1 3495 95 IDENTIFICATION OF MIRNAS POTENTIALLY INVOLVED IN BRONCHIOLITIS OBLITERANS SYNDROME: A COMPUTATIONAL STUDY. THE PATHOGENESIS OF BRONCHIOLITIS OBLITERANS SYNDROME (BOS), THE MAIN CLINICAL PHENOTYPE OF CHRONIC LUNG ALLOGRAFT DYSFUNCTION, IS POORLY UNDERSTOOD. RECENT STUDIES SUGGEST THAT EPIGENETIC REGULATION OF MICRORNAS MIGHT PLAY A ROLE IN ITS DEVELOPMENT. IN THIS PAPER WE PRESENT THE APPLICATION OF A COMPLEX COMPUTATIONAL PIPELINE TO PERFORM ENRICHMENT ANALYSIS OF MIRNAS IN PATHWAYS APPLIED TO THE STUDY OF BOS. THE ANALYSIS CONSIDERED THE FULL SET OF MIRNAS ANNOTATED IN MIRBASE (VERSION 21), AND APPLIED A SEQUENCE OF FILTERING APPROACHES AND STATISTICAL ANALYSES TO REDUCE THIS SET AND TO SCORE THE CANDIDATE MIRNAS ACCORDING TO THEIR POTENTIAL INVOLVEMENT IN BOS DEVELOPMENT. DYSREGULATION OF TWO OF THE SELECTED CANDIDATE MIRNAS-MIR-34A AND MIR-21 -WAS CLEARLY SHOWN IN IN-SITU HYBRIDIZATION (ISH) ON FIVE EXPLANTED HUMAN BOS LUNGS AND ON A RAT MODEL OF ACUTE AND CHRONIC LUNG REJECTION, THUS DEFINITELY IDENTIFYING MIR-34A AND MIR-21 AS PATHOGENIC FACTORS IN BOS AND CONFIRMING THE EFFECTIVENESS OF THE COMPUTATIONAL PIPELINE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
2 4371 40 MIRNAS POTENTIALLY INVOLVED IN POST LUNG TRANSPLANT-OBLITERATIVE BRONCHIOLITIS: THE ROLE OF MIR-21-5P. EPIGENETIC CHANGES, INCLUDING MIRNAS DEREGULATION, HAVE BEEN SUGGESTED TO PLAY A SIGNIFICANT ROLE IN DEVELOPMENT OF OBLITERATIVE BRONCHIOLITIS (OB) IN TRANSPLANTED LUNGS. MANY STUDIES HAVE TRIED TO IDENTIFY IDEAL CANDIDATE MIRNAS AND THE DOWNSTREAM PATHWAYS IMPLICATED IN THE BRONCHIOLAR FIBRO-OBLITERATIVE PROCESS. SEVERAL CANDIDATE MIRNAS, PREVIOUSLY INDICATED AS POSSIBLY BEING ASSOCIATED WITH OB, WERE ANALYZED BY COMBINING THE QUANTITATIVE REAL TIME-POLYMERASE CHAIN REACTION (QRT-PCR) AND IN SITU HYBRIDIZATION (ISH) OF LUNG TISSUES OF OB AFFECTED PATIENTS. DISEASE AND OB-LESION-SPECIFIC EXPRESSION OF MIR-21-5P WAS CONFIRMED AND BY COMPUTATIONAL ANALYSIS WE WERE ABLE TO IDENTIFY THE NETWORK OF GENES MOST PROBABLY ASSOCIATED MIR-21-5P IN THE CONTEXT OF OB FIBROGENESIS. AMONG ALL POTENTIALLY ASSOCIATED GENES, STAT3 HAD A VERY HIGH PROBABILITY SCORE. IMMUNOHISTOCHEMISTRY SHOWED THAT STAT3/MIR-21-5P WERE CO-OVER EXPRESSED IN OB LESIONS, THUS, SUGGESTING MIR-21-5P COULD REGULATE STAT3 EXPRESSION. HOWEVER, MIR-21-5P INHIBITION IN CULTURES OF BRONCHIOLITIS OBLITERANS SYNDROME (BOS) DERIVED MYOFIBROBLASTS DID NOT SIGNIFICANTLY AFFECT STAT3 MRNA AND PROTEIN EXPRESSION LEVELS. THIS STUDY DEMONSTRATES THE SPECIFICITY OF MIR-21-5P OVER-EXPRESSION IN OB LESIONS AND CONTRIBUTES TO EXISTING KNOWLEDGE ON THE MIR-21-5P DOWNSTREAM PATHWAY. ACTIVATION OF STAT3 IS ASSOCIATED WITH MIR-21-5P UPREGULATION, HOWEVER, STAT-3 NETWORK ACTIVATION IS MOST LIKELY COMPLEX AND MIR-21-5P IS NOT THE SOLE REGULATOR OF STAT3.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
