1 3477 112 IDENTIFICATION OF ABNORMALLY METHYLATED DIFFERENTIALLY EXPRESSED GENES IN CHRONIC PERIODONTITIS BY INTEGRATED BIOINFORMATICS ANALYSIS. BACKGROUND: DNA METHYLATION PLAYS A VITAL ROLE AS AN EPIGENETIC CHANGE THAT CONTRIBUTES TO CHRONIC PERIODONTITIS. OBJECTIVE: THIS STUDY AIMED TO INTEGRATE TWO METHYLATION DATASETS (GSE173081 AND GSE59962) AND TWO GENE EXPRESSION DATASETS (GSE10334 AND GES16134) TO IDENTIFY ABNORMALLY METHYLATED DIFFERENTIALLY EXPRESSED GENES RELATED TO CHRONIC PERIODONTITIS. METHODS: DIFFERENTIALLY METHYLATED GENES WERE OBTAINED. FUNCTIONAL ENRICHMENT ANALYSIS OF DMGS WAS PERFORMED. THE PROTEIN-PROTEIN INTERACTION (PPI) NETWORK WAS CONSTRUCTED USING STRING AND CYTOSCAPE SOFTWARE. FINALLY, THE HUB GENES WERE SELECTED FROM THE PPI NETWORK BY USING CYTOHUBBA. RESULTS: IN TOTAL, 122 HYPOMETHYLATED AND HIGHLY EXPRESSED GENES WERE ENRICHED IN THE BIOLOGICAL MECHANISMS THAT ARE INVOLVED IN THE DIFFERENTIATION OF EXTRACELLULAR MATRIX ORGANIZATION, EXTRACELLULAR STRUCTURE ORGANIZATION, AND CELL CHEMOTAXIS. THE THREE SELECTED HUB GENES OF THE PPI NETWORK WERE IL1B, KDR, AND MMP9. A TOTAL OF 122 HYPERMETHYLATED AND LOWLY EXPRESSED GENES WERE IDENTIFIED, AND BIOLOGICAL PROCESSES, SUCH AS CORNIFICATION, EPIDERMIS DEVELOPMENT, SKIN DEVELOPMENT, AND KERATINOCYTE DIFFERENTIATION WERE ENRICHED. CDSN DSG1, AND KRT2 WERE IDENTIFIED AS THE TOP 3 HUB GENES OF THE PPI NETWORK. CONCLUSION: BASED ON THE COMPREHENSIVE BIOINFORMATICS ANALYSIS, SIX HUB GENES (IL1B, KDR, MMP9, CDSN DSG1, AND KRT2) WERE ASSOCIATED WITH CHRONIC PERIODONTITIS. OUR FINDINGS PROVIDE NOVEL INSIGHTS INTO THE MECHANISMS UNDERLYING EPIGENETIC CHANGES IN CHRONIC PERIODONTITIS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
2 4868  45 OSTEOARTHRITIS RELATED EPIGENETIC VARIATIONS IN MIRNA EXPRESSION AND DNA METHYLATION. OSTEOARTHRITIS (OA) IS CHRONIC ARTHRITIS CHARACTERIZED BY ARTICULAR CARTILAGE DEGRADATION. HOWEVER, A COMPREHENSIVE REGULATORY NETWORK FOR OA-RELATED MICRORNAS AND DNA METHYLATION MODIFICATIONS HAS YET TO BE ESTABLISHED. THUS, WE AIMED TO IDENTIFY EPIGENETIC CHANGES IN MICRORNAS AND DNA METHYLATION AND ESTABLISH THE REGULATORY NETWORK BETWEEN MIRNAS AND DNA METHYLATION. THE MRNA, MIRNA, AND DNA METHYLATION EXPRESSION PROFILES OF HEALTHY OR OSTEOARTHRITIS ARTICULAR CARTILAGE SAMPLES WERE DOWNLOADED FROM GENE EXPRESSION OMNIBUS (GEO) DATABASE, INCLUDING GSE169077, GSE175961, AND GSE162484. THE DIFFERENTIALLY EXPRESSED GENES (DEGS), DIFFERENTIALLY EXPRESSED MIRNAS (DEMS), AND DIFFERENTIALLY METHYLATED GENES (DMGS) WERE ANALYZED BY THE ONLINE TOOL GEO2R. DAVID AND STRING DATABASES WERE APPLIED FOR FUNCTIONAL ENRICHMENT ANALYSIS AND PROTEIN-PROTEIN INTERACTION (PPI) NETWORK. POTENTIAL THERAPEUTIC COMPOUNDS FOR THE TREATMENT OF OA WERE IDENTIFIED BY CONNECTIVITY MAP (CMAP) ANALYSIS. A TOTAL OF 1424 UP-REGULATED DEGS, 1558 DOWN-REGULATED DEGS, 5 DEMS WITH HIGH EXPRESSION, 6 DEMS WITH LOW EXPRESSION, 1436 HYPERMETHYLATED GENES, AND 455 HYPOMETHYLATED GENES WERE SELECTED. A TOTAL OF 136 UP-REGULATED AND 65 DOWNREGULATED GENES WERE IDENTIFIED BY OVERLAPPING DEGS AND DEMS PREDICTED TARGET GENES WHICH WERE ENRICHED IN APOPTOSIS AND CIRCADIAN RHYTHM. A TOTAL OF 39 HYPOMETHYLATED AND 117 HYPERMETHYLATED GENES WERE OBTAINED BY OVERLAPPING DEGS AND DMGS, WHICH WERE ASSOCIATED WITH ECM RECEPTOR INTERACTIONS AND CELLULAR METABOLIC PROCESSES, CELL CONNECTIVITY, AND TRANSCRIPTION. MOREOVER, THE PPI NETWORK SHOWED COL5A1, COL6A1, LAMA4, T3GAL6A, AND TP53 WERE THE MOST CONNECTIVE PROTEINS. AFTER OVERLAPPING OF DEGS, DMGS AND DEMS PREDICTED TARGETED GENES, 4 UP-REGULATED GENES AND 11 DOWN-REGULATED GENES WERE ENRICHED IN THE AXON GUIDANCE PATHWAY. THE TOP TEN GENES RANKED BY PPI NETWORK CONNECTIVITY DEGREE IN THE UP-REGULATED AND DOWNREGULATED OVERLAPPING GENES OF DEGS AND DMGS WERE FURTHER ANALYZED BY THE CMAP DATABASE, AND NINE CHEMICALS WERE PREDICTED AS POTENTIAL DRUGS FOR THE TREATMENT OF OA. IN CONCLUSION, TP53, COL5A1, COL6A1, LAMA4, AND ST3GAL6 MAY PLAY IMPORTANT ROLES IN OA GENESIS AND DEVELOPMENT.	2023	
                                                                                                                                                                                 
