1 3758 131 INTEGRATED MRNA AND MICRORNA TRANSCRIPTOME PROFILING DURING DIFFERENTIATION OF HUMAN NASAL POLYP EPITHELIUM REVEALS AN ALTERED CILIOGENESIS. BACKGROUND: HUMAN ADULT BASAL STEM/PROGENITOR CELLS (BSCS) OBTAINED FROM CHRONIC RHINOSINUSITIS WITH NASAL POLYPS (CRSWNP) WHEN DIFFERENTIATED IN AN AIR-LIQUID INTERFACE (ALI) USUALLY PROVIDE A PSEUDOSTRATIFIED AIRWAY EPITHELIUM WITH SIMILAR ABNORMALITIES THAN ORIGINAL IN VIVO PHENOTYPE. HOWEVER, THE INTRINSIC MECHANISMS REGULATING THIS COMPLEX PROCESS ARE NOT WELL DEFINED AND THEIR UNDERSTANDING COULD OFFER POTENTIAL NEW THERAPIES FOR CRSWNP (INCURABLE DISEASE). METHODS: WE PERFORMED A TRANSCRIPTOME-WIDE ANALYSIS DURING IN VITRO MUCOCILIARY DIFFERENTIATION OF HUMAN ADULT BSCS FROM CRSWNP, COMPARED TO THOSE ISOLATED FROM CONTROL NASAL MUCOSA (CONTROL-NM), IN ORDER TO IDENTIFY WHICH KEY MRNA AND MICRORNAS ARE REGULATING THIS COMPLEX PROCESS IN PATHOLOGICAL AND HEALTHY CONDITIONS. RESULTS: A NUMBER OF GENES, MIRS, BIOLOGICAL PROCESSES, AND PATHWAYS WERE IDENTIFIED DURING MUCOCILIARY DIFFERENTIATION OF BOTH CRSWNP AND CONTROL-NM EPITHELIA, AND NOTABLY, WE HAVE DEMONSTRATED FOR THE FIRST TIME THAT GENETIC TRANSCRIPTIONAL PROGRAM RESPONSIBLE OF CILIOGENESIS AND CILIA FUNCTION IS SIGNIFICANTLY IMPAIRED IN CRSWNP EPITHELIUM, PRESUMABLY PRODUCED BY AN ALTERED EXPRESSION OF MICRORNAS, PARTICULARLY OF THOSE MIRS BELONGING TO MIR-34 AND MI-449 FAMILIES. CONCLUSIONS: THIS STUDY PROVIDES FOR THE FIRST TIME A NOVEL INSIGHT INTO THE MOLECULAR BASIS OF SINONASAL MUCOCILIARY DIFFERENTIATION, DEMONSTRATING THAT TRANSCRIPTOME RELATED TO CILIOGENESIS AND CILIA FUNCTION IS SIGNIFICANTLY IMPAIRED DURING DIFFERENTIATION OF CRSWNP EPITHELIUM DUE TO AN ALTERED EXPRESSION OF MICRORNAS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
2 6349  38 THE ROLE OF EPIGENETICS IN THE CHRONIC SINUSITIS WITH NASAL POLYP. PURPOSE OF REVIEW: CHRONIC RHINOSINUSITIS WITH NASAL POLYPS (CRSWNP) IS A COMMON AND HETEROGENEOUS INFLAMMATORY DISEASE. THE UNDERLYING EPIGENETIC MECHANISMS AND TREATMENT OF CRSWNP ARE PARTIALLY UNDERSTOOD. OF THE DIFFERENT EPIGENETIC CHANGES IN CRSWNP, HISTONE DEACETYLASES (HDACS), METHYLATION OF DNA, AND THE LEVELS OF MIRNA ARE WIDELY STUDIED. HERE, WE REVIEW THE HUMAN STUDIES OF EPIGENETIC MECHANISMS IN CRSWNP. RECENT FINDINGS: THE PROMOTERS OF COL18A1, PTGES, PLAT, AND TSLP GENES ARE HYPERMETHYLATED IN CRSWNP COMPARED WITH THOSE OF CONTROLS, WHILE THE PROMOTERS OF PGDS, ALOX5AP, LTB4R, IL-8, AND FZD5 GENES ARE HYPOMETHYLATED IN CRSWNP. PROMOTER HYPERMETHYLATION SUPPRESSES THE GENE EXPRESSION, WHILE PROMOTER HYPOMETHYLATION INCREASES THE GENE EXPRESSION. STUDIES HAVE SHOWN THE ELEVATION IN THE LEVELS OF HDAC2, HDAC4, AND H3K4ME3 IN