3 2331 28 EPIGENETIC REGULATION OF INFLAMMATION BY MICRORNAS IN POST-INFECTIOUS BRONCHIOLITIS OBLITERANS. OBJECTIVES: POST-INFECTIOUS BRONCHIOLITIS OBLITERANS (PIBO) IS A RARE, CHRONIC DISEASE INITIATED BY SEVERE INFECTION AND FOLLOWED BY PERPETUATING INFLAMMATION AND OBLITERATION OF THE SMALL AIRWAYS. MICRORNAS (MIRNAS) HAVE BEEN PROPOSED TO PLAY A CENTRAL ROLE AS EPIGENETIC REGULATORS, WHICH CONTROL RESOLUTION AND PREVENT THE UNCONTROLLED PROGRESS OF INFLAMMATION. THE AIM OF THIS STUDY WAS TO DEFINE BIOMARKERS ON THE LEVEL OF POST-TRANSCRIPTIONAL GENE REGULATION IN ORDER TO CHARACTERISE PIBO. METHODS: A TOTAL OF 39 PATIENTS WITH WELL-DEFINED PIBO AND 31 CONTROLS FROM TWO CENTRES, BARCELONA, SPAIN, AND FRANKFURT, GERMANY, WERE ANALYSED BY NEXT-GENERATION SEQUENCING (NGS). THE EVALUATION OF THE BIOLOGICAL TARGETS OF THE MIRNAS WAS PERFORMED BY PATHWAY ENRICHMENT ANALYSIS AND PROTEIN-PROTEIN INTERACTION NETWORK ANALYSIS RESPECTIVELY. RESULTS: PATIENTS WITH PIBO HAD SIGNIFICANTLY LOWER LUNG FUNCTION VALUES AND INCREASED AIRWAY INFLAMMATION IN INDUCED SPUTUM AS INDICATED BY TOTAL CELL COUNTS, NEUTROPHILS, IL-1BETA, IL-6, IL-8 AND TGF-BETA COMPARED TO CONTROLS.NEXT-GENERATION SEQUENCING ANALYSIS REVEALED A TOTAL OF 22 DYSREGULATED MIRNAS, WHICH PASSED SIGNIFICANCE THRESHOLD FOR PADJ </= 0.001 WITH 17 BEING UPREGULATED AND 5 BEING DOWNREGULATED. OF THESE DYSREGULATED MIRNAS, MIR-335-5P, MIR-186-5P, MIR-30B-5P AND MIR-30C-5P WERE FURTHER VALIDATED USING QRT-PCR. INTERESTINGLY, THESE MIRNAS ARE FUNCTIONALLY IMPLICATED IN CYTOKINE-CYTOKINE RECEPTOR INTERACTION, TGF-BETA SIGNALLING AND FOXO SIGNALLING PATHWAY AND SIGNIFICANTLY CORRELATED WITH LUNG FUNCTION VALUES (FEV1). CONCLUSION: OUR RESULTS DEMONSTRATE AN ABERRANT MIRNA EXPRESSION PROFILE IN PIBO, WHICH IMPACTS PATHWAYS RESPONSIBLE FOR THE REGULATION OF INFLAMMATION AND FIBROSIS. THE DEFINED MIRNAS ARE USEFUL BIOMARKERS AND SHOULD BE ASSESSED AS POTENTIAL TARGET IN THE FIELD OF MIRNA THERAPEUTICS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
4 2909 24 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
5 1131 25 COMPREHENSIVE CIRCULAR RNA EXPRESSION PROFILING WITH ASSOCIATED CERNA NETWORK REVEALS THEIR THERAPEUTIC POTENTIAL IN CHOLESTEATOMA. CHOLESTEATOMA IS A CHRONIC DISEASE THAT PATHOLOGICALLY DISPLAYS A BENIGN TUMOR WITH EXCESSIVE SQUAMOUS EPITHELIAL CELL PROLIFERATION IN THE MIDDLE EAR. CLINICALLY, HOWEVER, IT CAN MANIFEST MALIGNANT BEHAVIOR BY DESTROYING ADJACENT TISSUES AND ORGANS. ALTHOUGH PREVIOUS STUDIES HAVE DEMONSTRATED THAT THE PATHOGENESIS OF CHOLESTEATOMA IS CORRELATED WITH EPIGENETIC DYSREGULATION, THE EXACT MECHANISM REMAINS UNCLEAR. CIRCULAR RNAS (CIRCRNAS) HAVE BEEN REVEALED AS BEING ABUNDANTLY EXPRESSED IN VARIOUS ORGANISMS AND HAVE BEEN FOUND TO CONTRIBUTE TO THE REGULATION OF MANY DISEASES. TO DATE, NO REPORTS HAVE ELUCIDATED THEIR EXPRESSION PROFILES AND FUNCTIONS IN CHOLESTEATOMA. IN THE PRESENT STUDY, THE CIRCRNA EXPRESSION PROFILE IN CHOLESTEATOMA WAS EXPLORED FOR THE FIRST TIME BY USING MICROARRAY ANALYSIS. WE OBTAINED A TOTAL OF 355 SIGNIFICANTLY DIFFERENTIALLY EXPRESSED CIRCRNAS IN CHOLESTEATOMA, AMONG WHICH 101 WERE IDENTIFIED TO BE UPREGULATED AND 254 DOWNREGULATED. BY CONSTRUCTING CIRCRNA?LNCRNA?MIRNA?MRNA COMPETING ENDOGENOUS RNA (CERNA) NETWORK, IT WAS DISCOVERED THAT CIRCRNAS MAY FUNCTION AS CERNAS AND CONTRIBUTE TO THE FORMATION OF CHOLESTEATOMA. THESE RESULTS PROVIDE NOVEL INSIGHT INTO THE PATHOGENESIS OF CHOLESTEATOMA AND SUGGEST CIRCRNAS AS POTENTIAL PROMISING THERAPEUTIC TARGETS FOR CHOLESTEATOMA.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