3  408  43 ANALYSIS OF GENE EXPRESSION AND METHYLATION DATASETS IDENTIFIED ADAMTS9, FKBP5, AND PFKBF3 AS BIOMARKERS FOR OSTEOARTHRITIS. BACKGROUND: OSTEOARTHRITIS (OA) IS A KIND OF CHRONIC OSTEOARTHROPATHY AND DEGENERATIVE JOINT DISEASE. EPIGENETIC REGULATION IN THE GENE EXPRESSION DYNAMICS HAS BECOME INCREASINGLY IMPORTANT IN OA. WE PERFORMED A COMBINED ANALYSIS OF TWO TYPES OF MICROARRAY DATASETS (GENE EXPRESSION AND DNA METHYLATION) TO IDENTIFY METHYLATION-BASED KEY BIOMARKERS TO PROVIDE A BETTER UNDERSTANDING OF MOLECULAR BIOLOGICAL MECHANISMS OF OA. METHODS: WE OBTAINED TWO EXPRESSION PROFILING DATASETS (GSE55235, GSE55457) AND ONE DNA METHYLATION PROFILING DATA SET (GSE63695) FROM THE GENE EXPRESSION OMNIBUS. FIRST, DIFFERENTIALLY EXPRESSED GENES (DEGS) BETWEEN PATIENTS WITH OA AND CONTROLS WERE IDENTIFIED USING THE LIMMA PACKAGE IN R(V3.4.4). THEN, FUNCTION ENRICHMENT ANALYSIS OF DEGS WAS PERFORMED USING A DAVID DATABASE. FOR DNA METHYLATION DATASETS, CHAMP METHYLATION ANALYSIS PACKAGE WAS USED TO IDENTIFY DIFFERENTIAL METHYLATION GENES (DMGS). FINALLY, A COMPREHENSIVE ANALYSIS OF DEGS AND DMGS WAS CONDUCTED TO IDENTIFY GENES THAT EXHIBITED DIFFERENTIAL EXPRESSION AND METHYLATION SIMULTANEOUSLY. RESULTS: WE IDENTIFIED 112 DEGS AND 2,896 DMGS IN PATIENTS WITH OA COMPARED WITH CONTROLS. FUNCTIONAL ANALYSIS OF DEGS OBTAINED THAT INFLAMMATORY RESPONSES, IMMUNE RESPONSES, AND POSITIVE REGULATION OF APOPTOSIS, TUMOR NECROSIS FACTOR (TNF) SIGNALING PATHWAY, AND OSTEOCLAST DIFFERENTIATION MAY BE INVOLVED IN THE PATHOGENESIS OF OA. CROSS-ANALYSIS REVEALED 26 GENES THAT EXHIBITED DIFFERENTIAL EXPRESSION AND METHYLATION IN OA. AMONG THEM, ADAMTS9, FKBP5, AND PFKBF3 WERE IDENTIFIED AS VALUABLE METHYLATION-BASED BIOMARKERS FOR OA. CONCLUSION: IN SUMMARY, OUR STUDY IDENTIFIED DIFFERENT MOLECULAR FEATURES BETWEEN PATIENTS WITH OA AND CONTROLS. THIS MAY PROVIDE NEW CLUES FOR CLARIFYING THE PATHOGENETIC MECHANISMS OF OA.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
4 3296  38 HIGH RESOLUTION INTEGRATIVE ANALYSIS REVEALS WIDESPREAD GENETIC AND EPIGENETIC CHANGES AFTER CHRONIC IN-VITRO ACID AND BILE EXPOSURE IN BARRETT'S EPITHELIUM CELLS. BARRETT'S EPITHELIUM (BE) IS A PREMALIGNANT CONDITION RESULTING FROM CHRONIC GASTROESOPHAGEAL REFLUX THAT MAY PROGRESS TO ESOPHAGEAL ADENOCARCINOMA (EAC). EARLY INTERVENTION HOLDS PROMISE IN PREVENTING BE PROGRESSION. HOWEVER, IDENTIFICATION OF HIGH-RISK BE PATIENTS REMAINS CHALLENGING DUE TO INADEQUATE BIOMARKERS FOR EARLY DIAGNOSIS. WE INVESTIGATED THE EFFECT OF PROLONGED CHRONIC ACID AND BILE EXPOSURE ON TRANSCRIPTOME, METHYLOME, AND MUTATOME OF CELLS IN AN IN-VITRO BE CARCINOGENESIS (BEC) MODEL. TWENTY WEEKS ACID AND BILE EXPOSED CELLS FROM THE BEC MODEL (BEC20W) WERE COMPARED WITH THEIR NAIVE PREDECESSORS HISEQ ILLUMINA BASED RNA SEQUENCING WAS PERFORMED ON RNA FROM BOTH THE CELLS FOR GENE EXPRESSION AND MUTATIONAL ANALYSIS. HELP TAGGING ASSAY WAS PERFORMED FOR DNA METHYLATION ANALYSIS. INGENUITY PATHWAY, GENE ONTOLOGY, AND KEGG PATHWAY ANALYSES WERE THEN PERFORMED ON DATASETS. WIDESPREAD ABERRANT GENETIC AND EPIGENETIC CHANGES WERE OBSERVED IN THE BEC20W CELLS. COMBINATORIAL ANALYSES REVEALED 433 FROM A TOTAL OF 863 DOWNREGULATED GENES HAD ACCOMPANYING HYPERMETHYLATION OF PROMOTERS. SIMULTANEOUSLY, 690 GENES FROM A TOTAL OF 1,492 WERE UPREGULATED WITH ACCOMPANYING PROMOTER HYPOMETHYLATION. IN ADDITION, 763 MUTATIONS WERE IDENTIFIED ON 637 GENES. INGENUITY PATHWAY ANALYSIS, GENE ONTOLOGY, AND KEGG PATHWAY ANALYSES ASSOCIATED THE GENETIC AND EPIGENETIC CHANGES IN BEC20W CELLS WITH CELLULAR AND BIOLOGICAL FUNCTIONS. INTEGRATION OF HIGH RESOLUTION COMPARATIVE ANALYSES OF NAIVE BAR-T AND BEC20W CELLS REVEALED STRIKING GENETIC AND EPIGENETIC CHANGES INDUCED BY CHRONIC ACID AND BILE EXPOSURE THAT MAY DISRUPT NORMAL CELLULAR FUNCTIONS AND PROMOTE CARCINOGENESIS. THIS NOVEL STUDY REVEALS SEVERAL POTENTIAL TARGETS FOR FUTURE BIOMARKERS AND THERAPEUTIC DEVELOPMENT.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
