1 3752 132 INTEGRATED ANALYSIS OF CIRCRNAS AND MRNAS EXPRESSION PROFILE REVEALED THE INVOLVEMENT OF HSA_CIRC_0007919 IN THE PATHOGENESIS OF ULCERATIVE COLITIS. BACKGROUND: ULCERATIVE COLITIS (UC) IS CHARACTERIZED BY CHRONIC INFLAMMATION IN THE COLON AND EPIGENETIC FACTORS UNDERLYING THE OCCURRENCE. CIRCULAR RNAS (CIRCRNAS) HAVE BEEN UNDER INTENSIVE FOCUS DUE TO THE CIRCULAR CONSTRUCT AND GENE-REGULATING FUNCTIONS. HOWEVER, THE CHANGES AND ROLES OF CIRCRNAS IN UC REMAIN UNKNOWN. METHODS: MICROARRAYS WERE USED TO DETECT THE DIFFERENTIALLY EXPRESSED GENES, AND QUANTITATIVE REAL-TIME PCR WAS USED TO IDENTIFY THE CHANGES IN UC. IN SILICO ANALYSES WERE PERFORMED TO PREDICT THE FUNCTIONS OF CIRCRNAS AND MRNAS. IN VITRO, EPITHELIAL CELL LINES WERE STIMULATED BY PRO-INFLAMMATION EFFECTORS TO TEST THE ALTERATIONS IN CIRCRNAS. CIRCRNAS-MICRORNAS-MRNAS NETWORK CLARIFIED THE POTENTIAL MECHANISMS UNDERLYING CIRCRNAS IN UC. THE BINDING SITE BETWEEN HSA_CIRC_0007919 AND MIR-138 OR LET-7A WAS VERIFIED USING DUAL-LUCIFERASE ASSAY. RESULTS: A TOTAL OF 264 SIGNIFICANTLY DYSREGULATED CIRCRNAS AND 1869 DIFFERENTIALLY EXPRESSED MRNAS IN INFLAMED MUCOSA WERE COMPARED WITH THE NON-INFLAMED MUCOSA IN UC. HSA_CIRC_0004662 AND HSA_CIRC_0007919 WERE ALTERED LARGELY IN UC TISSUES. HSA_CIRC_0007919 WAS REDUCED PERSISTENTLY AFTER INFLAMMATORY TREATMENTS, AND IT WAS RELEVANT TO MAYO ENDOSCOPIC SUBSCORES AND THE EXPRESSION OF TIGHT JUNCTION MOLECULES. FINALLY, HSA_CIRC_0007919 COULD HARBOR MIR-138, AND LET-7A TO REGULATE THE TARGETED MRNAS EPC1 AND VIPR1. CONCLUSIONS: SEVERAL CIRCRNAS WERE DIFFERENTIALLY EXPRESSED IN UC. HSA_CIRC_0007919 IS RELATED TO CLINICAL CHARACTERISTICS AND EPITHELIAL INTEGRITY BY BINDING TO HSA-LET-7A, HSA-MIR-138 TO REGULATE THE TARGET GENES. CIRCRNAS, ESPECIALLY HSA_CIRC_0007919, ARE ASSOCIATED WITH THE PATHOGENESIS AND DEVELOPMENT OF UC, WITH POTENTIAL DIAGNOSTIC AND THERAPEUTIC IMPLICATIONS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
2 3504  44 IDENTIFICATION OF POTENTIALLY FUNCTIONAL CIRCRNAS AND PREDICTION OF CIRCRNA-MIRNA-MRNA REGULATORY NETWORK IN PERIODONTITIS: BRIDGING THE GAP BETWEEN BIOINFORMATICS AND CLINICAL NEEDS. BACKGROUND AND OBJECTIVE: PERIODONTITIS IS A MULTIFACTORIAL CHRONIC INFLAMMATORY DISEASE THAT CAN LEAD TO THE IRREVERSIBLE DESTRUCTION OF DENTAL SUPPORT TISSUES. AS AN EPIGENETIC FACTOR, THE EXPRESSION OF CIRCRNA IS TISSUE-DEPENDENT AND DISEASE-DEPENDENT. THIS STUDY AIMED TO IDENTIFY NOVEL PERIODONTITIS-ASSOCIATED CIRCRNAS AND PREDICT RELEVANT CIRCRNA-PERIODONTITIS REGULATORY NETWORK BY USING RECENTLY DEVELOPED BIOINFORMATIC TOOLS AND INTEGRATING SEQUENCING PROFILING WITH CLINICAL INFORMATION FOR GETTING A BETTER AND MORE THOROUGH IMAGE OF PERIODONTITIS PATHOGENESIS, FROM GENE TO CLINIC. MATERIAL AND METHODS: HIGH-THROUGHPUT SEQUENCING AND RT-QPCR WERE CONDUCTED TO IDENTIFY DIFFERENTIALLY EXPRESSED CIRCRNAS IN GINGIVAL TISSUES FROM PERIODONTITIS PATIENTS. THE RELATIONSHIP BETWEEN UPREGULATED CIRCRNAS EXPRESSION AND PROBING DEPTH (PD) WAS PERFORMED USING SPEARMAN'S CORRELATION ANALYSIS. BIOINFORMATIC ANALYSES INCLUDING GO ANALYSIS, CIRCRNA-DISEASE ASSOCIATION PREDICTION, AND CIRCRNA-MIRNA-MRNA NETWORK PREDICTION WERE PERFORMED TO CLARIFY POTENTIAL REGULATORY FUNCTIONS OF IDENTIFIED CIRCRNAS IN PERIODONTITIS. A RECEIVER-OPERATING CHARACTERISTIC (ROC) CURVE WAS ESTABLISHED TO ASSESS THE DIAGNOSTIC SIGNIFICANCE OF IDENTIFIED CIRCRNAS. RESULTS: HIGH-THROUGHPUT SEQUENCING IDENTIFIED 70 DIFFERENTIALLY EXPRESSED CIRCRNAS (68 UPREGULATED AND 2 DOWNREGULATED CIRCRNAS) IN HUMAN PERIODONTITIS (FOLD CHANGE >2.0 AND P < .05). THE TOP FIVE UPREGULATED CIRCRNAS WERE VALIDATED BY RT-QPCR THAT HAD STRONG ASSOCIATIONS WITH MULTIPLE HUMAN DISEASES, INCLUDING PERIODONTITIS. THE UPREGULATION OF CIRCRNAS WERE POSITIVELY CORRELATED WITH PD (R = .40-.69, P < .05, MODERATE). A CIRCRNA-MIRNA-MRNA NETWORK WITH THE TOP FIVE UPREGULATED