT IN SLE, LAYING FOUNDATIONS FOR NEW STRATEGY OF DIAGNOSIS AND MONITORING OF LN PATIENTS, OMITTING INVASIVE KIDNEY BIOPSIES. 2019 6 2257 19 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 7 6321 23 THE ROLE AND MECHANISM OF LYSINE METHYLTRANSFERASE AND ARGININE METHYLTRANSFERASE IN KIDNEY DISEASES. METHYLATION CAN OCCUR IN BOTH HISTONES AND NON-HISTONES. KEY LYSINE AND ARGININE METHYLTRANSFERASES UNDER INVESTIGATION FOR RENAL DISEASE TREATMENT INCLUDE ENHANCER OF ZESTE HOMOLOG 2 (EZH2), G9A, DISRUPTOR OF TELOMERIC SILENCING 1-LIKE PROTEIN (DOT1L), AND PROTEIN ARGININE METHYLTRANSFERASES (PRMT) 1 AND 5. RECENT STUDIES HAVE SHOWN THAT METHYLTRANSFERASES EXPRESSION AND ACTIVITY ARE ALSO INCREASED IN SEVERAL ANIMAL MODELS OF KIDNEY INJURY, SUCH AS ACUTE KIDNEY INJURY(AKI), OBSTRUCTIVE NEPHROPATHY, DIABETIC NEPHROPATHY AND LUPUS NEPHRITIS. THE INHIBITION OF MOST METHYLTRANSFERASES CAN ATTENUATE KIDNEY INJURY, WHILE THE ROLE OF METHYLTRANSFERASE IN DIFFERENT ANIMAL MODELS REMAINS CONTROVERSIAL. IN THIS ARTICLE, WE SUMMARIZE THE ROLE AND MECHANISM OF LYSINE METHYLTRANSFERASE AND ARGININE METHYLTRANSFERASE IN VARIOUS KIDNEY DISEASES AND HIGHLIGHT METHYLTRANSFERASE AS A POTENTIAL THERAPEUTIC TARGET FOR KIDNEY DISEASES. 2022 8 5885 24 SYSTEMIC LUPUS ERYTHEMATOSUS FOLLOWING HUMAN PAPILLOMAVIRUS VACCINATION: A CASE-BASED REVIEW. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A HETEROGENEOUS SYSTEMIC AUTOIMMUNE DISEASES (AIDS) WITH MANY PATHOGENIC FACTORS, RANGING FROM GENETIC TO EPIGENETIC TO ENVIRONMENTAL. THE HUMAN PAPILLOMAVIRUS (HPV), A VIRAL INFECTIOUS AGENT, IS A COMMON CONTRIBUTOR TO THE ONSET AND EXACERBATION OF SLE. HPV INFECTIONS ARE MORE PREVALENT AMONG SLE PATIENTS THAN HEALTHY INDIVIDUALS, BRINGING ABOUT A SUBSTANTIAL NEED FOR TREATMENT. WHILE HPV RECOMBINANT GENE VACCINES ARE ACCEPTED AS A UNIVERSAL METHOD FOR INFECTION PREVENTION, THEY POSE A RISK FOR ADVERSE EVENTS SUCH AS FEVER, JOINT PAIN, AND RASHES. IN RARE CASES, THEY MIGHT EVEN TRIGGER AIDS SUCH AS SLE, ESPECIALLY IN PATIENTS WITH A PERSONAL OR FAMILY HISTORY OF SUCH DISEASES. IN THIS ARTICLE, WE PROVIDE A REPORT OF A CASE OF SLE ONSET FOLLOWING HPV VACCINATION AND A REVIEW OF 11 SIMILAR CASES. AN ANALYSIS OF 12 PATIENTS REVEALED THAT 7 CASES OF SLE DEVELOPED BETWEEN 3 WEEKS AND 2 MONTHS POST-VACCINATION. SYMPTOMS OF SLE GENERALLY MANIFEST AS FATIGUE, FEVER, JOINT PAIN, AND MYALGIA. TWO PATIENTS HAD LUPUS NEPHRITIS, 2 SHOWED CENTRAL NERVOUS SYSTEM INVOLVEMENT, INCLUDING ABNORMAL BEHAVIOR AND EPILEPTIC SEIZURES, AND 1 HAD INTESTINAL PSEUDO-OBSTRUCTION. ALL