6 1508 26 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	
                                                                                                           
7 1025 25 CIRCULATING MIRNAS ARE ASSOCIATED WITH INFLAMMATION BIOMARKERS IN CHILDREN WITH OVERWEIGHT AND OBESITY: RESULTS OF THE I.FAMILY STUDY. INCREASING DATA SUGGEST THAT OVERNUTRITION-INDUCED OBESITY MAY TRIGGER AN INFLAMMATORY PROCESS IN ADIPOSE TISSUE AND UPTURN IN THE INNATE IMMUNE SYSTEM. NUMEROUS PLAYERS HAVE BEEN INVOLVED IN GOVERNING THE INFLAMMATORY RESPONSE, INCLUDING EPIGENETICS. AMONG EPIGENETIC PLAYERS, MIRNAS ARE EMERGING AS CRUCIAL REGULATORS OF IMMUNE CELL DEVELOPMENT, IMMUNE RESPONSES, AUTOIMMUNITY, AND INFLAMMATION. IN THIS STUDY, WE AIMED AT IDENTIFYING THE INVOLVEMENT OF CANDIDATE MIRNAS IN RELATION TO INFLAMMATION-ASSOCIATED BIOMARKERS IN A SUBSAMPLE OF EUROPEAN CHILDREN WITH OVERWEIGHT AND OBESITY PARTICIPATING IN THE I.FAMILY STUDY. THE STUDY SAMPLE INCLUDED INDIVIDUALS WITH INCREASED ADIPOSITY SINCE THIS CONDITION CONTRIBUTES TO THE EARLY OCCURRENCE OF CHRONIC LOW-GRADE INFLAMMATION. WE FOCUSED ON THE ACUTE-PHASE REAGENT C-REACTIVE PROTEIN (CRP) AS THE PRIMARY OUTCOME AND SELECTED CYTOKINES AS PLAUSIBLE BIOMARKERS OF INFLAMMATION. WE FOUND THAT CHRONIC LOW-GRADE CRP ELEVATION SHOWS A HIGHLY SIGNIFICANT ASSOCIATION WITH MIR-26B-3P AND HSA-MIR-576-5P IN BOYS. FURTHERMORE, THE ASSOCIATION OF CRP WITH HSA-MIR-10B-5P AND HSA-MIR-31-5P IS HIGHLY SIGNIFICANT IN GIRLS. WE ALSO OBSERVED MAJOR SEX-RELATED ASSOCIATIONS OF CANDIDATE MIRNAS WITH SELECTED CYTOKINES. EXCEPT FOR IL-6, A SIGNIFICANT ASSOCIATION OF HSA-MIR-26B-3P AND HSA-MIR-576-5P WITH TNF-ALPHA, IL1-RA, IL-8, AND IL-15 LEVELS WAS FOUND EXCLUSIVELY IN BOYS. THE FINDINGS OF THIS EXPLORATORY STUDY SUGGEST SEX DIFFERENCES IN THE ASSOCIATION OF CIRCULATING MIRNAS WITH INFLAMMATORY RESPONSE BIOMARKERS, AND INDICATE A POSSIBLE ROLE OF MIRNAS AMONG THE CANDIDATE EPIGENETIC MECHANISMS RELATED TO THE PROCESS OF LOW-GRADE INFLAMMATION IN CHILDHOOD OBESITY.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
8 3770 26 INTEGRATIVE SMALL AND LONG RNA OMICS ANALYSIS OF HUMAN HEALING AND NONHEALING WOUNDS DISCOVERS COOPERATING MICRORNAS AS THERAPEUTIC TARGETS. MICRORNAS (MIR), AS IMPORTANT EPIGENETIC CONTROL FACTORS, REPORTEDLY REGULATE WOUND REPAIR. HOWEVER, OUR INSUFFICIENT KNOWLEDGE OF CLINICALLY RELEVANT MIRS HINDERS THEIR POTENTIAL THERAPEUTIC USE. FOR THIS, WE PERFORMED PAIRED SMALL AND LONG RNA-SEQUENCING AND INTEGRATIVE OMICS ANALYSIS IN HUMAN TISSUE SAMPLES, INCLUDING MATCHED SKIN AND ACUTE WOUNDS COLLECTED AT EACH HEALING STAGE AND CHRONIC NONHEALING VENOUS ULCERS (VUS). ON THE BASIS OF THE FINDINGS, WE DEVELOPED A COMPENDIUM (HTTPS://WWW.XULANDENLAB.COM/HUMANWOUNDS-MIRNA-MRNA), WHICH WILL BE AN OPEN, COMPREHENSIVE RESOURCE TO BROADLY