CRSWNP. IN CRSWNP PATIENTS, THERE IS ALSO AN UPREGULATION OF CERTAIN MIRNAS INCLUDING MIR-125B, MIR-155, MIR-19A, MIR-142-3P, AND MIR-21 AND DOWNREGULATION OF MIR-4492. EPIGENETICS TAKES PART IN THE IMMUNOLOGY OF CRSWNP AND MAY GIVE RISE TO ENDOTYPES OF CRSWNP. BOTH HDAC2 AND THE MIRNA INCLUDING MIR-18A, MIR-124A, AND MIR-142-3P MAY TAKE FUNCTION IN THE REGULATION OF GLUCOCORTICOID RESISTANCE. HDAC INHIBITORS AND KDM2B HAVE SHOWN EFFECTIVENESS IN DECREASING NASAL POLYP, AND DNA METHYLTRANSFERASE (DNMT) OR HDAC INHIBITORS MAY HAVE A POTENTIAL EFFICACY FOR THE TREATMENT OF CRSWNP. RECENT ADVANCES IN THE EPIGENETICS OF CRSWNP HAVE LED TO THE IDENTIFICATION OF SEVERAL POTENTIAL THERAPEUTIC TARGETS FOR THIS DISEASE. THE USE OF EPIGENETICS MAY PROVIDE NOVEL AND EFFECTIVE BIOMARKERS AND THERAPIES FOR THE TREATMENT OF NASAL POLYP.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
3 2406  46 EPIGENETIC RESPONSES TO RHINOVIRUS EXPOSURE IN AIRWAY EPITHELIAL CELLS ARE CORRELATED WITH KEY TRANSCRIPTIONAL PATHWAYS IN CHRONIC RHINOSINUSITIS. BACKGROUND: VIRUSES MAY DRIVE IMMUNE MECHANISMS RESPONSIBLE FOR CHRONIC RHINOSINUSITIS WITH NASAL POLYPOSIS (CRSWNP), BUT LITTLE IS KNOWN ABOUT THE UNDERLYING MOLECULAR MECHANISMS. OBJECTIVES: TO IDENTIFY EPIGENETIC AND TRANSCRIPTIONAL RESPONSES TO A COMMON UPPER RESPIRATORY PATHOGEN, RHINOVIRUS (RV), THAT ARE SPECIFIC TO PATIENTS WITH CRSWNP USING A PRIMARY SINONASAL EPITHELIAL CELL CULTURE MODEL. METHODS: AIRWAY EPITHELIAL CELLS WERE COLLECTED AT SURGERY FROM PATIENTS WITH CRSWNP (CASES) AND FROM CONTROLS WITHOUT SINUS DISEASE, CULTURED, AND THEN EXPOSED TO RV OR VEHICLE FOR 48 H. DIFFERENTIAL GENE EXPRESSION AND DNA METHYLATION (DNAM) BETWEEN CASES AND CONTROLS IN RESPONSE TO RV WERE DETERMINED USING LINEAR MIXED MODELS. WEIGHTED GENE CO-EXPRESSION ANALYSIS (WGCNA) WAS USED TO IDENTIFY (A) CO-REGULATED GENE EXPRESSION AND DNAM SIGNATURES, AND (B) GENES, PATHWAYS, AND REGULATORY MECHANISMS SPECIFIC TO CRSWNP. RESULTS: WE IDENTIFIED 5585 DIFFERENTIAL TRANSCRIPTIONAL AND 261 DNAM RESPONSES (FDR <0.10) TO RV BETWEEN CRSWNP CASES AND CONTROLS. THESE DIFFERENTIAL RESPONSES FORMED THREE CO-EXPRESSION/CO-METHYLATION MODULES THAT WERE RELATED TO CRSWNP AND THREE THAT WERE RELATED TO RV (BONFERRONI CORRECTED P < .01). MOST (95%) OF THE DIFFERENTIALLY METHYLATED CPGS (DMCS) WERE IN MODULES RELATED TO CRSWNP, WHEREAS THE DIFFERENTIALLY EXPRESSED GENES (DEGS) WERE MORE EQUALLY DISTRIBUTED BETWEEN THE CRSWNP- AND RV-RELATED MODULES. GENES IN THE CRSWNP-RELATED MODULES WERE ENRICHED IN KNOWN CRS AND/OR VIRAL RESPONSE IMMUNE PATHWAYS. CONCLUSION: RV ACTIVATES SPECIFIC EPIGENETIC PROGRAMS AND CORRELATED TRANSCRIPTIONAL NETWORKS IN THE SINONASAL EPITHELIUM OF INDIVIDUALS WITH CRSWNP. THESE NOVEL OBSERVATIONS SUGGEST EPIGENETIC SIGNATURES SPECIFIC TO PATIENTS WITH CRSWNP MODULATE RESPONSE TO VIRAL PATHOGENS AT THE MUCOSAL ENVIRONMENTAL INTERFACE. DETERMINING HOW VIRAL RESPONSE PATHWAYS ARE INVOLVED IN EPITHELIAL INFLAMMATION IN CRSWNP COULD LEAD TO THERAPEUTIC TARGETS FOR THIS BURDENSOME AIRWAY DISORDER.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