5 1590  28 DNA METHYLATION PROFILING IN HUMAN LUNG TISSUE IDENTIFIES GENES ASSOCIATED WITH COPD. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A SMOKING-RELATED DISEASE CHARACTERIZED BY GENETIC AND PHENOTYPIC HETEROGENEITY. ALTHOUGH ASSOCIATION STUDIES HAVE IDENTIFIED MULTIPLE GENOMIC REGIONS WITH REPLICATED ASSOCIATIONS TO COPD, GENETIC VARIATION ONLY PARTIALLY EXPLAINS THE SUSCEPTIBILITY TO LUNG DISEASE, AND SUGGESTS THE RELEVANCE OF EPIGENETIC INVESTIGATIONS. WE PERFORMED GENOME-WIDE DNA METHYLATION PROFILING IN HOMOGENIZED LUNG TISSUE SAMPLES FROM 46 CONTROL SUBJECTS WITH NORMAL LUNG FUNCTION AND 114 SUBJECTS WITH COPD, ALL FORMER SMOKERS. THE DIFFERENTIALLY METHYLATED LOCI WERE INTEGRATED WITH PREVIOUS GENOME-WIDE ASSOCIATION STUDY RESULTS. THE TOP 535 DIFFERENTIALLY METHYLATED SITES, FILTERED FOR A MINIMUM MEAN METHYLATION DIFFERENCE OF 5% BETWEEN CASES AND CONTROLS, WERE ENRICHED FOR CPG SHELVES AND SHORES. PATHWAY ANALYSIS REVEALED ENRICHMENT FOR TRANSCRIPTION FACTORS. THE TOP DIFFERENTIALLY METHYLATED SITES FROM THE INTERSECTION WITH PREVIOUS GWAS WERE IN CHRM1, GLT1D1, AND C10ORF11; SORTED BY GWAS P-VALUE, THE TOP SITES INCLUDED FRMD4A, THSD4, AND C10ORF11. EPIGENETIC ASSOCIATION STUDIES COMPLEMENT GENETIC ASSOCIATION STUDIES TO IDENTIFY GENES POTENTIALLY INVOLVED IN COPD PATHOGENESIS. ENRICHMENT FOR GENES IMPLICATED IN ASTHMA AND LUNG FUNCTION AND FOR TRANSCRIPTION FACTORS SUGGESTS THE POTENTIAL PATHOGENIC RELEVANCE OF GENES IDENTIFIED THROUGH DIFFERENTIAL METHYLATION AND THE INTERSECTION WITH A BROADER RANGE OF GWAS ASSOCIATIONS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
6 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
7 3482  30 IDENTIFICATION OF CDC5L AS BRIDGE GENE BETWEEN CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND LUNG ADENOCARCINOMA. AIM: THIS STUDY AIMED TO EXPLORE THE GENETIC AND EPIGENETIC SIMILARITIES BETWEEN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND LUNG ADENOCARCINOMA (LUAD). MATERIALS & METHODS: WE MAINLY USED WEIGHTED CORRELATION NETWORK ANALYSIS, PROTEIN-PROTEIN INTERACTION NETWORK AND PIVOT ANALYSIS TO IDENTIFY HUB MODULES, BRIDGE REGULATORS, BRIDGE GENES AND HUB-DRIVING GENES IN BOTH DISEASES AND CARRIED OUT VERIFYING USING EXTERNAL DATASETS. RESULTS: WE IDENTIFIED EIGHT BRIDGE REGULATORS, 19 KEY MOLECULES IN THE COPD MODEL AND TEN KEY MOLECULES IN THE LUAD MODEL. MOREOVER, WE VALIDATED THAT CDC5L COULD BE A RELIABLE BIOMARKER IN COPD AND MAY REGULATE CELL PROLIFERATION AND METASTASIS IN LUAD VIA PROMOTER METHYLATION. CONCLUSION: OUR RESULTS MIGHT FORM A THEORETICAL FOUNDATION FOR FUTURE STUDY AT AN EPIGENETIC LEVEL.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
8 1909  48 ENRICHMENT OF GENOMIC PATHWAYS BASED ON DIFFERENTIAL DNA METHYLATION PROFILES ASSOCIATED WITH CHRONIC MUSCULOSKELETAL PAIN IN OLDER ADULTS: AN EXPLORATORY STUDY. OUR STUDY AIMED TO IDENTIFY DIFFERENTIALLY METHYLATED CPGS/REGIONS AND THEIR ENRICHED GENOMIC PATHWAYS ASSOCIATED WITH UNDERLYING CHRONIC MUSCULOSKELETAL PAIN IN OLDER INDIVIDUALS. WE RECRUITED COGNITIVELY HEALTHY OLDER ADULTS WITH (N = 20) AND WITHOUT (N = 9) SELF-REPORTED MUSCULOSKELETAL PAIN AND COLLECTED DNA FROM PERIPHERAL BLOOD THAT WAS ANALYZED USING METHYLATIONEPIC ARRAYS. WE IDENTIFIED 31,739 HYPERMETHYLATED CPG AND 10,811 HYPOMETHYLATED CPG PROBES (PS </= 0.05). ALL CPG PROBES WERE CLUSTERED INTO 5966 