CIRCRNAS, DIFFERENTIALLY EXPRESSED MRNAS, AND OVERLAPPED PREDICTED MIRNAS INDICATED POTENTIAL ROLES OF CIRCRNAS IN IMMUNE RESPONSE, CELL APOPTOSIS, MIGRATION, ADHESION, AND REACTION TO OXIDATIVE STRESS. THE ROC CURVE SHOWED THAT CIRCRNAS HAD POTENTIAL VALUE IN PERIODONTITIS DIAGNOSIS (AUC = 0.7321-0.8667, P < .05). CONCLUSION: CIRCRNA-DISEASE ASSOCIATIONS WERE PREDICTED BY ONLINE BIOINFORMATIC TOOLS. POSITIVE CORRELATION BETWEEN UPREGULATED CIRCRNAS, CIRCPTP4A2, CHR22:23101560-23135351+, CIRCARHGEF28, CIRCBARD1 AND CIRCRASA2, AND PD SUGGESTED FUNCTION OF CIRCRNAS IN PERIODONTITIS. NETWORK PREDICTION FURTHER FOCUSED ON DOWNSTREAM TARGETS REGULATED BY CIRCRNAS DURING PERIODONTITIS PATHOGENESIS.	2022	

3 1022  42 CIRCULAR RNA HSA_CIRC_0098181 INHIBITS METASTASIS IN HEPATOCELLULAR CARCINOMA BY ACTIVATING THE HIPPO SIGNALING PATHWAY VIA INTERACTION WITH EEF2. INTRODUCTION AND OBJECTIVES: THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC) IS A MULTI-STEP PROCESS THAT ACCUMULATES GENETIC AND EPIGENETIC ALTERATIONS, INCLUDING CHANGES IN CIRCULAR RNA (CIRCRNA). THIS STUDY AIMED TO UNDERSTAND THE ALTERATIONS IN CIRCRNA EXPRESSION IN HCC DEVELOPMENT AND METASTASIS AND TO EXPLORE THE BIOLOGICAL FUNCTIONS OF CIRCRNA. MATERIALS AND METHODS: TEN PAIRS OF ADJACENT CHRONIC HEPATITIS TISSUES AND HCC TISSUES FROM PATIENTS WITHOUT VENOUS METASTASES, AND TEN HCC TISSUES FROM PATIENTS WITH VENOUS METASTASES WERE ANALYZED USING HUMAN CIRCRNA MICROARRAYS. DIFFERENTIALLY EXPRESSED CIRCRNAS WERE THEN VALIDATED BY QUANTITATIVE REAL-TIME PCR. IN VITRO AND IN VIVO ASSAYS WERE PERFORMED TO ASSESS THE ROLES OF THE CIRCRNA IN HCC PROGRESSION. RNA PULL-DOWN ASSAY, MASS SPECTROMETRY ANALYSIS, AND RNA-BINDING PROTEIN IMMUNOPRECIPITATION WERE CONDUCTED TO EXPLORE THE PROTEIN PARTNERS OF THE CIRCRNA. RESULTS: CIRCRNA MICROARRAYS REVEALED THAT THE EXPRESSION PATTERNS OF CIRCRNAS ACROSS THE THREE GROUPS WERE SIGNIFICANTLY DIFFERENT. AMONG THESE, HSA_CIRC_0098181 WAS VALIDATED TO BE LOWLY EXPRESSED AND ASSOCIATED WITH POOR PROGNOSIS IN HCC PATIENTS. ECTOPIC EXPRESSION OF HSA_CIRC_0098181 DELAYED HCC METASTASIS IN VITRO AND IN VIVO. MECHANISTICALLY, HSA_CIRC_0098181 SEQUESTERED EUKARYOTIC TRANSLATION ELONGATION FACTOR 2 (EEF2) AND DISSOCIATED EEF2 FROM FILAMENTOUS ACTIN (F-ACTIN) TO PREVENT F-ACTIN FORMATION, WHICH BLOCKED ACTIVATION OF THE HIPPO SIGNALING PATHWAY. IN ADDITION, THE RNA BINDING PROTEIN QUAKING-5 BOUND DIRECTLY TO HSA_CIRC_0098181 AND INDUCED ITS BIOGENESIS. CONCLUSIONS: OUR STUDY REVEALS CHANGES IN CIRCRNA EXPRESSION FROM CHRONIC HEPATITIS, PRIMARY HCC, TO METASTATIC HCC. FURTHER, THE QKI5-HSA_CIRC_0098181-EEF2-HIPPO SIGNALING PATHWAY EXERTS A REGULATORY ROLE IN HCC.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
4 2331  39 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
5   51  42 A DISTINCT EPIGENETIC PROFILE DISTINGUISHES STENOTIC FROM NON-INFLAMED FIBROBLASTS IN THE ILEAL MUCOSA OF CROHN'S DISEASE PATIENTS. BACKGROUND: THE CHRONIC REMITTING AND RELAPSING INTESTINAL INFLAMMATION CHARACTERISTIC OF CROHN'S DISEASE FREQUENTLY LEADS TO FIBROSIS AND SUBSEQUENT STENOSIS OF THE INFLAMED REGION. APPROXIMATELY A THIRD OF ALL CROHN'S DISEASE PATIENTS REQUIRE RESECTION AT SOME STAGE IN THEIR DISEASE COURSE. AS THE PATHOGENESIS OF CROHN'S DISEASE ASSOCIATED FIBROSIS IS LARGELY UNKNOWN, A STRONG NECESSITY EXISTS TO BETTER UNDERSTAND THE PATHOPHYSIOLOGY THEREOF. METHODS: IN THIS STUDY, WE INVESTIGATED CHANGES OF THE DNA METHYLOME AND TRANSCRIPTOME OF ILEUM-DERIVED FIBROBLASTS ASSOCIATED TO THE OCCURRENCE OF CROHN'S DISEASE ASSOCIATED FIBROSIS. EIGHTEEN SAMPLES WERE INCLUDED IN A DNA METHYLATION ARRAY AND TWENTY-ONE SAMPLES WERE USED FOR RNA SEQUENCING. RESULTS: MOST DIFFERENTIALLY METHYLATED REGIONS AND DIFFERENTIALLY EXPRESSED GENES WERE OBSERVED WHEN COMPARING STENOTIC WITH NON-INFLAMED SAMPLES. BY CONTRAST, FEW DIFFERENCES WERE OBSERVED WHEN COMPARING CROHN'S DISEASE WITH NON-CROHN'S DISEASE, OR INFLAMED WITH NON-INFLAMED TISSUE. INTEGRATIVE METHYLATION AND GENE EXPRESSION ANALYSES REVEALED DYSREGULATION OF GENES ASSOCIATED TO THE PRKACA AND E2F1 NETWORK, WHICH IS INVOLVED IN CELL CYCLE PROGRESSION, ANGIOGENESIS, EPITHELIAL TO MESENCHYMAL TRANSITION, AND BILE METABOLISM. CONCLUSION: OUR RESEARCH PROVIDES EVIDENCE THAT THE METHYLOME AND THE TRANSCRIPTOME ARE SYSTEMATICALLY DYSREGULATED IN STENOSIS-ASSOCIATED FIBROBLASTS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