AID WOUND HEALING RESEARCH. WITH THIS FIRST CLINICAL, WOUND-CENTRIC RESOURCE OF MIRS AND MRNAS, WE IDENTIFIED 17 PATHOLOGICALLY RELEVANT MIRS THAT EXHIBITED ABNORMAL VU EXPRESSION AND DISPLAYED THEIR TARGETS ENRICHED EXPLICITLY IN THE VU GENE SIGNATURE. INTERMESHING REGULATORY NETWORKS CONTROLLED BY THESE MIRS REVEALED THEIR HIGH COOPERATIVITY IN CONTRIBUTING TO CHRONIC WOUND PATHOLOGY CHARACTERIZED BY PERSISTENT INFLAMMATION AND PROLIFERATIVE PHASE INITIATION FAILURE. FURTHERMORE, WE DEMONSTRATED THAT MIR-34A, MIR-424, AND MIR-516, UPREGULATED IN VU, COOPERATIVELY SUPPRESSED KERATINOCYTE MIGRATION AND GROWTH WHILE PROMOTING INFLAMMATORY RESPONSE. BY COMBINING MIR EXPRESSION PATTERNS WITH THEIR SPECIFIC TARGET GENE EXPRESSION CONTEXT, WE IDENTIFIED MIRS HIGHLY RELEVANT TO VU PATHOLOGY. OUR STUDY OPENS THE POSSIBILITY OF DEVELOPING INNOVATIVE WOUND TREATMENT THAT TARGETS PATHOLOGICALLY RELEVANT COOPERATING MIRS TO ATTAIN HIGHER THERAPEUTIC EFFICACY AND SPECIFICITY.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
9 3503 20 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
10 6468 21 TISSUE-SPECIFIC ENRICHMENT OF LYMPHOMA RISK LOCI IN REGULATORY ELEMENTS. THOUGH NUMEROUS POLYMORPHISMS HAVE BEEN ASSOCIATED WITH RISK OF DEVELOPING LYMPHOMA, HOW THESE VARIANTS FUNCTION TO PROMOTE TUMORIGENESIS IS POORLY UNDERSTOOD. HERE, WE REPORT THAT LYMPHOMA RISK SNPS, ESPECIALLY IN THE NON-HODGKIN'S LYMPHOMA SUBTYPE CHRONIC LYMPHOCYTIC LEUKEMIA, ARE SIGNIFICANTLY ENRICHED FOR CO-LOCALIZATION WITH EPIGENETIC MARKS OF ACTIVE GENE REGULATION. THESE ENRICHMENTS WERE SEEN IN A LYMPHOID-SPECIFIC MANNER FOR NUMEROUS ENCODE DATASETS, INCLUDING DNASE-HYPERSENSITIVITY AS WELL AS MULTIPLE SEGMENTATION-DEFINED ENHANCER REGIONS. FURTHERMORE, WE IDENTIFY PUTATIVELY FUNCTIONAL SNPS THAT ARE BOTH IN REGULATORY ELEMENTS IN LYMPHOCYTES AND ARE ASSOCIATED WITH GENE EXPRESSION CHANGES IN BLOOD. WE DEVELOPED AN ALGORITHM, UES, THAT USES A MONTE CARLO SIMULATION APPROACH TO CALCULATE THE ENRICHMENT OF PREVIOUSLY IDENTIFIED RISK SNPS IN VARIOUS FUNCTIONAL ELEMENTS. THIS MULTISCALE APPROACH INTEGRATING MULTIPLE DATASETS HELPS DISENTANGLE THE UNDERLYING BIOLOGY OF LYMPHOMA, AND MORE BROADLY, IS GENERALLY APPLICABLE TO GWAS RESULTS FROM OTHER DISEASES AS WELL.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
11 6431 23 THE USE OF TARGETED NEXT GENERATION SEQUENCING TO EXPLORE CANDIDATE REGULATORS OF TGF-BETA1'S IMPACT ON KIDNEY CELLS. AIMS/HYPOTHESIS: TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA1) PLAYS AN IMPORTANT REGULATORY ROLE IN THE PROGRESSION OF CHRONIC KIDNEY FAILURE. FURTHER, DAMAGE TO KIDNEY GLOMERULAR MESANGIAL CELLS IS CENTRAL TO THE PROGRESSION OF DIABETIC NEPHROPATHY. THE AIM OF THIS STUDY WAS TO EXPLORE THE GENETIC ASSOCIATIONS BETWEEN MRNA, MICRORNA, AND EPIGENETICS IN MESANGIAL CELLS IN RESPONSE TO TGF-BETA1. METHODS: THE REGULATORY EFFECTS OF TGF-BETA1 ON MESANGIAL CELLS WERE INVESTIGATED AT DIFFERENT MOLECULAR LEVELS BY TREATING MESANGIAL CELLS WITH TGF-BETA1 FOR 3 DAYS FOLLOWED BY GENOME-WIDE MIRNA, RNA, DNA METHYLATION, AND H3K27ME3 EXPRESSION