PATIENTS SHOWED RAPID REMISSION WITH GLUCOCORTICOID AND IMMUNOSUPPRESSIVE THERAPY AND REMAINED STABLE DURING SEVERAL MONTHS OF FOLLOW-UP. 2022 9 398 23 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 10 868 26 CHRONIC ADVANCED-GLYCATION END PRODUCTS TREATMENT INDUCES TXNIP EXPRESSION AND EPIGENETIC CHANGES IN GLOMERULAR PODOCYTES IN VIVO AND IN VITRO. ADVANCED GLYCATION END PRODUCTS (AGES) PLAY AN IMPORTANT ROLE IN OXIDATIVE STRESS AND INFLAMMATION, PROCESSES IMPLICATED IN THE DEVELOPMENT AND PROGRESSION OF KIDNEY DYSFUNCTION. IN THE PRESENT STUDY, WE INVESTIGATED THE PARTICIPATION OF THE PRO-OXIDANT PROTEIN THIOREDOXIN-INTERACTING PROTEIN (TXNIP) AND OF EPIGENETIC MECHANISMS ON KIDNEY TISSUE (IN VIVO, IN NON-DIABETIC RATS) AND ON TERMINALLY DIFFERENTIATED GLOMERULAR PODOCYTES (IN VITRO) CHRONICALLY EXPOSED TO AGES. AGES INDUCED TOTAL KIDNEY AND GLOMERULAR TXNIP EXPRESSION AND DECREASED H3K27ME3 CONTENT. CONCOMITANT TREATMENT WITH THE ANTIOXIDANT N-ACETYL-CYSTEINE (NAC) REVERSED ONLY THE INCREASED TXNIP EXPRESSION. TXNIP EXPRESSION POSITIVELY CORRELATED WITH PROTEINURIA AND NEGATIVELY CORRELATED WITH H3K27ME3 CONTENT. IN VITRO STUDIES IN PODOCYTES SHOWED THAT 72 H EXPOSURE TO AGES DECREASED NEPHRIN EXPRESSION AND INCREASED TXNIP, NOX4, COL4A1, AND EPITHELIAL-TO-MESENCHYMAL TRANSITION (EMT) MARKERS (ACTA2, SNAIL1, AND TGFB1). PODOCYTES TREATMENT WITH NAC REVERSED NOX4, COL4A1, ACTA2, AND TGFB1 INCREASED EXPRESSION BUT DID NOT ABROGATE THE REDUCED EXPRESSION OF NEPHRIN. MIR-29A EXPRESSION WAS DOWNREGULATED BY AGES IN VIVO, BUT NOT IN VITRO. IN CONCLUSION, TREATMENT OF NON-DIABETIC RATS WITH AGES INDUCED TXNIP EXPRESSION AND DECREASED THE CONTENTS OF THE REPRESSIVE EPIGENETIC MARK H3K27ME3 AND OF MIR-29A, POTENTIALLY DRIVING INJURY TO GLOMERULAR FILTRATION BARRIER AND PODOCYTES DYSFUNCTION. 2021 11 3367 28 HISTONE METHYLTRANSFERASE EZH2: A POTENTIAL THERAPEUTIC TARGET FOR KIDNEY DISEASES. ENHANCER OF ZESTE HOMOLOG 2 (EZH2) IS A HISTONE-LYSINE N-METHYLTRANSFERASE ENZYME THAT CATALYZES THE ADDITION OF METHYL GROUPS TO HISTONE H3 AT LYSINE 27, LEADING TO GENE SILENCING. MUTATION OR OVER-EXPRESSION OF EZH2 HAS BEEN LINKED TO MANY CANCERS INCLUDING RENAL CARCINOMA. RECENT STUDIES HAVE SHOWN THAT EZH2 EXPRESSION AND ACTIVITY ARE ALSO INCREASED IN SEVERAL ANIMAL MODELS OF KIDNEY INJURY, SUCH AS ACUTE KIDNEY INJURY (AKI), RENAL FIBROSIS, DIABETIC NEPHROPATHY, LUPUS NEPHRITIS (LN), AND RENAL TRANSPLANTATION REJECTION. THE PHARMACOLOGICAL AND/OR GENETIC INHIBITION OF EZH2 CAN ALLEVIATE AKI, RENAL FIBROSIS, AND LN, BUT POTENTIATE PODOCYTE INJURY IN ANIMAL MODELS, SUGGESTING THAT THE FUNCTIONAL ROLE OF EZH2 VARIES WITH RENAL CELL TYPE AND DISEASE MODEL. IN THIS ARTICLE, WE SUMMARIZE THE ROLE OF EZH2 IN THE PATHOLOGY OF RENAL INJURY AND RELEVANT MECHANISMS AND HIGHLIGHT EZH2 AS A POTENTIAL THERAPEUTIC TARGET FOR KIDNEY DISEASES. 