4 3014  34 GENETICS AND EPIGENETICS OF CHRONIC RHINOSINUSITIS. DISCERNING THE GENETICS AND EPIGENETICS OF CHRONIC RHINOSINUSITIS (CRS) MAY OPTIMIZE OUTCOMES THROUGH EARLY DIAGNOSTICS, PERSONALIZED AND NOVEL THERAPEUTICS, AND EARLY PROGNOSTICATION. CRS ASSOCIATED WITH CYSTIC FIBROSIS AND PRIMARY CILIARY DYSKINESIA HAS WELL-CHARACTERIZED GENETIC MUTATIONS. MOST CRS SUBJECTS, HOWEVER, DO NOT EXHIBIT IDENTIFIABLE MONOGENIC ALTERATIONS. CLUSTERING IN RELATED INDIVIDUALS IS SEEN IN CRS WITH NASAL POLYPS. SPOUSES OF SUBJECTS WITH CRS WITHOUT NASAL POLYPS ALSO MAY BE AT INCREASED RISK OF THE SAME DISEASE. THESE OBSERVATIONS GENERATE QUESTIONS ON GENETIC AND ENVIRONMENTAL INFLUENCES IN CRS. GENOME-WIDE ASSOCIATION STUDIES HAVE IDENTIFIED VARIATIONS AND POLYMORPHISMS BETWEEN CRS AND CONTROL SUBJECTS IN GENES RELATED TO INNATE AND ADAPTIVE IMMUNITY. CANDIDATE GENE AND TRANSCRIPTOMICS STUDIES HAVE INVESTIGATED AND IDENTIFIED GENETIC VARIATIONS RELATED TO IMMUNITY, INFLAMMATION, EPITHELIAL BARRIER FUNCTION, STRESS-RESPONSE, ANTIGEN PROCESSING, T-CELL REGULATION, AND CYTOKINES IN CRS. EPIGENETIC STUDIES HAVE IDENTIFIED MECHANISMS THROUGH WHICH ENVIRONMENTAL FACTORS MAY AFFECT THESE GENE FUNCTIONS. HOWEVER, CAUSALITY IS NOT DETERMINED FOR MOST VARIATIONS. INFERENCES DRAWN FROM THESE DATA MUST BE MEASURED BECAUSE MOST INVESTIGATIONS REPORT UNREPLICATED RESULTS FROM SMALL STUDY POPULATIONS. LARGE, REPLICATED STUDIES IN TIGHT COHORTS ACROSS DIVERSE POPULATIONS REMAIN A PRESSING NEED IN STUDYING CRS GENETICS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
5  327  42 ALLERGIC INFLAMMATORY MEMORY IN HUMAN RESPIRATORY EPITHELIAL PROGENITOR CELLS. BARRIER TISSUE DYSFUNCTION IS A FUNDAMENTAL FEATURE OF CHRONIC HUMAN INFLAMMATORY DISEASES(1). SPECIALIZED SUBSETS OF EPITHELIAL CELLS-INCLUDING SECRETORY AND CILIATED CELLS-DIFFERENTIATE FROM BASAL STEM CELLS TO COLLECTIVELY PROTECT THE UPPER AIRWAY(2-4). ALLERGIC INFLAMMATION CAN DEVELOP FROM PERSISTENT ACTIVATION(5) OF TYPE 2 IMMUNITY(6) IN THE UPPER AIRWAY, RESULTING IN CHRONIC RHINOSINUSITIS, WHICH RANGES IN SEVERITY FROM RHINITIS TO SEVERE NASAL POLYPS(7). BASAL CELL HYPERPLASIA IS A HALLMARK OF SEVERE DISEASE(7-9), BUT IT IS NOT KNOWN HOW THESE PROGENITOR CELLS(2,10,11) CONTRIBUTE TO CLINICAL PRESENTATION AND BARRIER TISSUE DYSFUNCTION IN