PROFILING USING NEXT GENERATION SEQUENCING (NGS). RESULTS: OUR RESULTS PROVIDE THE FIRST COMPREHENSIVE, COMPUTATIONALLY INTEGRATED REPORT OF RNA-SEQ, MIRNA-SEQ, AND EPIGENOMIC ANALYSES ACROSS ALL GENETIC VARIATIONS, CONFIRMING THE OCCURRENCE OF DNA METHYLATION AND H3K27ME3 IN RESPONSE TO TGF-BETA1. OUR FINDINGS SHOW THAT THE EXPRESSION OF KLF7 AND GJA4 ARE INVOLVED IN TGF-BETA1 REGULATED DNA METHYLATION. OUR DATA ALSO PROVIDE EVIDENCE OF THE ASSOCIATION BETWEEN EPIGENETIC CHANGES AND THE EXPRESSION OF GENES CLOSELY RELATED TO TGF-BETA1 REGULATION. CONCLUSION: THIS STUDY HAS ADVANCED OUR CURRENT KNOWLEDGE OF MECHANISMS THAT CONTRIBUTE TO THE EXPRESSION OF TGF-BETA1-REGULATED GENES INVOLVED IN THE PATHOGENESIS OF KIDNEY DISEASE. THE MOLECULAR UNDERPINNINGS OF TGF-BETA1 STIMULATION OF KIDNEY CELLS WAS DETERMINED, THEREBY PROVIDING A ROBUST PLATFORM FOR FURTHER TARGET EXPLORATION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
12 6013 27 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	

13 1979 23 EPIGENETIC ALTERATIONS IN CHRONIC DISEASE FOCUSING ON BEHCET'S DISEASE: REVIEW. OBJECTIVE: 'EPIGENETICS' IS SPECIFIED AS THE INHERITABLE CHANGES IN GENE EXPRESSION WITH NO ALTERATIONS IN DNA SEQUENCES. EPIGENETICS IS A RAPIDLY OVERSPREADING SCIENTIFIC FIELD, AND THE STUDY OF EPIGENETIC REGULATION IN CHRONIC DISEASE IS EMERGING. THIS STUDY AIMS TO EVALUATE EPIGENETIC CHANGES INCLUDING DNA METHYLATION, HISTONE MODIFICATION, AND NON-CODING RNAS (NCRNAS) IN INFLAMMATORY DISEASE, WITH FOCUS ON BEHCET'S DISEASE. IN THIS REVIEW, FIRST WE DESCRIBE THE HISTORY AND CLASSIFICATION OF EPIGENETIC CHANGES, AND THEN THE ROLE OF EPIGENETIC ALTERATIONS IN CHRONIC DISEASES IS EXPLAINED. METHODS: SYSTEMATIC SEARCH OF MEDLINE, EMBASE, AND COCHRANE LIBRARY WAS CONDUCTED FOR ALL COMPARATIVE STUDIES SINCE 2000 TO 2015 WITH THE LIMITATIONS OF THE ENGLISH LANGUAGE. RESULTS: FOR A NOTABLE PERIOD OF TIME, RESEARCHERS HAVE MAINLY FOCUSED ON THE EPIGENETIC PATHWAYS THAT ARE INVOLVED IN THE MODULATION OF INFLAMMATORY AND ANTI-INFLAMMATORY GENES. RECENT STUDIES HAVE PROPOSED A CENTRAL ROLE FOR CHRONIC INFLAMMATION IN THE PATHOGENESIS OF CHRONIC DISEASE, INCLUDING BEHCET'S DISEASE. CONCLUSION: STUDIES HAVE BEEN REPORTED ON THE EPIGENETIC OF BD SHOWED THE ROLE OF ALTERATIONS IN THE METHYLATION LEVEL OF IRS ELEMENTS; HISTONE MODIFICATIONS SUCH AS H3K4ME27 AND H3K4ME3; UP REGULATION OF MIR-182 AND MIR-3591-3P; DOWN REGULATION OF MIR-155, MIR-638 AND MIR-4488 IN THE PATHOGENESIS OF THE DISEASE.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
14 3308 23 HIGH-RESOLUTION TRANSCRIPTOMIC AND EPIGENETIC PROFILING IDENTIFIES NOVEL REGULATORS OF COPD. PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) ARE STILL WAITING FOR CURATIVE TREATMENTS. CONSIDERING ITS ENVIRONMENTAL CAUSE, WE HYPOTHESIZED THAT COPD WILL BE ASSOCIATED WITH ALTERED EPIGENETIC SIGNALING IN LUNG CELLS. WE GENERATED GENOME-WIDE DNA METHYLATION MAPS AT SINGLE CPG RESOLUTION OF PRIMARY HUMAN LUNG FIBROBLASTS (HLFS) ACROSS COPD STAGES. WE SHOW THAT THE EPIGENETIC LANDSCAPE IS CHANGED EARLY IN COPD, WITH DNA METHYLATION