6 1131  45 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
7 4350  38 MIR-181A-5P IS A POTENTIAL CANDIDATE EPIGENETIC BIOMARKER IN MULTIPLE SCLEROSIS. MULTIPLE SCLEROSIS (MS) IS A CHRONIC INFLAMMATORY DISEASE OF THE CENTRAL NERVOUS SYSTEM (CNS) CHARACTERIZED BY DEMYELINATION AND AXONAL DEGENERATION. ABNORMAL EXPRESSION OF MICRORNAS (MIRNAS) PLAYS AN IMPORTANT ROLE IN MS PATHOLOGY. IN THIS COHORT STUDY, DIFFERENTIAL EXPRESSION OF THE FOUR MIRNAS (HSA-MIR-155-5P, HSA-MIR-9-5P, HSA-MIR-181A-5P, AND HSA-MIR-125B-5P) WAS INVESTIGATED IN 69 INDIVIDUALS, INCLUDING 39 MS PATIENTS (RELAPSING-REMITTING MS (RRMS), N = 27; SECONDARY PROGRESSIVE MS (SPMS), N = 12) AND 30 HEALTHY CONTROLS. IN SILICO ANALYSES REVEALED POSSIBLE GENES AND PATHWAYS SPECIFIC TO MIRNAS. PERIPHERAL BLOOD MIRNA EXPRESSIONS WERE DETECTED BY QUANTITATIVE REAL-TIME PCR (QPCR). HSA-MIR-181A-5P WAS DOWNREGULATED AND ASSOCIATED WITH INCREASED MS RISK (P = 0.012). THE OTHER THREE MIRNAS WERE UPREGULATED AND NOT ASSOCIATED WITH MS (P < 0.05). THE AREA UNDER THE CURVE (AUC) IS 0.779. IN SILICO ANALYSES SHOWED THAT HSA-MIR-181A-5P MAY PARTICIPATE IN MS PATHOLOGY BY TARGETING MAP2K1, CREB1, ATXN1, AND ATXN3 GENES IN INFLAMMATION AND NEURODEGENERATION PATHWAYS. THE CIRCULATORY HSA-MIR-181A-5P CAN REGULATE TARGET GENES, REVERSING THE MECHANISMS INVOLVED IN MS PATHOLOGIES SUCH AS PROTEIN UPTAKE AND PROCESSING, CELL PROLIFERATION AND SURVIVAL, INFLAMMATION, AND NEURODEGENERATION. THUS, THIS MIRNA COULD BE USED AS AN EPIGENOMIC-GUIDED DIAGNOSTIC TOOL AND FOR THERAPEUTIC PURPOSE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
8 2957  34 GENETIC AND EPIGENETIC IMPACT OF CHRONIC INFLAMMATION ON COLON MUCOSA CELLS. CHRONIC INFLAMMATION INCREASES CANCER RISK, AND CANCER DEVELOPMENT IS CHARACTERIZED BY STEPWISE ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS. DURING CHRONIC INFLAMMATION, INFECTIOUS AGENTS AND INTRINSIC MEDIATORS OF INFLAMMATORY RESPONSES CAN INDUCE GENETIC AND EPIGENETIC CHANGES. THIS STUDY TRIED TO EVALUATE BOTH THE GENETIC AND EPIGENETIC INFLUENCE OF CHRONIC INFLAMMATION ON COLON MUCOSA CELLS. REPETITIVE DEXTRAN SULFATE SODIUM (DSS) TREATMENT INDUCED CHRONIC COLITIS MODEL. WHOLE-EXOME SEQUENCING (WES) (200X COVERAGE) WAS PERFORMED TO DETECT SOMATIC VARIATIONS IN COLON MUCOSA CELLS. WITH THE USE OF WHOLE-GENOME BISULFITE SEQUENCING (BS) AT 34-FOLD COVERAGE (17-FOLD PER STRAND), THE METHYLOME OF BOTH THE COLITIS AND CONTROL TISSUE WAS COMPARATIVELY ANALYZED. BIOINFORMATICS ASSAY SHOWED THAT THERE WAS NO SIGNIFICANT SINGLE-NUCLEOTIDE POLYMORPHISM/INSERTION OR DELETION (SNP/INDEL) MUTATION ACCUMULATION IN COLITIS TISSUE, WHILE IT ACCUMULATED IN AGED MICE. FORTY-EIGHT GENES WITH SNP/INDEL MUTATION WERE OVERLAPPED IN THE THREE COLITIS TISSUES, TWO (WNT3A AND LAMA2) OF WHICH ARE IN THE CANCER DEVELOPMENT-RELATED SIGNALING PATHWAY. DIFFERENTIALLY METHYLATED REGION (DMR) ASSAY SHOWED THAT MANY GENES IN THE COLITIS TISSUE ARE ENRICHED IN THE CANCER DEVELOPMENT-RELATED SIGNALING PATHWAY, SUCH AS PI3K-AKT, RAS, WNT, TGF-BETA, AND MAPK SIGNALING PATHWAY. TOGETHER, THESE DATA SUGGESTED THAT EVEN THOUGH CHRONIC INFLAMMATION DID NOT OBVIOUSLY INCREASE GENETIC MUTATION ACCUMULATION, IT COULD BOTH GENETICALLY AND EPIGENETICALLY ALTER SOME GENES RELATED TO CANCER DEVELOPMENT.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