REGIONS, AMONG WHICH 600 REGIONS WERE DIFFERENTIALLY METHYLATED AT P </= 0.05 LEVEL, INCLUDING 294 HYPERMETHYLATED REGIONS AND 306 HYPOMETHYLATED REGIONS (DIFFERENTIALLY METHYLATED REGIONS). INGENUITY PATHWAY ENRICHMENT ANALYSIS REVEALED THAT THE PAIN-RELATED DIFFERENTIALLY METHYLATED REGIONS WERE ENRICHED ACROSS MULTIPLE PATHWAYS. THE TOP 10 CANONICAL PATHWAYS WERE LINKED TO CELLULAR SIGNALING PROCESSES RELATED TO IMMUNE RESPONSES (I.E. ANTIGEN PRESENTATION, PROGRAMED CELL DEATH 1 RECEPTOR/PD-1 LIGAND 1, INTERLEUKIN-4, OX40 SIGNALING, T CELL EXHAUSTION, AND APOPTOSIS) AND GAMMA-AMINOBUTYRIC ACID RECEPTOR SIGNALING. FURTHER, WEIGHTED GENE CORRELATION NETWORK ANALYSIS REVEALED A COMETHYLATION NETWORK MODULE IN THE PAIN GROUP THAT WAS NOT PRESERVED IN THE CONTROL GROUP, WHERE THE HUB GENE WAS THE CYCLIC ADENOSINE MONOPHOSPHATE-DEPENDENT TRANSCRIPTION FACTOR ATF-2. OUR PRELIMINARY FINDINGS PROVIDE NEW EPIGENETIC INSIGHTS INTO THE ROLE OF ABERRANT IMMUNE SIGNALING IN MUSCULOSKELETAL PAIN IN OLDER ADULTS WHILE FURTHER SUPPORTING INVOLVEMENT OF DYSFUNCTIONAL GABAERGIC SIGNALING MECHANISMS IN CHRONIC PAIN. OUR FINDINGS NEED TO BE URGENTLY REPLICATED IN LARGER COHORTS AS THEY MAY SERVE AS A BASIS FOR DEVELOPING AND TARGETING FUTURE INTERVENTIONS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
9 2664  45 ESTABLISHMENT AND VALIDATION OF EXHAUSTED CD8+ T CELL FEATURE AS A PROGNOSTIC MODEL OF HCC. OBJECTIVES: THE EXHAUSTED CD8+T (TEX) CELLS ARE A UNIQUE CELL POPULATION OF ACTIVATED T CELLS THAT EMERGES IN RESPONSE TO PERSISTENT VIRAL INFECTION OR TUMOR ANTIGENS. TEX CELLS SHOWED THE CHARACTERISTICS OF AGING CELLS, INCLUDING WEAKENED SELF-RENEWAL ABILITY, EFFECTOR FUNCTION INHIBITION, SUSTAINED HIGH EXPRESSION OF INHIBITORY RECEPTORS INCLUDING PD-1, TIGIT, TIM-3, AND LAG-3, AND ALWAYS ACCOMPANIED BY METABOLIC AND EPIGENETIC REPROGRAMMING. TEX CELLS ARE GETTING MORE AND MORE ATTENTION IN RESEARCHING IMMUNE-RELATED DISEASES AND TUMOR IMMUNOTHERAPY. HOWEVER, STUDIES ON TEX-RELATED MODELS FOR TUMOR PROGNOSIS ARE STILL LACKING. WE HOPE TO ESTABLISH A RISK MODEL BASED ON TEX-RELATED GENES FOR HCC PROGNOSIS. METHODS: TEX-RELATED GEO DATASETS FROM DIFFERENT PATHOLOGIC FACTORS (CHRONIC HBV, CHRONIC HCV, AND TELOMERE SHORTENING) WERE ANALYZED RESPECTIVELY TO ACQUIRE DIFFERENTIALLY EXPRESSED GENES (DEGS) BY THE 'LIMMA' PACKAGE OF R. GENES WITH AT LEAST ONE INTERSECTION WERE INCORPORATED INTO TEX-RELATED GENE SET. GO, KEGG, AND GSEA ENRICHMENT ANALYSES WERE PRODUCED. HUB GENES AND THE PPI NETWORK WERE ESTABLISHED AND VISUALIZED BY THE STRING WEBSITE AND CYTOSCAPE SOFTWARE. TRANSCRIPTION FACTORS AND TARGETING SMALL MOLECULES WERE PREDICTED BY THE TRUST AND CLUE WEBSITES. THE TEX-RELATED HCC PROGNOSTIC MODEL WAS BUILT BY COX REGRESSION AND VERIFIED BASED ON DIFFERENT DATASETS. TUMOR IMMUNE DYSFUNCTION AND EXCLUSION (TIDE) AND SUBMAP ALGORITHMS TESTED IMMUNOTHERAPY SENSITIVITY. FINALLY, QRT-PCR AND FLOW CYTOMETRY WAS USED TO CONFIRM THE BIOINFORMATIC RESULTS. RESULTS: HUB GENES SUCH AS AKT1, CDC6, TNF AND THEIR UPSTREAM TRANSCRIPTION FACTOR ILF3, REGULATORY FACTOR X-ASSOCIATED PROTEIN, STAT3, JUN, AND RELA/NFKB1 WERE IDENTIFIED AS POTENTIAL MOTIVATORS FOR TEX. TEX-RELATED GENES SLC16A11, CACYBP, HSF2, AND ATG10 BUILT THE HCC PROGNOSTIC MODEL AND HELPED WITH IMMUNOTHERAPY SENSITIVITY PREDICTION. CONCLUSION: OUR STUDY DEMONSTRATED THAT TEX-RELATED GENES MIGHT PROVIDE ACCURATE PREDICTION FOR HCC PATIENTS IN CLINICAL DECISION-MAKING, PROGNOSTIC ASSESSMENT, AND IMMUNOTHERAPY. IN ADDITION, TARGETING THE HUB GENES OR TRANSCRIPTION FACTORS MAY HELP TO REVERSE T CELL FUNCTION AND ENHANCE THE EFFECT OF TUMOR IMMUNOTHERAPY.	2023	
                                                                                                                                                       
10 3764  35 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