2021 12 5363 19 RECENT ADVANCES IN DIABETIC KIDNEY DISEASES: FROM KIDNEY INJURY TO KIDNEY FIBROSIS. DIABETIC KIDNEY DISEASE (DKD) IS THE LEADING CAUSE OF CHRONIC KIDNEY DISEASE AND END-STAGE RENAL DISEASE. THE NATURAL HISTORY OF DKD INCLUDES GLOMERULAR HYPERFILTRATION, PROGRESSIVE ALBUMINURIA, DECLINING ESTIMATED GLOMERULAR FILTRATION RATE, AND, ULTIMATELY, KIDNEY FAILURE. IT IS KNOWN THAT DKD IS ASSOCIATED WITH METABOLIC CHANGES CAUSED BY HYPERGLYCEMIA, RESULTING IN GLOMERULAR HYPERTROPHY, GLOMERULOSCLEROSIS, AND TUBULOINTERSTITIAL INFLAMMATION AND FIBROSIS. HYPERGLYCEMIA IS ALSO KNOWN TO CAUSE PROGRAMMED EPIGENETIC MODIFICATION. HOWEVER, THE DETAILED MECHANISMS INVOLVED IN THE ONSET AND PROGRESSION OF DKD REMAIN ELUSIVE. IN THIS REVIEW, WE DISCUSS RECENT ADVANCES REGARDING THE PATHOGENIC MECHANISMS INVOLVED IN DKD. 2021 13 6748 24 WHOLE GENOME METHYLATION ARRAY ANALYSIS REVEALS NEW ASPECTS IN BALKAN ENDEMIC NEPHROPATHY ETIOLOGY. BACKGROUND: BALKAN ENDEMIC NEPHROPATHY (BEN) REPRESENTS A CHRONIC PROGRESSIVE INTERSTITIAL NEPHRITIS IN STRIKING CORRELATION WITH UROEPITHELIAL TUMOURS OF THE UPPER URINARY TRACT. THE DISEASE HAS ENDEMIC DISTRIBUTION IN THE DANUBE RIVER REGIONS IN SEVERAL BALKAN COUNTRIES.DNA METHYLATION IS A PRIMARY EPIGENETIC MODIFICATION THAT IS INVOLVED IN MAJOR PROCESSES SUCH AS CANCER, GENOMIC IMPRINTING, GENE SILENCING, ETC. THE SIGNIFICANCE OF CPG ISLAND METHYLATION STATUS IN NORMAL DEVELOPMENT, CELL DIFFERENTIATION AND GENE EXPRESSION IS WIDELY RECOGNIZED, ALTHOUGH STILL STAYS POORLY UNDERSTOOD. METHODS: WE PERFORMED WHOLE GENOME DNA METHYLATION ARRAY ANALYSIS ON DNA POOL SAMPLES FROM PERIPHERAL BLOOD FROM 159 AFFECTED INDIVIDUALS AND 170 HEALTHY INDIVIDUALS. THIS TECHNIQUE ALLOWED US TO DETERMINE THE METHYLATION STATUS OF 27 627 CPG ISLANDS THROUGHOUT THE WHOLE GENOME IN HEALTHY CONTROLS AND BEN PATIENTS. THUS WE OBTAINED THE METHYLATION PROFILE OF BEN PATIENTS FROM BULGARIAN AND SERBIAN ENDEMIC REGIONS. RESULTS: USING SPECIFICALLY DEVELOPED SOFTWARE WE COMPARED THE METHYLATION PROFILES OF BEN PATIENTS AND CORRESPONDING CONTROLS AND REVEALED THE DIFFERENTLY METHYLATED REGIONS. WE THEN COMPARED THE DMRS BETWEEN ALL PATIENT-CONTROL PAIRS TO DETERMINE COMMON CHANGES IN THE EPIGENETIC