9 1727  42 DYSREGULATION OF LONG NON-CODING RNAS IN MOUSE MODELS OF LOCALIZATION-RELATED EPILEPSY. GENOME-WIDE PROFILING HAS REVEALED THAT EUKARYOTIC GENOMES ARE TRANSCRIBED INTO NUMEROUS NON-CODING RNAS. IN PARTICULAR, LONG NON-CODING RNAS (LNCRNAS) HAVE BEEN IMPLICATED IN VARIOUS HUMAN DISEASES DUE TO THEIR BIOCHEMICAL AND FUNCTIONAL DIVERSITY. EPILEPTIC DISORDERS HAVE BEEN CHARACTERIZED BY DYSREGULATION OF EPIGENETIC REGULATORY MECHANISMS, AND RECENT STUDIES HAVE IDENTIFIED SEVERAL LNCRNAS INVOLVED IN NEURAL DEVELOPMENT AND NETWORK FUNCTION. HOWEVER, COMPREHENSIVE PROFILING OF LNCRNAS IMPLICATED IN CHRONIC EPILEPSY HAS BEEN LACKING. IN THIS STUDY, MICROARRAY ANALYSIS WAS PERFORMED TO OBTAIN THE EXPRESSION PROFILE OF LNCRNAS DYSREGULATED IN PILOCARPINE AND KAINATE MODELS, TWO MODELS OF TEMPORAL LOBE EPILEPSY COMMONLY USED FOR STUDYING EPILEPTIC MECHANISMS. TOTAL OF 4622 LNCRNAS WERE ANALYZED: 384 LNCRNAS WERE SIGNIFICANTLY DYSREGULATED IN PILOCARPINE MODEL, AND 279 LNCRNAS WERE SIGNIFICANTLY DYSREGULATED IN KAINATE MODEL COMPARED WITH CONTROL MICE (>/=3.0-FOLD, P < 0.05). AMONG THESE, 54 AND 14 LNCRNAS, RESPECTIVELY, HAD ADJACENT PROTEIN-CODING GENES WHOSE EXPRESSIONS WERE ALSO SIGNIFICANTLY DYSREGULATED (>/=2.0-FOLD, P < 0.05). MAJORITY OF THESE PAIRS OF LNCRNAS AND ADJACENT GENES SHARED THE SAME DIRECTION OF DYSREGULATION. FOR THE SELECTED ADJACENT GENE-LNCRNA PAIRS, SIGNIFICANT GENE ONTOLOGY TERMS WERE EMBRYONIC APPENDAGE MORPHOGENESIS AND NEURON DIFFERENTIATION. THIS WAS THE FIRST STUDY TO COMPREHENSIVELY IDENTIFY DYSREGULATED LNCRNAS IN TWO DIFFERENT MODELS OF CHRONIC EPILEPSY AND WILL LIKELY PROVIDE A NOVEL INSIGHT INTO DEVELOPING LNCRNA THERAPEUTICS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
10 2637  32 EPIGENOME-WIDE STUDY IDENTIFIES EPIGENETIC OUTLIERS IN NORMAL MUCOSA OF PATIENTS WITH COLORECTAL CANCER. NONGENETIC PREDISPOSITION TO COLORECTAL CANCER CONTINUES TO BE DIFFICULT TO MEASURE PRECISELY, HAMPERING EFFORTS IN TARGETED PREVENTION AND SCREENING. EPIGENETIC CHANGES IN THE NORMAL MUCOSA OF PATIENTS WITH COLORECTAL CANCER CAN SERVE AS A TOOL IN PREDICTING COLORECTAL CANCER OUTCOMES. WE IDENTIFIED EPIGENETIC CHANGES AFFECTING THE NORMAL MUCOSA OF PATIENTS WITH COLORECTAL CANCER. DNA METHYLATION PROFILING ON NORMAL COLON MUCOSA FROM 77 PATIENTS WITH COLORECTAL CANCER AND 68 CONTROLS IDENTIFIED A DISTINCT SUBGROUP OF NORMALLY-APPEARING MUCOSA WITH MARKEDLY DISRUPTED DNA METHYLATION AT A LARGE NUMBER OF CPGS, TERMED AS "OUTLIER METHYLATION PHENOTYPE" (OMP) AND ARE PRESENT IN 15 OF 77 PATIENTS WITH CANCER VERSUS 0 OF 68 CONTROLS (P < 0.001). SIMILAR FINDINGS WERE ALSO SEEN IN PUBLICLY AVAILABLE DATASETS. COMPARISON OF NORMAL COLON MUCOSA TRANSCRIPTION PROFILES OF PATIENTS WITH OMP CANCER WITH THOSE OF PATIENTS WITH NON-OMP CANCER INDICATES GENES WHOSE PROMOTERS ARE HYPERMETHYLATED IN THE OMP PATIENTS ARE ALSO TRANSCRIPTIONALLY DOWNREGULATED, AND THAT MANY OF THE GENES MOST AFFECTED ARE INVOLVED IN INTERACTIONS BETWEEN EPITHELIAL CELLS, THE MUCUS LAYER, AND THE MICROBIOME. ANALYSIS OF 16S RRNA PROFILES SUGGESTS THAT NORMAL COLON MUCOSA OF OMPS ARE ENRICHED IN BACTERIAL GENERA ASSOCIATED WITH COLORECTAL CANCER RISK, ADVANCED TUMOR STAGE, CHRONIC INTESTINAL INFLAMMATION, MALIGNANT TRANSFORMATION, NOSOCOMIAL INFECTIONS, AND KRAS MUTATIONS. IN CONCLUSION, OUR STUDY IDENTIFIES AN EPIGENETICALLY DISTINCT OMP GROUP IN THE NORMAL MUCOSA OF PATIENTS WITH COLORECTAL CANCER THAT IS CHARACTERIZED BY A DISRUPTED METHYLOME, ALTERED GENE EXPRESSION, AND MICROBIAL DYSBIOSIS. PROSPECTIVE STUDIES ARE NEEDED TO DETERMINE WHETHER OMP COULD SERVE AS A BIOMARKER FOR AN ELEVATED EPIGENETIC RISK FOR COLORECTAL CANCER DEVELOPMENT. PREVENTION RELEVANCE: OUR STUDY IDENTIFIES AN EPIGENETICALLY DISTINCT OMP GROUP IN THE NORMAL MUCOSA OF PATIENTS WITH COLORECTAL CANCER THAT IS CHARACTERIZED BY A DISRUPTED METHYLOME, ALTERED GENE EXPRESSION, AND MICROBIAL DYSBIOSIS. IDENTIFICATION OF OMPS IN HEALTHY CONTROLS AND PATIENTS WITH COLORECTAL CANCER WILL LEAD TO PREVENTION AND BETTER PROGNOSIS, RESPECTIVELY.	2022	
                                                                                                                                                                                                                                                                                                                    