11 5887  41 SYSTEMIC STEROID EXPOSURE IS ASSOCIATED WITH DIFFERENTIAL METHYLATION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE. RATIONALE: SYSTEMIC GLUCOCORTICOIDS ARE USED THERAPEUTICALLY TO TREAT A VARIETY OF MEDICAL CONDITIONS. EPIGENETIC PROCESSES SUCH AS DNA METHYLATION MAY REFLECT EXPOSURE TO GLUCOCORTICOIDS AND MAY BE INVOLVED IN MEDIATING THE RESPONSES AND SIDE EFFECTS ASSOCIATED WITH THESE MEDICATIONS. OBJECTIVES: TO TEST THE HYPOTHESIS THAT DIFFERENCES IN DNA METHYLATION ARE ASSOCIATED WITH CURRENT SYSTEMIC STEROID USE. METHODS: WE OBTAINED DNA METHYLATION DATA AT 27,578 CPG SITES IN 14,475 GENES THROUGHOUT THE GENOME IN TWO LARGE, INDEPENDENT COHORTS: THE INTERNATIONAL COPD GENETICS NETWORK (N(DISCOVERY) = 1,085) AND THE BOSTON EARLY ONSET COPD STUDY (N(REPLICATION) = 369). SITES WERE TESTED FOR ASSOCIATION WITH CURRENT SYSTEMIC STEROID USE USING GENERALIZED LINEAR MIXED MODELS. MEASUREMENTS AND MAIN RESULTS: A TOTAL OF 511 SITES DEMONSTRATED SIGNIFICANT DIFFERENTIAL METHYLATION BY SYSTEMIC CORTICOSTEROID USE IN ALL THREE OF OUR PRIMARY MODELS. PYROSEQUENCING VALIDATION CONFIRMED ROBUST DIFFERENTIAL METHYLATION AT CPG SITES ANNOTATED TO GENES SUCH AS SLC22A18, LRP3, HIPK3, SCNN1A, FXYD1, IRF7, AZU1, SIT1, GPR97, ABHD16B, AND RABGEF1. FUNCTIONAL ANNOTATION CLUSTERING DEMONSTRATED SIGNIFICANT ENRICHMENT IN INTRINSIC MEMBRANE COMPONENTS, HEMOSTASIS AND COAGULATION, CELLULAR ION HOMEOSTASIS, LEUKOCYTE AND LYMPHOCYTE ACTIVATION AND CHEMOTAXIS, PROTEIN TRANSPORT, AND RESPONSES TO NUTRIENTS. CONCLUSIONS: OUR ANALYSES SUGGEST THAT SYSTEMIC STEROID USE IS ASSOCIATED WITH SITE-SPECIFIC DIFFERENTIAL METHYLATION THROUGHOUT THE GENOME. DIFFERENTIALLY METHYLATED CPG SITES WERE FOUND IN BIOLOGICALLY PLAUSIBLE AND PREVIOUSLY UNSUSPECTED PATHWAYS; THESE GENES AND PATHWAYS MAY BE RELEVANT IN THE DEVELOPMENT OF NOVEL TARGETED THERAPIES.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
12 2730  44 EXPLORING THE BIOLOGICAL FUNCTION OF IMMUNE CELL-RELATED GENES IN HUMAN IMMUNODEFICIENCY VIRUS (HIV)-1 INFECTION BASED ON WEIGHTED GENE CO-EXPRESSION NETWORK ANALYSIS (WGCNA). BACKGROUND: ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS) IS A CHRONIC INFECTIOUS DISEASE CHARACTERIZED BY CONSISTENT IMMUNE DYSFUNCTION. THE OBJECTIVE OF THIS STUDY IS TO DETERMINE WHETHER IMMUNE CELL-RELATED GENES CAN BE USED AS BIOMARKERS FOR THE OCCURRENCE OF AIDS AND POTENTIAL MOLECULAR MECHANISMS. METHODS: A WEIGHTED GENE CO-EXPRESSION NETWORK ANALYSIS WAS PERFORMED USING THE GSE6740 DATASET FROM THE GENE EXPRESSION SYNTHESIS DATABASE TO IDENTIFY THE HUB GENE, WHICH CONTAINED MICROARRAY DATA FROM HIV-1 POSITIVE (HIV-1(+)) AND HIV-1 NEGATIVE (HIV-1(-)) INDIVIDUALS. THE HIV-1(+)-RELATED DIFFERENTIALLY EXPRESSED GENES WERE THEN IDENTIFIED USING THE LIMMA PACKAGE. SUBSEQUENTLY, THE CHARACTERISTIC IMMUNE CELL-RELATED GENES WERE IDENTIFIED AS DIAGNOSTIC BIOMARKERS FOR HIV-1(+) USING THE RANDOM FOREST MODEL (RF), SUPPORT VECTOR MACHINE MODEL, AND GENERALIZED LINEAR MODEL. RESULTS: MEDARKGREEN EXHIBITED THE STRONGEST CORRELATION WITH HIV CLINICAL FEATURES OF ANY OF THESE MODULES. AS THE BEST MODEL FOR DIAGNOSING HIV-1(+/-), RF WAS USED TO SELECT FOUR CRITICAL IMMUNE CELL-RELATED GENES, NAMELY, ARRB1, DPEP2, LTBP3, AND RGCC, AND A NOMOGRAM MODEL WAS CREATED TO PREDICT THE OCCURRENCE OF HIV-1 INFECTION BASED ON FOUR KEY IMMUNE CELL-RELATED GENES. DIAGNOSTIC GENES WERE SHOWN TO BE ENGAGED IN IMMUNE-RELATED PATHWAYS, SUGGESTING THAT IMMUNOLOGICAL MOLECULES, IMMUNE CELLS, AND IMMUNE PATHWAYS ALL HAVE A ROLE IN HIV-1 INFECTION. THE CTD DATABASE WAS EXPLORED FOR PROSPECTIVE MEDICATIONS OR MOLECULAR COMPOUNDS THAT MIGHT BE UTILIZED TO TREAT HIV-1(+) PATIENTS. = MOREOVER, IN HIV-1(+) INDIVIDUALS, THE CERNA NETWORK REVEALED THAT ARRB1, DPEP2, LTBP3, AND RGCC COULD BE REGULATED BY LNCRNAS THROUGH THE CORRESPONDING MIRNAS. ULTIMATELY, RT-PCR RESULTS FROM CLINICAL BLOOD SAMPLES DEMONSTRATED THAT THE FOUR DIAGNOSTIC GENES WERE SIGNIFICANTLY DOWNREGULATED IN HIV-1(+) PATIENTS. CONCLUSION: WE SCREENED FOUR IMMUNE CELL-RELATED GENES, ARRB1, DPEP2, LTBP3, AND RGCC, WHICH MAY BE CONSIDERED AS THE DIAGNOSTIC MARKERS FOR HIV-1/AIDS. OUR FINDINGS REVEAL THAT IMMUNE RELATED GENES AND PATHWAYS INVOLVED IN HIV-1 PATHOGENESIS WERE REGULATED ON BOTH GENETIC AND EPIGENETIC LEVELS BY CONSTRUCTING A CERNA NETWORK ASSOCIATED WITH LNCRNA.	2022	
                                                                     