PROFILES.SEC61G, IL17RA, HDAC11 PROVED TO BE DIFFERENTLY METHYLATED THROUGHOUT ALL PATIENT-CONTROL PAIRS. THE CPG ISLANDS OF ALL 3 GENES WERE HYPOMETHYLATED COMPARED TO CONTROLS. THIS SUGGESTS THAT DYSREGULATION OF THESE GENES INVOLVED IN IMMUNOLOGICAL RESPONSE COULD BE A COMMON MECHANISM IN BEN PATHOGENESIS IN BOTH ENDEMIC REGIONS AND IN BOTH GENDERS. CONCLUSION: OUR DATA PROPOSE A NEW HYPOTHESIS THAT IMMUNOLOGIC DYSREGULATION HAS A PLACE IN BEN ETIOPATHOGENESIS. 2013 14 3006 26 GENETIC, GENOMIC AND EPIGENOMIC STUDIES OF BALKAN ENDEMIC NEPHROPATHY (BEN). BEN IS A PRIMARY, CHRONIC TUBULOINTERSTITIAL NEPHRITIS CHARACTERIZED WITH CHRONIC ANEMIA, ABSENCE OF EDEMA, XANTODERMA, NORMAL BLOOD PRESSURE AND NORMAL FINDINGS ON THE FUNDUS OCULI. THE DISEASE IS DISTRIBUTED IN RESTRICTED AREAS IN BULGARIA, ROMANIA, CROATIA, BOSNIA, FORMER YUGOSLAVIA. DESPITE NUMEROUS STUDIES ON GENETIC AND ENVIRONMENTAL FACTORS AND THEIR POSSIBLE INVOLVEMENT IN BEN, ITS ETIOPATHOGENESIS STILL REMAINS ELUSIVE. OUR RECENT STUDY AIM TO ELUCIDATE THE POSSIBLE EPIGENETIC COMPONENT IN BEN DEVELOPMENT. WHOLE GENOME DNA ARRAY METHYLATION ANALYSIS WAS APPLIED TO COMPARE THE METHYLATION PROFILES OF MALE AND FEMALE BEN PATIENTS FROM ENDEMIC REGIONS IN BULGARIA AND SERBIA AND HEALTHY CONTROLS. ALL THREE MOST PROMINENT CANDIDATE GENES WITH ABERRATIONS IN THE EPIGENETIC PROFILE DISCOVERED WITH THIS STUDY ARE INVOLVED IN THE INFLAMMATORY/IMMUNE PROCESSES AND ONCOGENESIS. THESE DATA ARE IN CONCORDANCE WITH THE REPORTED PATHOLOGICAL ALTERATIONS IN BEN. THIS RESEARCH SUPPORTS THE ROLE OF EPIGENETIC CHANGES IN BEN PATHOLOGY. EXOME SEQUENCING OF 22.000 GENES WITH ILLUMINA NEXTERA EXOME ENRICHMENT KIT REVEALED THREE MUTANT GENES (CELA1, HSPG2, AND KCNK5) IN BEN PATIENTS WHICH ENCODE PROTEINS INVOLVED IN BASEMENT MEMBRANE/EXTRACELLULAR MATRIX AND VASCULAR TONE, TIGHTLY CONNECTED TO PROCESS OF ANGIOGENESIS. WE SUGGEST THAT AN ABNORMAL PROCESS OF ANGIOGENESIS PLAYS A KEY ROLE IN THE MOLECULAR PATHOGENESIS OF BEN. 2015 15 1983 33 EPIGENETIC ALTERATIONS IN PODOCYTES IN DIABETIC NEPHROPATHY. RECENTLY, EPIGENETIC ALTERATIONS HAVE BEEN SHOWN TO BE INVOLVED IN THE PATHOGENESIS OF DIABETES AND ITS COMPLICATIONS. KIDNEY PODOCYTES, WHICH ARE GLOMERULAR EPITHELIAL CELLS, ARE IMPORTANT CELLS THAT FORM A SLIT MEMBRANE-A BARRIER FOR PROTEINURIA. PODOCYTES ARE TERMINALLY DIFFERENTIATED CELLS WITHOUT CELL DIVISION OR REPLENISHMENT ABILITIES. THEREFORE, PODOCYTE DAMAGE IS SUGGESTED TO BE ONE OF THE KEY FACTORS DETERMINING RENAL PROGNOSIS. RECENT STUDIES, INCLUDING OURS, SUGGEST THAT EPIGENETIC CHANGES IN