11 3959  39 LONG NON-CODING RNAS TARGET PATHOGENETICALLY RELEVANT GENES AND PATHWAYS IN RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE DRIVEN BY GENETIC, ENVIRONMENTAL AND EPIGENETIC FACTORS. LONG NON-CODING RNAS (LNCRNAS) ARE A KEY COMPONENT OF THE EPIGENETIC MECHANISMS AND ARE KNOWN TO BE INVOLVED IN THE DEVELOPMENT OF AUTOIMMUNE DISEASES. IN THIS WORK WE AIMED TO IDENTIFY SIGNIFICANTLY DIFFERENTIALLY EXPRESSED LNCRNAS (DE-LNCRNAS) THAT ARE FUNCTIONALLY CONNECTED TO MODULATED GENES STRICTLY ASSOCIATED WITH RA. IN TOTAL, 542,500 TRANSCRIPTS HAVE BEEN PROFILED IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM FOUR PATIENTS WITH EARLY ONSET RA PRIOR ANY TREATMENT AND FOUR HEALTHY DONORS USING CLARIOM D ARRAYS. RESULTS WERE CONFIRMED BY REAL-TIME PCR IN 20 PATIENTS AND 20 CONTROLS. SIX DE-LNCRNAS TARGET EXPERIMENTALLY VALIDATED MIRNAS ABLE TO REGULATE DIFFERENTIALLY EXPRESSED GENES (DEGS) IN RA; AMONG THEM, ONLY FTX, HNRNPU-AS1 AND RP11-498C9.15 TARGETED A LARGE NUMBER OF DEGS. MOST IMPORTANTLY, RP11-498C9.15 TARGETED THE LARGEST NUMBER OF SIGNALLING PATHWAYS THAT WERE FOUND TO BE ENRICHED BY THE GLOBAL AMOUNT OF RA-DEGS AND THAT HAVE ALREADY BEEN ASSOCIATED WITH RA AND RA-SYNOVIOCYTES. MOREOVER, RP11-498C9.15 TARGETED THE MOST HIGHLY CONNECTED GENES IN THE RA INTERACTOME, THUS SUGGESTING ITS INVOLVEMENT IN CRUCIAL GENE REGULATION. THESE RESULTS INDICATE THAT, BY MODULATING BOTH MICRORNAS AND GENE EXPRESSION, RP11-498C9.15 MAY PLAY A PIVOTAL ROLE IN RA PATHOGENESIS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
12 4293  32 MICRORNA PROFILING IN MUC2 KNOCKOUT MICE OF COLITIS-ASSOCIATED CANCER MODEL REVEALS EPIGENETIC ALTERATIONS DURING CHRONIC COLITIS MALIGNANT TRANSFORMATION. OUR PREVIOUS STUDIES HAVE DEMONSTRATED THAT GENETIC DELETION OF THE MUC2 GENE CAUSES COLORECTAL CANCERS IN MICE. THE CURRENT STUDY FURTHER SHOWED THAT AT THE EARLY STAGE (<3 MONTHS) THE MUC2 KNOCKOUT MICE SPONTANEOUSLY DEVELOPED CHRONIC INFLAMMATION IN COLON AND RECTUM, SIMILAR PATHOLOGICAL FEATURES AS HUMAN COLITIS; AND AT THE LATE STAGE (>3 MONTHS) THE MICE EXHIBITED COLORECTAL CANCER, INCLUDING A UNIQUE PHENOTYPE OF RECTAL PROLAPSED (RECTAL SEVERE INFLAMMATION AND ADENOCARCINOMA). THUS, THE AGE OF 3 MONTHS MIGHT BE THE KEY POINT OF THE TRANSITION FROM CHRONIC INFLAMMATION TO CANCER. TO DETERMINE THE MECHANISMS OF THE MALIGNANT TRANSFORMATION, WE CONDUCTED MIRNA ARRAY ON THE COLONIC EPITHELIAL CELLS FROM THE 3-MONTH MUC2-/- AND +/+ MICE. MICRORNA PROFILING SHOWED DIFFERENTIAL EXPRESSION OF MIRNAS (I.E. LOWER OR HIGHER EXPRESSION ENRICHMENTS) IN MUC2-/- MICE. 15 OF THEM WERE VALIDATED BY QUANTITATIVE PCR. BASED ON RELEVANCE TO CYTOKINE AND CANCER, 4 MIRNAS (MIR-138, MIR-145, MIR-146A, AND MIR-150) WERE VALIDATE AND WERE FOUND SIGNIFICANTLY DOWNREGULATED IN HUMAN COLITIS AND COLORECTAL CANCER TISSUES. THE NETWORK OF THE TARGETS OF THESE MIRNAS WAS CHARACTERIZED, AND INTERESTEDLY, MIRNA-ASSOCIATED CYTOKINES WERE SIGNIFICANTLY INCREASED IN MUC2-/-MICE. THIS IS THE FIRST TO REVEAL THE IMPORTANCE OF ABERRANT EXPRESSION OF MIRNAS IN DYNAMICALLY TRANSFORMATION FROM CHRONIC COLITIS TO COLITIS-ASSOCIATED CANCER. THESE FINDINGS SHED LIGHT ON REVEALING THE MECHANISMS OF CHRONIC COLITIS MALIGNANT TRANSFORMATION.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
13 1587  33 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