CHANGES OCCURRING PREDOMINANTLY IN REGULATORY REGIONS. RNA SEQUENCING OF MATCHED FIBROBLASTS DEMONSTRATED DYSREGULATION OF GENES INVOLVED IN PROLIFERATION, DNA REPAIR, AND EXTRACELLULAR MATRIX ORGANIZATION. DATA INTEGRATION IDENTIFIED 110 CANDIDATE REGULATORS OF DISEASE PHENOTYPES THAT WERE LINKED TO FIBROBLAST REPAIR PROCESSES USING PHENOTYPIC SCREENS. OUR STUDY PROVIDES HIGH-RESOLUTION MULTI-OMIC MAPS OF HLFS ACROSS COPD STAGES. WE REVEAL NOVEL TRANSCRIPTOMIC AND EPIGENETIC SIGNATURES ASSOCIATED WITH COPD ONSET AND PROGRESSION AND IDENTIFY NEW CANDIDATE REGULATORS INVOLVED IN THE PATHOGENESIS OF CHRONIC LUNG DISEASES. THE PRESENCE OF VARIOUS EPIGENETIC FACTORS AMONG THE CANDIDATES DEMONSTRATES THAT EPIGENETIC REGULATION IN COPD IS AN EXCITING RESEARCH FIELD THAT HOLDS PROMISE FOR NOVEL THERAPEUTIC AVENUES FOR PATIENTS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
15  343 30 ALTERATIONS OF THE LUNG METHYLOME IN ALLERGIC AIRWAY HYPER-RESPONSIVENESS. ASTHMA IS A CHRONIC AIRWAY DISORDER CHARACTERIZED BY RECURRENT ATTACKS OF BREATHLESSNESS AND WHEEZING, AFFECTING 300 MILLION PEOPLE AROUND THE WORLD (AVAILABLE AT: WWW.WHO.INT). TO DATE, GENETIC FACTORS ASSOCIATED WITH ASTHMA SUSCEPTIBILITY HAVE BEEN UNABLE TO EXPLAIN THE FULL ETIOLOGY OF ASTHMA. RECENT STUDIES HAVE DEMONSTRATED THAT THE EPIGENETIC DISRUPTION OF GENE EXPRESSION PLAYS AN EQUALLY IMPORTANT ROLE IN THE DEVELOPMENT OF ASTHMA THROUGH INTERACTION WITH OUR ENVIRONMENT. WE SENSITIZED 6-WEEK-OLD C57BL/6J MICE WITH HOUSE-DUST-MITE (HDM) EXTRACTS INTRAPERITONEALLY FOLLOWED BY 5 WEEKS OF EXPOSURE TO HDM CHALLENGES (THREE TIMES A WEEK) INTRATRACHEALLY. HDM-EXPOSED MICE SHOWED AN INCREASE IN AIRWAY HYPER-RESPONSIVENESS (AHR) AND INFLAMMATION TOGETHER WITH STRUCTURAL REMODELING OF THE AIRWAYS. WE APPLIED METHYLATED DNA IMMUNOPRECIPITATION-NEXT GENERATION SEQUENCING (MEDIP-SEQ) FOR PROFILING OF DNA METHYLATION CHANGES IN THE LUNGS IN RESPONSE TO HDM. WE OBSERVED ABOUT 20 MILLION READS BY A SINGLE-RUN OF MASSIVE PARALLEL SEQUENCING. WE PERFORMED BIOINFORMATICS AND PATHWAY ANALYSIS ON THE RAW SEQUENCING DATA TO IDENTIFY DIFFERENTIALLY METHYLATED CANDIDATE GENES IN HDM-EXPOSED MICE. SPECIFICALLY, WE HAVE REVEALED THAT THE TRANSFORMING GROWTH FACTOR BETA SIGNALING PATHWAY IS EPIGENETICALLY MODULATED BY CHRONIC EXPOSURE TO HDM. HERE, WE DEMONSTRATED THAT A SPECIFIC ALLERGEN MAY PLAY A ROLE IN AHR THROUGH AN EPIGENETIC MECHANISM BY DISRUPTING THE EXPRESSION OF GENES IN LUNGS THAT MIGHT BE INVOLVED IN AIRWAY INFLAMMATION AND REMODELING. OUR FINDINGS PROVIDE NEW INSIGHTS INTO THE POTENTIAL MECHANISMS BY WHICH ENVIRONMENTAL ALLERGENS INDUCE ALLERGIC ASTHMA AND SUCH INSIGHTS MAY ASSIST IN THE DEVELOPMENT OF NOVEL PREVENTIVE AND THERAPEUTIC OPTIONS FOR THIS DEBILITATIVE DISEASE.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