PODOCYTES ARE ASSOCIATED WITH CHRONIC KIDNEY DISEASE, INCLUDING DIABETIC NEPHROPATHY. FURTHERMORE, THE ASSOCIATION BETWEEN DNA DAMAGE REPAIR AND EPIGENETIC CHANGES IN DIABETIC PODOCYTES HAS BEEN DEMONSTRATED. DETECTION OF PODOCYTE DNA DAMAGE AND EPIGENETIC CHANGES USING HUMAN SAMPLES, SUCH AS KIDNEY BIOPSY AND URINE-DERIVED CELLS, MAY BE A PROMISING STRATEGY FOR ESTIMATING KIDNEY DAMAGE AND RENAL PROGNOSES IN PATIENTS WITH DIABETES. TARGETING EPIGENETIC PODOCYTE CHANGES AND ASSOCIATED DNA DAMAGE MAY BECOME A NOVEL THERAPEUTIC STRATEGY FOR PREVENTING PROGRESSION TO END-STAGE RENAL DISEASE (ESRD) AND PROVIDE A POSSIBLE PROGNOSTIC MARKER IN DIABETIC NEPHROPATHY. THIS REVIEW SUMMARIZES RECENT ADVANCES REGARDING EPIGENETIC CHANGES, ESPECIALLY DNA METHYLATION, IN PODOCYTES IN DIABETIC NEPHROPATHY AND ADDRESSES DETECTION OF THESE ALTERATIONS IN HUMAN SAMPLES. ADDITIONALLY, WE FOCUSED ON DNA DAMAGE, WHICH IS INCREASED UNDER HIGH-GLUCOSE CONDITIONS AND ASSOCIATED WITH THE GENERATION OF EPIGENETIC CHANGES IN PODOCYTES. FURTHERMORE, EPIGENETIC MEMORY IN DIABETES IS DISCUSSED. UNDERSTANDING THE ROLE OF EPIGENETIC CHANGES IN PODOCYTES IN DIABETIC NEPHROPATHY MAY BE OF GREAT IMPORTANCE CONSIDERING THE INCREASING DIABETIC NEPHROPATHY PATIENT POPULATION IN AN AGING SOCIETY. 2021 16 6565 23 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 17 6275 34 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 18 5371 21 RECENT ADVANCES IN UNDERSTANDING THE GENETIC BASIS OF SYSTEMIC LUPUS ERYTHEMATOSUS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A POLYGENIC CHRONIC AUTOIMMUNE DISEASE LEADING TO MULTIPLE ORGAN DAMAGE. A LARGE HERITABILITY OF UP TO 66% IS ESTIMATED IN SLE, WITH ROUGHLY 180 REPORTED SUSCEPTIBILITY LOCI THAT HAVE BEEN IDENTIFIED MOSTLY BY GENOME-WIDE ASSOCIATION STUDIES (GWASS) AND ACCOUNT FOR APPROXIMATELY 30% OF GENETIC HERITABILITY. A VAST MAJORITY OF RISK VARIANTS RESIDE IN NON-CODING REGIONS, WHICH MAKES IT QUITE CHALLENGING TO INTERPRET THEIR FUNCTIONAL IMPLICATIONS IN THE SLE-AFFECTED IMMUNE SYSTEM, SUGGESTING THE IMPORTANCE OF UNDERSTANDING CELL TYPE-SPECIFIC EPIGENETIC REGULATION AROUND SLE GWAS VARIANTS. THE LATEST GENETIC STUDIES HAVE BEEN HIGHLY FRUITFUL AS SEVERAL DOZENS OF SLE LOCI WERE NEWLY DISCOVERED IN THE LAST FEW YEARS AND MANY LOCI HAVE COME TO BE UNDERSTOOD IN SYSTEMIC APPROACHES INTEGRATING GWAS SIGNALS WITH OTHER BIOLOGICAL RESOURCES. IN THIS REVIEW, WE SUMMARIZE SLE-ASSOCIATED GENETIC VARIANTS IN BOTH THE MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) AND NON-MHC LOCI, EXAMINING POLYGENETIC