14 3765  46 INTEGRATIVE ANALYSIS OF TRANSCRIPTOMIC AND PROTEOMIC PROFILING IN INFLAMMATORY BOWEL DISEASE COLON BIOPSIES. BACKGROUND: CROHN'S DISEASE (CD) AND ULCERATIVE COLITIS (UC) ARE INTESTINAL CHRONIC INFLAMMATORY CONDITIONS CHARACTERIZED BY ALTERED EPITHELIAL BARRIER FUNCTION AND TISSUE DAMAGE. DESPITE SIGNIFICANT EFFORTS TO UNDERSTANDING THE BIOLOGICAL MECHANISMS RESPONSIBLE FOR GUT INFLAMMATION, THE PATHOPHYSIOLOGY OF CD AND UC REMAINS POORLY UNDERSTOOD. METHODS: TO HELP ELUCIDATE THE POTENTIAL MECHANISMS RESPONSIBLE FOR GUT INFLAMMATION IN CD AND UC, TRANSCRIPTOMIC AND PROTEOMIC PROFILING OF HUMAN COLON BIOPSY SPECIMENS WAS PERFORMED. DYSREGULATED GENES AND PROTEINS IN DISEASE TISSUES COMPARED WITH NORMAL TISSUES WERE CHARACTERIZED FROM THE EXPRESSION PROFILES AND FURTHER SUBJECTED TO PATHWAY ANALYSIS TO IDENTIFY ALTERED BIOLOGICAL PROCESSES AND SIGNALING PATHWAYS. RESULTS: SAMPLE ANALYSIS SHOWED 4250 GENES WITH MATCHED PROTEIN EXPRESSION AND A WIDE RANGE OF CORRELATION OF RNA-PROTEIN ABUNDANCE ACROSS SAMPLES. PATHWAY ANALYSIS OF DYSREGULATED GENES AND PROTEINS IN CD AND UC SHOWED ALTERATIONS IN IMMUNE AND INFLAMMATORY RESPONSES, COMPLEMENT CASCADE, AND THE SUPPRESSION OF METABOLIC PROCESSES AND PPAR SIGNALING. IN CD, INCREASED T-HELPER CELL DIFFERENTIATION AND ELEVATED TOLL-LIKE RECEPTOR AND JAK/STAT SIGNALING WERE OBSERVED. INTERESTINGLY, INCREASED MAPK SIGNALING WAS ONLY OBSERVED IN UC. WEIGHTED GENE CO-EXPRESSION NETWORK ANALYSIS SUGGESTED A POSSIBLE ROLE OF EPIGENETIC REGULATION IN UC. OF NOTE, A LARGE DISCREPANCY BETWEEN REGULATION OF RNA AND PROTEIN LEVELS IN INFLAMED COLON SAMPLES WAS DETECTED FOR PREVIOUSLY IDENTIFIED BIOMARKERS INCLUDING MMP14 AND LAMP1. CONCLUSIONS: WITH THE ANALYSIS OF DYSREGULATED GENES AND PATHWAYS, THE PRESENT STUDY UNRAVELS KEY MECHANISMS CONTRIBUTING TO CD AND UC PATHOGENESIS AND EMPHASIZES THAT INTEGRATIVE ANALYSIS OF MULTI-OMICS DATA SETS CAN PROVIDE MORE INSIGHT INTO UNDERSTANDING COMPLEX DISEASE MECHANISMS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
15 1718  35 DYSREGULATED LONG NON-CODING RNAS IN THE TEMPORAL LOBE EPILEPSY MOUSE MODEL. PURPOSE: TO PERFORM COMPREHENSIVE PROFILING OF LONG NON-CODING RNAS (LNCRNAS) IN TEMPORAL LOBE EPILEPSY. METHODS: WE PERFORMED EXTENSIVE PROFILING OF LNCRNAS AND MRNAS IN THE MOUSE PILOCARPINE MODEL IN SPECIFIC BRAIN REGIONS, THE HIPPOCAMPUS AND CORTEX, AND COMPARED THE RESULTS TO THOSE OF THE CONTROL MOUSE. DIFFERENTIALLY EXPRESSED LNCRNAS AND MRNAS WERE IDENTIFIED WITH A MICROARRAY ANALYSIS (ARRAYSTAR MOUSE LNCRNA EXPRESSION MICROARRAY V3.0). THEN, GENE ONTOLOGY (GO) AND PATHWAY ANALYSIS WERE PERFORMED TO INVESTIGATE THE POTENTIAL ROLES OF THE DIFFERENTIALLY EXPRESSED MRNAS IN THE PILOCARPINE MODEL. PROTEIN-PROTEIN INTERACTIONS TRANSCRIBED BY DYSREGULATED MRNAS WITH/WITHOUT CO-DYSREGULATED LNCRNAS WERE ANALYZED USING STRING V10 (HTTP://STRING-DB.ORG/). RESULTS: A TOTAL OF 22 AND 83 LNCRNAS WERE UP- AND DOWN-REGULATED (>/=2.0-FOLD, ALL P < .05), RESPECTIVELY, IN THE HIPPOCAMPUS OF THE EPILEPSY MODEL, WHILE 46 AND 659 LNCRNAS WERE UP- AND DOWN-REGULATED, RESPECTIVELY, IN THE CORTEX OF THE EPILEPSY MODEL. GO AND PATHWAY ANALYSIS REVEALED THAT THE DYSREGULATED MRNAS WERE CLOSELY ASSOCIATED WITH A PROCESS ALREADY KNOWN TO BE INVOLVED IN EPILEPTOGENESIS: ACUTE INFLAMMATION, CALCIUM ION REGULATION, EXTRACELLULAR MATRIX REMODELING, AND NEURONAL DIFFERENTIATION. AMONG THE LNCRNAS, WE IDENTIFIED 10 LNCRNAS COMMONLY DYSREGULATED WITH CORRESPONDING MRNAS IN THE CORTEX. THE STRING ANALYSIS SHOWED THAT THE DYSREGULATED MRNAS WERE INTERCONNECTED AROUND TWO CENTERS: THE MTOR PATHWAY-RELATED GENES AND REST PATHWAY-RELATED GENES. CONCLUSION: LNCRNAS WERE DYSREGULATED IN THE PILOCARPINE MOUSE MODEL ACCORDING TO THE BRAIN REGIONS OF THE HIPPOCAMPUS AND CORTEX. THE DYSREGULATED LNCRNAS WITH CO-DYSREGULATED MRNAS MIGHT BE POSSIBLE THERAPEUTIC TARGETS FOR THE EPIGENETIC REGULATION OF CHRONIC EPILEPSY.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