13 2767  39 EXPRESSION, PROGNOSTIC VALUE, AND FUNCTIONAL MECHANISM OF THE KDM5 FAMILY IN PANCREATIC CANCER. BACKGROUND: THE HISTONE LYSINE DEMETHYLASE KDM5 FAMILY IS AN IMPORTANT EPIGENETIC STATE-MODIFYING ENZYME FAMILY. INCREASING EVIDENCE SUPPORTS THAT EPIGENETIC ABNORMALITIES IN THE KDM5 FAMILY ARE RELATED TO MULTIPLE CANCERS IN HUMANS. HOWEVER, THE ROLE OF THE KDM5 FAMILY IN PANCREATIC CANCER IS NOT CLEAR, AND RELATED RESEARCH IS VERY SCARCE. METHODS: R SOFTWARE, KAPLAN-MEIER PLOTTER, CBIOPORTAL, TIMER, LINKEDOMICS, STRING, METASCAPE, TISIDB, AND THE GSCA LITE ONLINE TOOL WERE UTILIZED FOR BIOINFORMATICS ANALYSIS. RESULTS: KDM5A/B/C WAS SIGNIFICANTLY OVEREXPRESSED IN MANY KINDS OF TUMOR TISSUES, INCLUDING PANCREATIC ADENOCARCINOMA (PAAD), WHILE THE EXPRESSION OF KDM5D WAS SIGNIFICANTLY DOWNREGULATED. THE HIGH EXPRESSION OF KDM5A/B/C WAS RELATED TO POOR CLINICAL FEATURES, SUCH AS WORSE TREATMENT EFFICACY, HIGHER TUMOR GRADE, AND MORE ADVANCED CLINICAL STAGE. PATIENTS WITH A FAMILY HISTORY OF BREAST CANCER AND MELANOMA, HISTORY OF DRINKING OR HISTORY CHRONIC PANCREATITIS WERE MORE LIKELY TO HAVE KDM5A/B/C GENE ABNORMALITIES, WHICH WERE RELATED TO A VARIETY OF ADVERSE CLINICAL FEATURES. THE RESULTS OF GENE ONTOLOGY (GO) AND KYOTO ENCYCLOPEDIA OF GENES AND GENOMES (KEGG) PATHWAY ANALYSES OF THE KDM5 FAMILY AND ITS 800 CO-EXPRESSED GENES SHOWED THAT MANY GENE TERMS RELATED TO CELL PROLIFERATION, MIGRATION AND MANY CARCINOGENIC PATHWAYS. NOTABLY, WE FOUND THAT THE EXPRESSION LEVEL OF KDM5A/B/C WAS POSITIVELY CORRELATED WITH THE EXPRESSION OF MULTIPLE KEY DRIVER GENES SUCH AS KRAS, BRCA1, AND BRCA2 ETC. IN ADDITION, PPI NETWORK ANALYSIS SHOWED KDM5 FAMILY PROTEINS HAVE STRONG INTERACTIONS WITH HISTONE DEACETYLASE FAMILY 1 (HDAC1), WHICH COULD MODIFY THE LYSINES OF HISTONE H3, AND CO-ACT ON MANY PATHWAYS, INCLUDING THE "LONGEVITY-REGULATING PATHWAY" AND "NOTCH SIGNALING PATHWAY". MOREOVER, THE UPREGULATION OF KDM5A/B/C EXPRESSION WAS ASSOCIATED WITH AN INCREASE IN THE INFILTRATION OF B CELLS, CD8(+) T CELLS AND OTHER INFILTRATING IMMUNE LYMPHOCYTES AND THE EXPRESSION LEVELS OF IMMUNE MOLECULES SUCH AS NT5E AND CD274. INTERESTINGLY, THE OVEREXPRESSION OF KDM5A/C WAS ALSO CORELATED WITH REDUCED SENSITIVITY OF PANCREATIC CANCER CELLS TO MANY KINDS OF PANCREATIC CANCER-TARGETING OR CHEMOTHERAPEUTIC DRUGS, INCLUDING AXITINIB AND GEMCITABINE. CONCLUSION: KDM5 FAMILY MEMBERS MAY BE PROGNOSTIC MARKERS AND NEW THERAPEUTIC TARGETS FOR PATIENTS WITH PANCREATIC CANCER.	2022	

14 3959  34 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
15 1081  36 CLUSTERED PROTOCADHERINS METHYLATION ALTERATIONS IN CANCER. BACKGROUND: CLUSTERED PROTOCADHERINS (PCDHS) MAP IN TANDEM AT HUMAN CHROMOSOME 5Q31 AND COMPRISE THREE MULTI-GENES CLUSTERS: ALPHA-, BETA- AND GAMMA-PCDH. THE EXPRESSION OF THIS CLUSTER CONSISTS OF A COMPLEX MECHANISM INVOLVING DNA HUB FORMATION THROUGH DNA-CCTC BINDING FACTOR (CTCF) INTERACTION. METHYLATION ALTERATIONS CAN AFFECT THIS INTERACTION, LEADING TO TRANSCRIPTIONAL DYSREGULATION. IN CANCER, CLUSTERED PCDHS UNDERGO A MECHANISM OF LONG-RANGE EPIGENETIC SILENCING BY HYPERMETHYLATION. RESULTS: IN THIS STUDY, WE DETECTED FREQUENT METHYLATION ALTERATIONS AT CPG ISLANDS ASSOCIATED TO THESE CLUSTERED PCDHS IN ALL THE SOLID TUMOURS ANALYSED (COLORECTAL, GASTRIC AND