HUMANS. HERE WE PROFILE PRIMARY HUMAN SURGICAL CHRONIC RHINOSINUSITIS SAMPLES (18,036 CELLS, N = 12) THAT SPAN THE DISEASE SPECTRUM USING SEQ-WELL FOR MASSIVELY PARALLEL SINGLE-CELL RNA SEQUENCING(12), REPORT TRANSCRIPTOMES FOR HUMAN RESPIRATORY EPITHELIAL, IMMUNE AND STROMAL CELL TYPES AND SUBSETS FROM A TYPE 2 INFLAMMATORY DISEASE, AND MAP KEY MEDIATORS. BY COMPARISON WITH NASAL SCRAPINGS (18,704 CELLS, N = 9), WE DEFINE SIGNATURES OF CORE, HEALTHY, INFLAMED AND POLYP SECRETORY CELLS. WE REVEAL MARKED DIFFERENCES BETWEEN THE EPITHELIAL COMPARTMENTS OF THE NON-POLYP AND POLYP CELLULAR ECOSYSTEMS, IDENTIFYING AND VALIDATING A GLOBAL REDUCTION IN CELLULAR DIVERSITY OF POLYPS CHARACTERIZED BY BASAL CELL HYPERPLASIA, CONCOMITANT DECREASES IN GLANDULAR CELLS, AND PHENOTYPIC SHIFTS IN SECRETORY CELL ANTIMICROBIAL EXPRESSION. WE DETECT AN ABERRANT BASAL PROGENITOR DIFFERENTIATION TRAJECTORY IN POLYPS, AND PROPOSE CELL-INTRINSIC(13), EPIGENETIC(14,15) AND EXTRINSIC FACTORS(11,16,17) THAT LOCK POLYP BASAL CELLS INTO THIS UNCOMMITTED STATE. FINALLY, WE FUNCTIONALLY DEMONSTRATE THAT EX VIVO CULTURED BASAL CELLS RETAIN INTRINSIC MEMORY OF IL-4/IL-13 EXPOSURE, AND TEST THE POTENTIAL FOR CLINICAL BLOCKADE OF THE IL-4 RECEPTOR ALPHA-SUBUNIT TO MODIFY BASAL AND SECRETORY CELL STATES IN VIVO. OVERALL, WE FIND THAT REDUCED EPITHELIAL DIVERSITY STEMMING FROM FUNCTIONAL SHIFTS IN BASAL CELLS IS A KEY CHARACTERISTIC OF TYPE 2 IMMUNE-MEDIATED BARRIER TISSUE DYSFUNCTION. OUR RESULTS DEMONSTRATE THAT EPITHELIAL STEM CELLS MAY CONTRIBUTE TO THE PERSISTENCE OF HUMAN DISEASE BY SERVING AS REPOSITORIES FOR ALLERGIC MEMORIES.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
6 3746  48 INSIGHTS INTO THE EPIGENETICS OF CHRONIC RHINOSINUSITIS WITH AND WITHOUT NASAL POLYPS: A SYSTEMATIC REVIEW. BACKGROUND: EPIGENETICS FACILITATES INSIGHTS ON THE IMPACT OF HOST ENVIRONMENT ON THE GENESIS OF CHRONIC RHINOSINUSITIS (CRS) THROUGH MODULATIONS OF HOST GENE EXPRESSION AND ACTIVITY. EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION CAUSE REVERSIBLE BUT HERITABLE CHANGES IN GENE EXPRESSION OVER GENERATIONS OF PROGENY, WITHOUT ALTERING THE DNA BASE-PAIR SEQUENCES. THESE STUDIES OFFER A CRITICAL UNDERSTANDING OF THE ENVIRONMENT-INDUCED CHANGES THAT RESULT IN HOST PREDISPOSITION TO DISEASE AND MAY HELP IN DEVELOPING NOVEL BIOMARKERS AND THERAPEUTICS. THE GOAL OF THIS SYSTEMATIC REVIEW IS TO SUMMARIZE THE CURRENT EVIDENCE ON EPIGENETICS OF CRS WITH A FOCUS ON CHRONIC RHINOSINUSITIS WITH NASAL POLYPS (CRSWNP) AND HIGHLIGHT GAPS THAT MERIT FURTHER RESEARCH. METHODS: A SYSTEMATIC REVIEW OF THE ENGLISH LANGUAGE LITERATURE WAS PERFORMED TO IDENTIFY INVESTIGATIONS RELATED TO EPIGENETIC STUDIES IN SUBJECTS WITH