16 1587 21 DNA METHYLATION PROFILING IDENTIFIES NOVEL MARKERS OF PROGRESSION IN HEPATITIS B-RELATED CHRONIC LIVER DISEASE. BACKGROUND: CHRONIC HEPATITIS B INFECTION IS CHARACTERIZED BY HEPATIC IMMUNE AND INFLAMMATORY RESPONSE WITH CONSIDERABLE VARIATION IN THE RATES OF PROGRESSION TO CIRRHOSIS. GENETIC VARIANTS AND ENVIRONMENTAL CUES INFLUENCE PREDISPOSITION TO THE DEVELOPMENT OF CHRONIC LIVER DISEASE; HOWEVER, IT REMAINS UNKNOWN IF ABERRANT DNA METHYLATION IS ASSOCIATED WITH FIBROSIS PROGRESSION IN CHRONIC HEPATITIS B. RESULTS: TO IDENTIFY EPIGENETIC MARKS ASSOCIATED WITH INFLAMMATORY AND FIBROTIC PROCESSES OF THE HEPATITIS B-INDUCED CHRONIC LIVER DISEASE, WE CARRIED OUT HEPATIC GENOME-WIDE METHYLATION PROFILING USING ILLUMINA INFINIUM BEADARRAYS COMPARING MILD AND SEVERE FIBROTIC DISEASE IN A DISCOVERY COHORT OF 29 PATIENTS. WE OBTAINED 310 DIFFERENTIALLY METHYLATED REGIONS AND SELECTED FOUR LOCI COMPRISING THREE GENES FROM THE TOP DIFFERENTIALLY METHYLATED REGIONS: HYPERMETHYLATION OF HOXA2 AND HDAC4 ALONG WITH HYPOMETHYLATION OF PPP1R18 WERE SIGNIFICANTLY LINKED TO SEVERE FIBROSIS. WE REPLICATED THE PROMINENT METHYLATION MARKS IN AN INDEPENDENT COHORT OF 102 PATIENTS BY BISULFITE MODIFICATION AND PYROSEQUENCING. THE TIMING AND CAUSAL RELATIONSHIP OF EPIGENETIC MODIFICATIONS WITH DISEASE SEVERITY WAS FURTHER INVESTIGATED USING A COHORT OF PATIENTS WITH SERIAL BIOPSIES. CONCLUSIONS: OUR FINDINGS SUGGEST A LINKAGE OF WIDESPREAD EPIGENETIC DYSREGULATION WITH DISEASE PROGRESSION IN CHRONIC HEPATITIS B INFECTION. CPG METHYLATION AT NOVEL GENES SHEDS LIGHT ON NEW MOLECULAR PATHWAYS, WHICH CAN BE POTENTIALLY EXPLOITED AS A BIOMARKER OR TARGETED TO ATTENUATE INFLAMMATION AND FIBROSIS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
17 4285 30 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
18 4292 29 MICRORNA PROFILES OF MATERNAL AND NEONATAL ENDOTHELIAL PROGENITOR CELLS IN PREECLAMPSIA. PREECLAMPSIA IS ASSOCIATED WITH AN INCREASED CARDIOVASCULAR MORBIDITY OF MOTHER AND OFFSPRING, THUS CONTRIBUTING TO A SUBSTANTIAL BURDEN IN WOMEN AND CHILDREN'S HEALTH. IT HAS BEEN PROVEN THAT ENDOTHELIAL PROGENITOR CELL (EPC) NUMBERS AND FUNCTIONAL CHARACTERISTICS ARE IMPAIRED IN CARDIOVASCULAR DISEASE AND PREECLAMPSIA, ALTHOUGH CAUSATIVE FACTORS FOR THE LATTER HAVE REMAINED ELUSIVE. MICRORNA (MIRNA) MODIFICATIONS ARE A POTENTIAL MECHANISM THROUGH WHICH EXPOSURE TO AN ALTERED ENVIRONMENT TRANSLATES INTO THE DEVELOPMENT OF CHRONIC DISEASE. IN THIS STUDY, WE EXAMINED WHETHER DEVELOPMENT OF PREECLAMPSIA CORRESPONDS TO ALTERATIONS OF MIRNAS IN MATERNAL- AND CORD-BLOOD-DERIVED EPC. TO TEST THIS END, WE ANALYZED MATERNAL AND NEONATAL MIRNAS VIA RNA SEQUENCING FROM ENDOTHELIAL CELLS OF PREECLAMPTIC AND HEALTHY CONTROLS IN DIFFERENT CELL CULTURE PASSAGES. WE WERE ABLE TO DEMONSTRATE DIFFERENTIALLY REPRESENTED MIRNAS IN ALL GROUPS. HSA-MIR-1270 SHOWED SIGNIFICANTLY DIFFERENT LEVELS IN CORD BLOOD EPC FROM PREECLAMPSIA VERSUS CONTROL AND WAS NEGATIVELY CORRELATED WITH MRNA LEVELS OF ITS PREDICTED TARGETS ANGPTL7 AND TFRC. TRANSFECTION WITH AN HSA-MIR-1270 INHIBITOR DECREASED THE TUBE FORMATION CAPACITY AND CHEMOTACTIC MOTILITY BUT DID NOT CHANGE PROLIFERATION IN VITRO. TARGET PREDICTIONS AND GENE SET ENRICHMENT ANALYSES IDENTIFIED ALTERNATIVE SPLICING AS A SIGNIFICANTLY ENRICHED PATHWAY FOR HSA-MIR-1270. THE TOP MIRNAS IN THREE OTHER GROUPS WERE