BILIARY TRACT CANCERS, PILOCYTIC ASTROCYTOMA), BUT NOT HEMATOLOGIC NEOPLASMS SUCH AS CHRONIC LYMPHOCYTIC LEUKEMIA. IMPORTANTLY, SEVERAL ALTERED CPG ISLANDS WERE ASSOCIATED WITH CTCF BINDING SITES. INTERESTINGLY, OUR ANALYSIS REVEALED A HYPOMETHYLATION EVENT IN PILOCYTIC ASTROCYTOMA, SUGGESTING THAT IN NEURONAL TISSUE, WHERE PCDHS ARE HIGHLY EXPRESSED, THESE GENES BECOME HYPOMETHYLATED IN THIS TYPE OF CANCER. ON THE OTHER HAND, IN TISSUES WHERE PCDHS ARE LOWLY EXPRESSED, THESE CPG ISLANDS ARE TARGETED BY DNA METHYLATION. IN FACT, PCDH-ASSOCIATED CPG ISLANDS RESULTED HYPERMETHYLATED IN GASTROINTESTINAL TUMOURS. CONCLUSIONS: OUR STUDY HIGHLIGHTED A STRONG ALTERATION OF THE CLUSTERED PCDHS METHYLATION PATTERN IN THE ANALYSED SOLID CANCERS AND SUGGESTED THESE METHYLATION ABERRATIONS IN THE CPG ISLANDS ASSOCIATED WITH PCDH GENES AS POWERFUL DIAGNOSTIC BIOMARKERS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
16 5567  41 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	
                                                                                                                                                    
17 1990  33 EPIGENETIC ANALYSIS OF PAGET'S DISEASE OF BONE IDENTIFIES DIFFERENTIALLY METHYLATED LOCI THAT PREDICT DISEASE STATUS. PAGET'S DISEASE OF BONE (PDB) IS CHARACTERIZED BY FOCAL INCREASES IN DISORGANIZED BONE REMODELING. THIS STUDY AIMS TO CHARACTERIZE PDB-ASSOCIATED CHANGES IN DNA METHYLATION PROFILES IN PATIENTS' BLOOD. META-ANALYSIS OF DATA FROM THE DISCOVERY AND CROSS-VALIDATION SET, EACH COMPRISING 116 PDB CASES AND 130 CONTROLS, REVEALED SIGNIFICANT DIFFERENCES IN DNA METHYLATION AT 14 CPG SITES, 4 CPG ISLANDS, AND 6 GENE-BODY REGIONS. THESE LOCI, INCLUDING TWO CHARACTERIZED AS FUNCTIONAL THROUGH EXPRESSION QUANTITATIVE TRAIT-METHYLATION ANALYSIS, WERE ASSOCIATED WITH FUNCTIONS RELATED TO OSTEOCLAST DIFFERENTIATION, MECHANICAL LOADING, IMMUNE FUNCTION, AND VIRAL INFECTION. A MULTIVARIATE CLASSIFIER BASED ON DISCOVERY SAMPLES WAS FOUND TO DISCRIMINATE PDB CASES AND CONTROLS FROM THE CROSS-VALIDATION WITH A SENSITIVITY OF 0.84, SPECIFICITY OF 0.81, AND AN AREA UNDER CURVE OF 92.8%. IN CONCLUSION, THIS STUDY HAS SHOWN FOR THE FIRST TIME THAT EPIGENETIC FACTORS CONTRIBUTE TO THE PATHOGENESIS OF PDB AND MAY OFFER DIAGNOSTIC MARKERS FOR PREDICTION OF THE DISEASE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
18 5238  36 PROFILING OF H3K27AC REVEALS THE INFLUENCE OF ASTHMA ON THE EPIGENOME OF THE AIRWAY EPITHELIUM. BACKGROUND: ASTHMA IS A CHRONIC AIRWAY DISEASE DRIVEN BY COMPLEX GENETIC-ENVIRONMENTAL INTERACTIONS. THE ROLE OF EPIGENETIC MODIFICATIONS IN BRONCHIAL EPITHELIAL CELLS (BECS) IN ASTHMA IS POORLY UNDERSTOOD. METHODS: WE PILOTED GENOME-WIDE PROFILING OF THE ENHANCER-ASSOCIATED HISTONE MODIFICATION H3K27AC IN BECS FROM PEOPLE WITH ASTHMA (N = 4) AND HEALTHY CONTROLS (N = 3). RESULTS: WE IDENTIFIED N = 4,321 (FDR < 0.05) REGIONS EXHIBITING DIFFERENTIAL H3K27AC ENRICHMENT BETWEEN ASTHMA AND HEALTH, CLUSTERING AT GENES ASSOCIATED PREDOMINATELY WITH EPITHELIAL PROCESSES (EMT). WE IDENTIFIED INITIAL EVIDENCE OF ASTHMA-ASSOCIATED SUPER-ENHANCERS ENCOMPASSING GENES ENCODING TRANSCRIPTION FACTORS (TP63) AND ENZYMES REGULATING LIPID METABOLISM (PTGS1). WE INTEGRATED PUBLISHED DATASETS TO IDENTIFY EPITHELIUM-SPECIFIC TRANSCRIPTION FACTORS ASSOCIATED WITH H3K27AC IN ASTHMA (TP73) AND IDENTIFY INITIAL RELATIONSHIPS BETWEEN ASTHMA-ASSOCIATED CHANGES IN H3K27AC AND TRANSCRIPTIONAL PROFILES. FINALLY, WE INVESTIGATED THE POTENTIAL OF CRISPR-BASED APPROACHES TO FUNCTIONALLY EVALUATE H3K27AC-ASTHMA LANDSCAPE IN VITRO BY IDENTIFYING GUIDE-RNAS CAPABLE OF TARGETING ACETYLATION TO ASTHMA DERS AND INDUCING GENE EXPRESSION (TLR3). CONCLUSION: OUR SMALL PILOT STUDY VALIDATES GENOME-WIDE APPROACHES FOR DECIPHERING EPIGENETIC MECHANISMS UNDERLYING ASTHMA PATHOGENESIS IN THE AIRWAYS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