CRS. RESULTS: THE REVIEW IDENTIFIED 65 STUDIES. THESE HAVE FOCUSED ON DNA METHYLATION AND NON-CODING RNAS, WITH ONLY A FEW ON HISTONE DEACETYLATION, ALTERNATIVE POLYADENYLATION, AND CHROMATIN ACCESSIBILITY. STUDIES INCLUDE THOSE INVESTIGATING IN VIVO AND IN VITRO CHANGES OR BOTH. STUDIES ALSO INCLUDE ANIMAL MODELS OF CRS. ALMOST ALL HAVE BEEN CONDUCTED IN ASIA. THE GENOME-WIDE STUDIES OF DNA METHYLATION FOUND DIFFERENCES IN GLOBAL METHYLATION BETWEEN CRSWNP AND CONTROLS, WHILE OTHERS SPECIFICALLY FOUND SIGNIFICANT DIFFERENCES IN METHYLATION OF THE CPG SITES OF THE THYMIC STROMAL LYMPHOPOIETIN (TSLP), IL-8, AND PLAT. IN ADDITION, DNA METHYLTRANSFERASE INHIBITORS AND HISTONE DEACETYLASE INHIBITORS WERE STUDIED AS POTENTIAL THERAPEUTIC AGENTS. MAJORITY OF THE STUDIES INVESTIGATING NON-CODING RNAS FOCUSED ON MICRO-RNAS (MIRNA) AND FOUND DIFFERENCES IN GLOBAL EXPRESSION OF MIRNA LEVELS. THESE STUDIES ALSO REVEALED SOME PREVIOUSLY KNOWN AS WELL AS NOVEL TARGETS AND PATHWAYS SUCH AS TUMOR NECROSIS FACTOR ALPHA, TGF BETA-1, IL-10, EGR2, ARYL HYDROCARBON RECEPTOR, PI3K/AKT PATHWAY, MUCIN SECRETION, AND VASCULAR PERMEABILITY. OVERALL, THE STUDIES HAVE FOUND A DYSREGULATION IN PATHWAYS/GENES INVOLVING INFLAMMATION, IMMUNE REGULATION, TISSUE REMODELING, STRUCTURAL PROTEINS, MUCIN SECRETION, ARACHIDONIC ACID METABOLISM, AND TRANSCRIPTION. CONCLUSIONS: EPIGENETIC STUDIES IN CRS SUBJECTS SUGGEST THAT THERE IS LIKELY A MAJOR IMPACT OF THE ENVIRONMENT. HOWEVER, THESE ARE ASSOCIATION STUDIES AND DO NOT DIRECTLY IMPLY PATHOGENESIS. LONGITUDINAL STUDIES IN GEOGRAPHICALLY AND RACIALLY DIVERSE POPULATION COHORTS ARE NECESSARY TO QUANTIFY GENETIC VS. ENVIRONMENTAL RISKS FOR CRSWNP AND CRS WITHOUT NASAL POLYPS AND ASSESS HERITABILITY RISK, AS WELL AS DEVELOP NOVEL BIOMARKERS AND THERAPEUTIC AGENTS.	2023	

7 3019  33 GENETICS AND EPIGENETICS OF NASAL POLYPOSIS: A SYSTEMATIC REVIEW. CHRONIC RHINOSINUSITIS (CRS) IS AN INFLAMMATORY DISEASE OF THE NOSE AND PARANASAL SINUSES THAT IS OFTEN ASSOCIATED WITH NASAL POLYPOSIS (CRSWNP) IN THE MOST SEVERE CASES. AS IN OTHER COMPLEX DISEASES, GENETIC FACTORS ARE THOUGHT TO PLAY AN IMPORTANT ROLE IN THE RISK AND DEVELOPMENT OF THE DISEASE. ENVIRONMENT MAY ALSO MODULATE THE EPIGENETIC SIGNATURE IN AFFECTED PATIENTS. IN THE PRESENT SYSTEMATIC REVIEW, WE AIMED TO COMPILE ALL PUBLISHED DATA ON GENETIC AND EPIGENETIC VARIATIONS IN CRSWNP SINCE 2000. WE FOUND 104 ARTICLES, 24 OF WHICH WERE RELATED TO EPIGENETIC STUDIES. WE IDENTIFIED MORE THAN 150 GENETIC VARIANTS IN 99 GENES INVOLVED IN THE PATHOGENESIS OF NASAL POLYPOSIS. THESE WERE CLUSTERED INTO 8 MAIN NETWORKS, LINKING GENES INVOLVED IN INFLAMMATION AND IMMUNE RESPONSE (EG, MHC), CYTOKINE GENES (EG, TNF), LEUKOTRIENE