RISK SCORES FOR SLE AND THEIR ASSOCIATIONS WITH CLINICAL FEATURES. FINALLY, VARIANT-DRIVEN PATHOGENETIC FUNCTIONS UNDERLYING GENETIC ASSOCIATIONS ARE DESCRIBED, COUPLED WITH DISCUSSION ABOUT CHALLENGES AND FUTURE DIRECTIONS IN GENETIC STUDIES ON SLE. 2022 19 3209 17 HEALTH DISPARITIES IN SYSTEMIC LUPUS ERYTHEMATOSUS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC MULTISYSTEM AUTOIMMUNE DISEASE CHARACTERIZED BY AUTOANTIBODY PRODUCTION AND DIVERSE CLINICAL MANIFESTATIONS. THE MANY COMPLEX, OVERLAPPING, AND CLOSELY ASSOCIATED FACTORS THAT INFLUENCE SLE SUSCEPTIBILITY AND OUTCOMES INCLUDE ETHNIC DISPARITIES, LOW ADHERENCE TO MEDICATIONS, AND POVERTY, AND GEOGRAPHY. EPIGENETIC MECHANISMS MAY PROVIDE THE LINK BETWEEN THESE ENVIRONMENTAL EXPOSURES AND BEHAVIORS AND THE DISPROPORTIONATE BURDEN OF SLE SEEN IN ETHNIC MINORITIES. ATTENTION TO THESE MODIFIABLE SOCIAL DETERMINANTS OF HEALTH WOULD NOT ONLY IMPROVE OUTCOMES FOR VULNERABLE PATIENTS WITH SLE BUT LIKELY REDUCE SUSCEPTIBILITY TO SLE AS WELL THROUGH EPIGENETIC CHANGES. 2020 20 3044 23 GENOME-WIDE ANALYSIS OF 5-HMC IN THE PERIPHERAL BLOOD OF SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS USING AN HMEDIP-CHIP. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC, POTENTIALLY FATAL SYSTEMIC AUTOIMMUNE DISEASE CHARACTERIZED BY THE PRODUCTION OF AUTOANTIBODIES AGAINST A WIDE RANGE OF SELF-ANTIGENS. TO INVESTIGATE THE ROLE OF THE 5-HMC DNA MODIFICATION WITH REGARD TO THE ONSET OF SLE, WE COMPARED THE LEVELS 5-HMC BETWEEN SLE PATIENTS AND NORMAL CONTROLS. WHOLE BLOOD WAS OBTAINED FROM PATIENTS, AND GENOMIC DNA WAS EXTRACTED. USING THE HMEDIP-CHIP ANALYSIS AND VALIDATION BY QUANTITATIVE RT-PCR (RT-QPCR), WE IDENTIFIED THE DIFFERENTIALLY HYDROXYMETHYLATED REGIONS THAT ARE ASSOCIATED WITH SLE. THERE WERE 1,701 GENES WITH SIGNIFICANTLY DIFFERENT 5-HMC LEVELS AT THE PROMOTER REGION IN THE SLE PATIENTS COMPARED WITH THE NORMAL CONTROLS. THE CPG ISLANDS OF 3,826 GENES SHOWED SIGNIFICANTLY DIFFERENT 5-HMC LEVELS IN THE SLE PATIENTS COMPARED WITH THE NORMAL CONTROLS. OUT OF THE DIFFERENTIALLY HYDROXYMETHYLATED GENES, THREE WERE SELECTED FOR VALIDATION, INCLUDING TREX1, CDKN1A AND CDKN1B. THE HYDROXYMETHYLATION LEVELS OF THE THREE GENES WERE CONFIRMED BY RT-QPCR. THE RESULTS SUGGESTED THAT THERE WERE SIGNIFICANT ALTERATIONS OF 5-HMC IN SLE PATIENTS. THUS, THESE DIFFERENTIALLY HYDROXYMETHYLATED GENES MAY CONTRIBUTE TO THE PATHOGENESIS OF SLE. THESE FINDINGS SHOW THE SIGNIFICANCE OF 5-HMC AS A POTENTIAL BIOMARKER OR PROMISING TARGET FOR EPIGENETIC-BASED SLE THERAPIES. 2015