19 1598  34 DNA METHYLATION SIGNATURE IN MONONUCLEAR CELLS AND PROINFLAMMATORY CYTOKINES MAY DEFINE MOLECULAR SUBTYPES IN SPORADIC MENIERE DISEASE. MENIERE DISEASE (MD) IS A MULTIFACTORIAL DISORDER OF THE INNER EAR CHARACTERIZED BY VERTIGO ATTACKS ASSOCIATED WITH SENSORINEURAL HEARING LOSS AND TINNITUS WITH A SIGNIFICANT HERITABILITY. ALTHOUGH MD HAS BEEN ASSOCIATED WITH SEVERAL GENES, NO EPIGENETIC STUDIES HAVE BEEN PERFORMED ON MD. HERE WE PERFORMED WHOLE-GENOME BISULFITE SEQUENCING IN 14 MD PATIENTS AND SIX HEALTHY CONTROLS, WITH THE AIM OF IDENTIFYING AN MD METHYLATION SIGNATURE AND POTENTIAL DISEASE MECHANISMS. WE OBSERVED A HIGH NUMBER OF DIFFERENTIALLY METHYLATED CPGS (DMC) WHEN COMPARING MD PATIENTS TO CONTROLS (N= 9545), SEVERAL OF THEM IN HEARING LOSS GENES, SUCH AS PCDH15,&NBSP;ADGRV1 AND CDH23. BIOINFORMATIC ANALYSES OF DMCS AND CIS-REGULATORY REGIONS PREDICTED PHENOTYPES RELATED TO ABNORMAL EXCITATORY POSTSYNAPTIC CURRENTS, ABNORMAL NMDA-MEDIATED RECEPTOR CURRENTS AND ABNORMAL GLUTAMATE-MEDIATED RECEPTOR CURRENTS WHEN COMPARING MD TO CONTROLS. MOREOVER, WE IDENTIFIED VARIOUS DMCS IN GENES PREVIOUSLY ASSOCIATED WITH COCHLEOVESTIBULAR PHENOTYPES IN MICE. WE HAVE ALSO FOUND 12 UNDERMETHYLATED REGIONS (UMR) THAT WERE EXCLUSIVE TO MD, INCLUDING TWO UMR IN AN INTER CPG ISLAND IN THE PHB GENE. WE SUGGEST THAT THE DNA METHYLATION SIGNATURE ALLOWS DISTINGUISHING BETWEEN MD PATIENTS AND CONTROLS. THE ENRICHMENT ANALYSIS CONFIRMS PREVIOUS FINDINGS OF A CHRONIC INFLAMMATORY PROCESS UNDERLYING MD.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
20 3468  38 HYPOXIA-INDUCED DNA HYPERMETHYLATION IN HUMAN PULMONARY FIBROBLASTS IS ASSOCIATED WITH THY-1 PROMOTER METHYLATION AND THE DEVELOPMENT OF A PRO-FIBROTIC PHENOTYPE. BACKGROUND: PULMONARY FIBROSIS IS A DEBILITATING AND LETHAL DISEASE WITH NO EFFECTIVE TREATMENT OPTIONS. UNDERSTANDING THE PATHOLOGICAL PROCESSES AT PLAY WILL DIRECT THE APPLICATION OF NOVEL THERAPEUTIC AVENUES. HYPOXIA HAS BEEN IMPLICATED IN THE PATHOGENESIS OF PULMONARY FIBROSIS YET THE PRECISE MECHANISM BY WHICH IT CONTRIBUTES TO DISEASE PROGRESSION REMAINS TO BE FULLY ELUCIDATED. IT HAS BEEN SHOWN THAT CHRONIC HYPOXIA CAN ALTER DNA METHYLATION PATTERNS IN TUMOUR-DERIVED CELL LINES. THIS EPIGENETIC ALTERATION CAN INDUCE CHANGES IN CELLULAR PHENOTYPE WITH PROMOTER METHYLATION BEING ASSOCIATED WITH GENE SILENCING. OF PARTICULAR RELEVANCE TO IDIOPATHIC PULMONARY FIBROSIS (IPF) IS THE OBSERVATION THAT THY-1 PROMOTER METHYLATION IS ASSOCIATED WITH A MYOFIBROBLAST PHENOTYPE WHERE LOSS OF THY-1 OCCURS ALONGSIDE INCREASED ALPHA SMOOTH MUSCLE ACTIN (ALPHA-SMA) EXPRESSION. THE INITIAL AIM OF THIS STUDY WAS TO DETERMINE WHETHER HYPOXIA REGULATES DNA METHYLATION IN NORMAL HUMAN LUNG FIBROBLASTS (CCD19LU). AS IT HAS BEEN REPORTED THAT HYPOXIA SUPPRESSES THY-1 EXPRESSION DURING LUNG DEVELOPMENT WE ALSO STUDIED THE EFFECT OF HYPOXIA ON THY-1 PROMOTER METHYLATION AND GENE EXPRESSION. METHODS: CCD19LU WERE GROWN FOR UP TO 8 DAYS IN HYPOXIA AND ASSESSED FOR GLOBAL CHANGES IN DNA METHYLATION USING FLOW CYTOMETRY. REAL-TIME PCR WAS USED TO QUANTIFY EXPRESSION OF THY-1, ALPHA-SMA, COLLAGEN I AND III. GENOMIC DNA WAS BISULPHITE TREATED AND METHYLATION SPECIFIC PCR (MSPCR) WAS USED TO EXAMINE THE METHYLATION STATUS OF THE THY-1 PROMOTER. RESULTS: SIGNIFICANT GLOBAL HYPERMETHYLATION WAS DETECTED IN HYPOXIC FIBROBLASTS RELATIVE TO NORMOXIC CONTROLS AND WAS ACCOMPANIED BY INCREASED EXPRESSION OF MYOFIBROBLAST MARKERS. THY-1 MRNA EXPRESSION WAS SUPPRESSED IN HYPOXIC CELLS, WHICH WAS RESTORED WITH THE DEMETHYLATING AGENT 5-AZA-2'-DEOXYCYTIDINE. MSPCR REVEALED THAT THY-1 BECAME METHYLATED FOLLOWING FIBROBLAST EXPOSURE TO 1% O2. CONCLUSION: THESE DATA SUGGEST THAT GLOBAL AND GENE-SPECIFIC CHANGES IN DNA METHYLATION MAY PLAY AN IMPORTANT ROLE IN FIBROBLAST FUNCTION IN HYPOXIA.	2012