METABOLISM, AND THE EXTRACELLULAR MATRIX. A TOTAL OF 89 MIRNAS WERE ALSO IDENTIFIED; THESE ARE ASSOCIATED MAINLY WITH BIOLOGICAL FUNCTIONS SUCH AS THE CELL CYCLE, INFLAMMATION, AND THE IMMUNE RESPONSE. WE PROPOSE A POTENTIAL RELATIONSHIP BETWEEN GENES AND THE MIRNAS IDENTIFIED THAT MAY OPEN NEW LINES OF INVESTIGATION. AN IN-DEPTH KNOWLEDGE OF GENE VARIANTS AND EPIGENETIC TRAITS COULD HELP US TO DESIGN MORE TAILORED TREATMENT FOR PATIENTS WITH CRSWNP.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
8 3765  49 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
9  348  46 ALTERED DNA METHYLATION IS ASSOCIATED WITH ABERRANT GENE EXPRESSION IN PARENCHYMAL BUT NOT AIRWAY FIBROBLASTS ISOLATED FROM INDIVIDUALS WITH COPD. BACKGROUND: CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A HETEROGENEOUS DISEASE OF THE LUNGS THAT IS CURRENTLY THE FOURTH LEADING CAUSE OF DEATH WORLDWIDE. GENETIC FACTORS ACCOUNT FOR ONLY A SMALL AMOUNT OF COPD RISK, BUT EPIGENETIC MECHANISMS, INCLUDING DNA METHYLATION, HAVE THE POTENTIAL TO MEDIATE THE INTERACTIONS BETWEEN AN INDIVIDUAL'S GENETICS AND ENVIRONMENTAL EXPOSURE. DNA METHYLATION IS HIGHLY CELL TYPE-SPECIFIC, AND INDIVIDUAL CELL TYPE STUDIES OF DNA METHYLATION IN COPD ARE SPARSE. FIBROBLASTS ARE PRESENT WITHIN THE AIRWAY AND PARENCHYMA OF THE LUNG AND CONTRIBUTE TO THE ABERRANT DEPOSITION OF EXTRACELLULAR MATRIX IN COPD. NO ASSESSMENT OR COMPARISON OF GENOME-WIDE DNA METHYLATION PROFILES IN THE AIRWAY AND PARENCHYMAL FIBROBLASTS FROM INDIVIDUALS WITH AND WITHOUT COPD HAS BEEN UNDERTAKEN. THESE DATA PROVIDE VALUABLE INSIGHT INTO THE MOLECULAR MECHANISMS CONTRIBUTING TO COPD AND THE DIFFERING PATHOLOGIES OF SMALL AIRWAYS DISEASE AND EMPHYSEMA IN COPD. METHODS: GENOME-WIDE DNA METHYLATION WAS EVALUATED AT OVER 485,000 CPG SITES USING THE ILLUMINA INFINIUM HUMANMETHYLATION450 BEADCHIP ARRAY IN THE AIRWAY (NON-COPD N = 8, COPD N = 7) AND PARENCHYMAL FIBROBLASTS (NON-COPD N = 17, COPD N = 29) ISOLATED FROM INDIVIDUALS WITH AND WITHOUT COPD. TARGETED GENE EXPRESSION WAS ASSESSED BY QPCR IN MATCHED RNA SAMPLES. RESULTS: DIFFERENTIALLY METHYLATED DNA REGIONS WERE IDENTIFIED BETWEEN CELLS ISOLATED FROM INDIVIDUALS WITH AND WITHOUT COPD IN BOTH AIRWAY AND PARENCHYMAL FIBROBLASTS. ONLY IN PARENCHYMAL FIBROBLASTS WAS DIFFERENTIAL DNA METHYLATION ASSOCIATED WITH DIFFERENTIAL GENE EXPRESSION. A SECOND ANALYSIS OF DIFFERENTIAL DNA METHYLATION VARIABILITY IDENTIFIED 359 INDIVIDUAL DIFFERENTIALLY VARIABLE CPG SITES IN PARENCHYMAL FIBROBLASTS. NO DIFFERENTIALLY VARIABLE CPG SITES WERE IDENTIFIED IN THE AIRWAY FIBROBLASTS. FIVE DIFFERENTIALLY VARIABLE-METHYLATED CPG SITES, ASSOCIATED WITH THREE GENES, WERE SUBSEQUENTLY ASSESSED FOR GENE