16 3770  30 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
17 3764  31 INTEGRATIVE ANALYSIS OF DNA METHYLATION AND GENE EXPRESSION DATA IDENTIFIES EPAS1 AS A KEY REGULATOR OF COPD. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A COMPLEX DISEASE. GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS ARE KNOWN TO CONTRIBUTE TO COPD RISK AND DISEASE PROGRESSION. THEREFORE WE DEVELOPED A SYSTEMATIC APPROACH TO IDENTIFY KEY REGULATORS OF COPD THAT INTEGRATES GENOME-WIDE DNA METHYLATION, GENE EXPRESSION, AND PHENOTYPE DATA IN LUNG TISSUE FROM COPD AND CONTROL SAMPLES. OUR INTEGRATIVE ANALYSIS IDENTIFIED 126 KEY REGULATORS OF COPD. WE IDENTIFIED EPAS1 AS THE ONLY KEY REGULATOR WHOSE DOWNSTREAM GENES SIGNIFICANTLY OVERLAPPED WITH MULTIPLE GENES SETS ASSOCIATED WITH COPD DISEASE SEVERITY. EPAS1 IS DISTINCT IN COMPARISON WITH OTHER KEY REGULATORS IN TERMS OF METHYLATION PROFILE AND DOWNSTREAM TARGET GENES. GENES PREDICTED TO BE REGULATED BY EPAS1 WERE ENRICHED FOR BIOLOGICAL PROCESSES INCLUDING SIGNALING, CELL COMMUNICATIONS, AND SYSTEM DEVELOPMENT. WE CONFIRMED THAT EPAS1 PROTEIN LEVELS ARE LOWER IN HUMAN COPD LUNG TISSUE COMPARED TO NON-DISEASE CONTROLS AND THAT EPAS1 GENE EXPRESSION IS REDUCED IN MICE CHRONICALLY EXPOSED TO CIGARETTE SMOKE. AS EPAS1 DOWNSTREAM GENES WERE SIGNIFICANTLY ENRICHED FOR HYPOXIA RESPONSIVE GENES IN ENDOTHELIAL CELLS, WE TESTED EPAS1 FUNCTION IN HUMAN ENDOTHELIAL CELLS. EPAS1 KNOCKDOWN BY SIRNA IN ENDOTHELIAL CELLS IMPACTED GENES THAT SIGNIFICANTLY OVERLAPPED WITH EPAS1 DOWNSTREAM GENES IN LUNG TISSUE INCLUDING HYPOXIA RESPONSIVE GENES, AND GENES ASSOCIATED WITH EMPHYSEMA SEVERITY. OUR FIRST INTEGRATIVE ANALYSIS OF GENOME-WIDE DNA METHYLATION AND GENE EXPRESSION PROFILES ILLUSTRATES THAT NOT ONLY DOES DNA METHYLATION PLAY A 'CAUSAL' ROLE IN THE MOLECULAR PATHOPHYSIOLOGY OF COPD, BUT IT CAN BE LEVERAGED TO DIRECTLY IDENTIFY NOVEL KEY MEDIATORS OF THIS PATHOPHYSIOLOGY.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
18 5567  37 ROLE OF LNCRNAS IN REMODELING OF THE CORONARY ARTERY PLAQUES IN PATIENTS WITH ATHEROSCLEROSIS. INTRODUCTION: CARDIOVASCULAR DISEASES (CVDS) ARE THE LEADING CAUSE OF DEATH WORLDWIDE ACCORDING TO WORLD HEALTH ORGANIZATION (WHO) DATA. ATHEROSCLEROSIS IS CONSIDERED AS A CHRONIC INFLAMMATORY DISEASE THAT DEVELOPS IN RESPONSE TO DAMAGE TO THE VASCULAR INTIMA-MEDIA LAYER IN MOST CASES. IN RECENT YEARS, EPIGENETIC EVENTS HAVE EMERGED AS IMPORTANT PLAYERS IN THE DEVELOPMENT AND PROGRESSION OF CVDS. SINCE NONCODING RNA (NCRNAS) ARE IMPORTANT REGULATORS IN THE ORGANIZATION OF THE PATHOPHYSIOLOGICAL PROCESSES OF THE CARDIOVASCULAR SYSTEM, THEY HAVE THE POTENTIAL TO BE USED AS THERAPEUTIC TARGETS, DIAGNOSTIC AND PROGNOSTIC BIOMARKERS. IN THIS STUDY LONG NONCODING RNA (LNCRNA) AND MRNA GENE EXPRESSION WERE COMPARED BETWEEN CORONARY ATHEROSCLEROTIC PLAQUES (CAP) AND THE INTERNAL MAMMARY ARTERY (IMA) WHICH HAS THE SAME GENETIC MAKEUP AND IS EXPOSED TO THE SAME ENVIRONMENTAL STRESS CONDITIONS WITH CAP IN THE SAME INDIVIDUAL. METHODS: LNCRNA AND MRNA GENE EXPRESSIONS WERE DETERMINED USING THE MICROARRAY IN THE SAMPLES. MICROARRAY RESULTS WERE VALIDATED BY RT-QPCR. DIFFERENTIALLY EXPRESSED GENES (DEGS; LNCRNAS AND MRNAS) WERE DETERMINED BY GENESPRING (VER 3.0) [P VALUES < 0.05 AND FOLD CHANGE (FC) > 2]. DAVID BIOINFORMATICS PROGRAM WAS USED FOR GENE ONTOLOGY (GO) ANNOTATION AND ENRICHMENT ANALYSES OF STATISTICALLY SIGNIFICANT GENES BETWEEN CAP AND IMA TISSUE. RESULTS AND CONCLUSIONS: IN OUR STUDY, 345 DEGS WERE FOUND TO BE STATISTICALLY SIGNIFICANT (P < 0.05; FC > 2) BETWEEN CAP AND IMA. OF THESE, 65 WERE LNCRNA AND 280 WERE MRNA. THIRTY-THREE LNCRNAS WERE UPREGULATED, WHILE 32 LNCRNAS WERE DOWNREGULATED. SOME OF THE IMPORTANT MRNAS ARE SPP1, CYP4B1, CHRDL1, MYOC, AND ALKAL2, WHILE SOME OF THE LNCRNAS ARE LOC105377123, LINC01857, DIO3OS, LOC101928134, AND KCNA3 BETWEEN CAP AND IMA TISSUE. WE ALSO IDENTIFIED GENES THAT CORRELATED WITH STATISTICALLY SIGNIFICANT LNCRNAS. THE RESULTS OF THIS STUDY ARE EXPECTED TO BE AN IMPORTANT SOURCE OF DATA IN THE DEVELOPMENT OF NEW GENETICALLY BASED DRUGS TO PREVENT ATHEROSCLEROTIC PLAQUE. IN ADDITION, THE DATA OBTAINED MAY CONTRIBUTE TO THE EXPLANATION OF THE EPIGENETIC MECHANISMS THAT PLAY A ROLE IN THE PATHOLOGICAL BASIS OF THE PROCESS THAT PROTECTS THE IMA FROM ATHEROSCLEROSIS.	