PREDICTED TO TARGET TRANSCRIPTIONAL AND DEVELOPMENTAL PATHWAYS. HERE, WE SHOWED FOR THE FIRST TIME SIGNIFICANTLY DIFFERENT LEVELS OF MIRNAS AND DIFFERENTLY REPRESENTED MRNA LEVELS OF PREDICTED TARGET GENES IN EPC DERIVED FROM PREECLAMPSIA. UNDERSTANDING THE EFFECTS OF PREECLAMPSIA ON THE EPIGENETIC MECHANISMS OF EPC WILL BE CRUCIAL AND MAY PROVIDE INITIAL INSIGHTS FOR FURTHER EVALUATION OF THE BENEFITS OF THERAPIES TARGETING THIS CELL POPULATION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
19  416 27 ANALYSIS OF THE DYNAMIC ABERRANT LANDSCAPE OF DNA METHYLATION AND GENE EXPRESSION DURING ARSENIC-INDUCED CELL TRANSFORMATION. INORGANIC ARSENIC IS A WELL-KNOWN CARCINOGEN ASSOCIATED WITH SEVERAL TYPES OF CANCER, BUT THE MECHANISMS INVOLVED IN ARSENIC-INDUCED CARCINOGENESIS ARE NOT FULLY UNDERSTOOD. RECENT EVIDENCE POINTS TO EPIGENETIC DYSREGULATION AS AN IMPORTANT MECHANISM IN THIS PROCESS; HOWEVER, THE EFFECTS OF EPIGENETIC ALTERATIONS IN GENE EXPRESSION HAVE NOT BEEN EXPLORED IN DEPTH. USING MICROARRAY DATA AND APPLYING A MULTIVARIATE CLUSTERING ANALYSIS IN A GAUSSIAN MIXTURE MODEL, WE DESCRIBE THE ALTERATIONS IN DNA METHYLATION AROUND THE PROMOTER REGION AND THE IMPACT ON GENE EXPRESSION IN HACAT CELLS DURING THE TRANSFORMATION PROCESS CAUSED BY CHRONIC EXPOSURE TO ARSENIC. USING THIS CLUSTERING APPROACH, THE GENES WERE GROUPED ACCORDING TO THEIR METHYLATION AND EXPRESSION STATUS IN THE EPIGENETIC LANDSCAPE, AND THE CHANGES THAT OCCURRED DURING THE CELLULAR TRANSFORMATION WERE IDENTIFIED ADEQUATELY. THUS, WE PRESENT A VALUABLE METHOD FOR IDENTIFYING EPIGENOMIC DYSREGULATION.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
20 4961 22 PATHOGENESIS OF PSORIASIS IN THE "OMIC" ERA. PART II. GENETIC, GENOMIC AND EPIGENETIC CHANGES IN PSORIASIS. PSORIASIS IS A MULTIFACTORIAL DISEASE IN WHICH GENETIC, ENVIRONMENTAL AND EPIGENETIC FACTORS REGULATING GENE EXPRESSION PLAY A KEY ROLE. IN THE "GENOMIC ERA", GENOME-WIDE ASSOCIATION STUDIES TOGETHER WITH TARGET GENOTYPING PLATFORMS PERFORMED IN DIFFERENT ETHNIC POPULATIONS HAVE FOUND MORE THAN 50 GENETIC SUSCEPTIBLE MARKERS ASSOCIATED WITH THE RISK OF PSORIASIS WHICH HAVE BEEN IDENTIFIED SO FAR. UP TILL NOW, THE STRONGEST ASSOCIATION WITH THE RISK OF THE DISEASE HAS BEEN PROVED FOR HLA-C*06 GENE. THE MAJORITY OF OTHER PSORIASIS RISK SNPS ARE SITUATED NEAR THE GENES ENCODING MOLECULES INVOLVED IN ADAPTIVE AND INNATE IMMUNITY, AND SKIN BARRIER FUNCTION. MANY CONTEMPORARY STUDIES INDICATE THAT THE EPIGENETIC CHANGES: HISTONE MODIFICATION, PROMOTER METHYLATIONS, LONG NON-CODING AND MICRO-RNA HYPEREXPRESSION ARE CONSIDERED AS FACTORS CONTRIBUTING TO PSORIASIS PATHOGENESIS AS THEY REGULATE ABNORMAL KERATINOCYTE DIFFERENTIATION AND PROLIFERATION, ABERRANT KERATINOCYTES - INFLAMMATORY CELLS COMMUNICATION, NEOANGIOGENESIS AND CHRONIC INFLAMMATION. THE CIRCULATING MIRNAS DETECTED IN THE BLOOD MAY BECOME SPECIFIC MARKERS IN THE DIAGNOSIS, PROGNOSIS AND RESPONSE TO THE TREATMENT OF THE DISEASE. THE INHIBITION OF EXPRESSION IN SELECTED MIRNAS MAY BE A NEW PROMISING THERAPY OPTION FOR PATIENTS WITH PSORIASIS.	2020