EXPRESSION DIFFERENCES. TWO GENES (OAT AND GRIK2) DISPLAYED SIGNIFICANTLY INCREASED GENE EXPRESSION IN CELLS ISOLATED FROM INDIVIDUALS WITH COPD. CONCLUSIONS: DIFFERENTIAL AND VARIABLE DNA METHYLATION WAS ASSOCIATED WITH COPD STATUS IN THE PARENCHYMAL FIBROBLASTS BUT NOT AIRWAY FIBROBLASTS. ABERRANT DNA METHYLATION WAS ASSOCIATED WITH ALTERED GENE EXPRESSION IMPARTING BIOLOGICAL FUNCTION TO DNA METHYLATION CHANGES. CHANGES IN DNA METHYLATION ARE THEREFORE IMPLICATED IN THE MOLECULAR MECHANISMS UNDERLYING COPD PATHOGENESIS AND MAY REPRESENT NOVEL THERAPEUTIC TARGETS.	2018	
                                                                                                                                         
10 1508  49 DNA METHYLATION AND MRNA AND MICRORNA EXPRESSION OF SLE CD4+ T CELLS CORRELATE WITH DISEASE PHENOTYPE. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS AN AUTOIMMUNE DISEASE WELL KNOWN FOR ITS CLINICAL HETEROGENEITY, AND ITS ETIOLOGY SECONDARY TO A CROSS-TALK INVOLVING GENETIC PREDISPOSITION AND ENVIRONMENTAL STIMULI. ALTHOUGH GENOME-WIDE ANALYSIS HAS CONTRIBUTED GREATLY TO OUR UNDERSTANDING OF THE GENETIC BASIS OF SLE, THERE IS INCREASING EVIDENCE FOR A ROLE OF EPIGENETICS. INDEED, RECENT DATA HAVE DEMONSTRATED THAT IN PATIENTS WITH SLE, THERE ARE STRIKING ALTERATIONS OF DNA METHYLATION, HISTONE MODIFICATIONS, AND DEREGULATED MICRORNA EXPRESSION, THE SUM OF WHICH CONTRIBUTE TO OVER-EXPRESSION OF SELECT AUTOIMMUNE-RELATED GENES AND LOSS OF TOLERANCE. TO ADDRESS THIS ISSUE AT THE LEVEL OF CLINICAL PHENOTYPE, WE PERFORMED DNA METHYLATION, MRNA AND MICRORNA EXPRESSION SCREENING USING HIGH-THROUGHPUT SEQUENCING OF PURIFIED CD4+ T CELLS FROM PATIENTS WITH SLE, COMPARED TO AGE AND SEX MATCHED CONTROLS. IN PARTICULAR, WE STUDIED 42 PATIENTS WITH SLE AND DIVIDED THIS GROUP INTO THREE CLINICAL PHENOTYPES: A) THE PRESENCE OF SKIN LESIONS WITHOUT SIGNS OF SYSTEMIC PATHOLOGY; B) SKIN LESIONS BUT ALSO CHRONIC RENAL PATHOLOGY; AND C) SKIN LESIONS, CHRONIC RENAL PATHOLOGY AND POLYARTICULAR DISEASE. INTERESTINGLY, AND AS EXPECTED, SEQUENCING DATA REVEALED CHANGES IN DNA METHYLATION IN SLE COMPARED TO CONTROLS. HOWEVER, AND MORE IMPORTANTLY, ALTHOUGH THERE WERE COMMON METHYLATION CHANGES FOUND IN ALL GROUPS OF SLE COMPARED TO CONTROLS, THERE WAS SPECIFIC DNA METHYLATION CHANGES THAT CORRELATED WITH CLINICAL PHENOTYPE. THESE INCLUDED CHANGES IN THE NOVEL KEY TARGET GENES NLRP2, CD300LB AND S1PR3, AS WELL AS CHANGES IN THE CRITICAL PATHWAYS, INCLUDING THE ADHERENS JUNCTION AND LEUKOCYTE TRANSENDOTHELIAL MIGRATION. WE ALSO NOTED THAT A SIGNIFICANT PROPORTION OF GENES UNDERGOING DNA METHYLATION CHANGES WERE INVERSELY CORRELATED WITH GENE EXPRESSION AND THAT MIRNA SCREENING REVEALED THE EXISTENCE OF SUBSETS WITH CHANGES IN EXPRESSION. INTEGRATED ANALYSIS OF THIS DATA HIGHLIGHTS SPECIFIC SETS OF MIRNAS CONTROLLED BY DNA METHYLATION, AND GENES THAT ARE ALTERED BY METHYLATION AND TARGETED BY MIRNAS. IN CONCLUSION, OUR FINDINGS SUGGEST SELECT EPIGENETIC MECHANISMS THAT CONTRIBUTE TO CLINICAL PHENOTYPES AND FURTHER SHED LIGHT ON A NEW VENUE FOR BASIC SLE RESEARCH.