2023	
                                                                                                                                                                                                                                                                                            
19 5120  35 POSSIBLE EPIGENETIC REGULATORY EFFECT OF DYSREGULATED CIRCULAR RNAS IN EPILEPSY. CIRCULAR RNAS (CIRCRNAS) INVOLVE IN THE EPIGENETIC REGULATION AND ITS MAJOR MECHANISM IS THE SEQUESTRATION OF THE TARGET MICRO RNAS (MIRNAS). WE HYPOTHESIZED THAT CIRCRNAS MIGHT BE RELATED WITH THE PATHOPHYSIOLOGY OF CHRONIC EPILEPSY AND EVALUATED THE ALTERED CIRCRNA EXPRESSIONS AND THEIR POSSIBLE REGULATORY EFFECTS ON THEIR TARGET MIRNAS AND MRNAS IN A MOUSE EPILEPSY MODEL. THE CIRCRNA EXPRESSION PROFILE IN THE HIPPOCAMPUS OF THE PILOCARPINE MICE WAS ANALYZED AND COMPARED WITH CONTROL. THE CORRELATION BETWEEN THE EXPRESSION OF MIRNA BINDING SITES (MIRNA RESPONSE ELEMENTS, MRE) IN THE DYSREGULATED CIRCRNAS AND THE EXPRESSION OF THEIR TARGET MIRNAS WAS EVALUATED. AS MIRNAS ALSO INHIBIT THEIR TARGET MRNAS, CIRCRNA-MIRNA-MRNA REGULATORY NETWORK, COMPRISED OF DYSREGULATED RNAS THAT TARGETS ONE ANOTHER WERE SEARCHED. FOR THE IDENTIFIED NETWORKS, BIOINFORMATICS ANALYSES WERE PERFORMED. AS THE RESULT, FORTY-THREE CIRCRNAS WERE DYSREGULATED IN THE HIPPOCAMPUS (UP-REGULATED, 26; DOWN-REGULATED, 17). THE CHANGE IN THE EXPRESSION OF MRE IN THOSE CIRCRNAS NEGATIVELY CORRELATED WITH THE CHANGE IN THE RELEVANT TARGET MIRNA EXPRESSION (R = -0.461, P<0.001), SUPPORTING THAT CIRCRNAS INHIBIT THEIR TARGET MIRNA. 333 DYSREGULATED CIRCRNA-MIRNA-MRNA NETWORKS WERE IDENTIFIED. GENE ONTOLOGY AND PATHWAY ANALYSES DEMONSTRATED THAT THE UP-REGULATED MRNAS IN THOSE NETWORKS WERE CLOSELY RELATED TO THE MAJOR PROCESSES IN EPILEPSY. AMONG THEM, STRING ANALYSIS IDENTIFIED 37 KEY MRNAS WITH ABUNDANT (>/=4) INTERACTIONS WITH OTHER DYSREGULATED TARGET MRNAS. THE DYSREGULATION OF THE CIRCRNAS WHICH HAD MULTIPLE INTERACTIONS WITH KEY MRNAS WERE VALIDATED BY PCR. WE CONCLUDED THAT DYSREGULATED CIRCRNAS MIGHT HAVE A PATHOPHYSIOLOGIC ROLE IN CHRONIC EPILEPSY BY REGULATING MULTIPLE DISEASE RELEVANT MRNAS VIA CIRCRNA-MIRNA-MRNA INTERACTIONS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
20 1584  23 DNA METHYLATION PROFILES OF SELECTED PRO-INFLAMMATORY CYTOKINES IN ALZHEIMER DISEASE. BY MEANS OF FUNCTIONAL GENOMICS ANALYSIS, WE RECENTLY DESCRIBED THE MRNA EXPRESSION PROFILES OF VARIOUS GENES INVOLVED IN THE NEUROINFLAMMATORY RESPONSE IN THE BRAINS OF SUBJECTS WITH LATE-ONSET ALZHEIMER DISEASE (LOAD). SOME OF THESE GENES, NAMELY INTERLEUKIN (IL)-1BETA AND IL-6, SHOWED DISTINCT EXPRESSION PROFILES WITH PEAK EXPRESSION DURING THE FIRST STAGES OF THE DISEASE AND CONTROL-LIKE LEVELS AT LATER STAGES. IL-1BETA AND IL-6 GENES ARE MODULATED BY DNA METHYLATION IN DIFFERENT CHRONIC AND DEGENERATIVE DISEASES; IT IS ALSO WELL KNOWN THAT LOAD MAY HAVE AN EPIGENETIC BASIS. INDEED, WE AND OTHERS HAVE PREVIOUSLY REPORTED GENE-SPECIFIC DNA METHYLATION ALTERATIONS IN LOAD AND IN RELATED ANIMAL MODELS. BASED ON THESE DATA, WE STUDIED THE DNA METHYLATION PROFILES, AT SINGLE CYTOSINE RESOLUTION, OF IL-1BETA AND IL-6 5'-FLANKING REGION BY BISULPHITE MODIFICATION IN THE CORTEX OF HEALTHY CONTROLS AND LOAD PATIENTS AT 2 DIFFERENT DISEASE STAGES: BRAAK I-II/A AND BRAAK V-VI/C. OUR ANALYSIS PROVIDES EVIDENCE THAT NEUROINFLAMMATION IN LOAD IS ASSOCIATED WITH (AND POSSIBLY MEDIATED BY) EPIGENETIC MODIFICATIONS.	2017