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
11 2022  34 EPIGENETIC CHANGES ASSOCIATED WITH DISEASE PROGRESSION IN A MOUSE MODEL OF CHILDHOOD ALLERGIC ASTHMA. DEVELOPMENT OF ASTHMA IN CHILDHOOD IS LINKED TO VIRAL INFECTIONS OF THE LOWER RESPIRATORY TRACT IN EARLY LIFE, WITH SUBSEQUENT CHRONIC EXPOSURE TO ALLERGENS. PROGRESSION TO PERSISTENT ASTHMA IS ASSOCIATED WITH A TH2-BIASED IMMUNOLOGICAL RESPONSE AND STRUCTURAL REMODELLING OF THE AIRWAYS. THE UNDERLYING MECHANISMS ARE UNCLEAR, BUT COULD INVOLVE EPIGENETIC CHANGES. TO INVESTIGATE THIS, WE EMPLOYED A RECENTLY DEVELOPED MOUSE MODEL IN WHICH SELF-LIMITED NEONATAL INFECTION WITH A PNEUMOVIRUS, FOLLOWED BY SENSITISATION TO OVALBUMIN VIA THE RESPIRATORY TRACT AND LOW-LEVEL CHRONIC CHALLENGE WITH AEROSOLISED ANTIGEN, LEADS TO DEVELOPMENT OF AN ASTHMATIC PHENOTYPE. WE ASSESSED EXPRESSION OF MICRORNA BY CELLS IN THE PROXIMAL AIRWAYS, COMPARING CHANGES OVER THE PERIOD OF DISEASE PROGRESSION, AND USED TARGET PREDICTION DATABASES TO IDENTIFY GENES LIKELY TO BE UP- OR DOWNREGULATED AS A CONSEQUENCE OF ALTERED REGULATION OF MICRORNA. IN PARALLEL, WE ASSESSED DNA METHYLATION IN PULMONARY CD4(+) T CELLS. WE FOUND THAT A LIMITED NUMBER OF MICRORNAS EXHIBITED MARKED UP- OR DOWNREGULATION FOLLOWING EARLY-LIFE INFECTION AND SENSITISATION, FOR MANY OF WHICH THE LEVELS OF EXPRESSION WERE FURTHER CHANGED FOLLOWING CHRONIC CHALLENGE WITH THE SENSITIZING ANTIGEN. TARGETS OF THESE MICRORNAS INCLUDED GENES INVOLVED IN IMMUNE OR INFLAMMATORY RESPONSES (E.G. GATA3, KITL) AND IN TISSUE REMODELLING (E.G. IGF1, TGFBR1), AS WELL AS GENES FOR VARIOUS TRANSCRIPTION FACTORS AND SIGNALLING PROTEINS. IN PULMONARY CD4(+) T CELLS, THERE WAS SIGNIFICANT DEMETHYLATION AT PROMOTER SITES FOR INTERLEUKIN-4 AND INTERFERON-GAMMA, THE LATTER INCREASING FOLLOWING CHRONIC CHALLENGE. WE CONCLUDE THAT, IN THIS MODEL, PROGRESSION TO AN ASTHMATIC PHENOTYPE IS LINKED TO EPIGENETIC REGULATION OF GENES ASSOCIATED WITH INFLAMMATION AND STRUCTURAL REMODELLING, AND WITH T-CELL COMMITMENT TO A TH2 IMMUNOLOGICAL RESPONSE. EPIGENETIC CHANGES ASSOCIATED WITH THIS PATTERN OF GENE ACTIVATION MIGHT PLAY A ROLE IN THE DEVELOPMENT OF CHILDHOOD ASTHMA.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
12 2909  40 GENE EXPRESSION PROFILING IN FIBROMYALGIA INDICATES AN AUTOIMMUNE ORIGIN OF THE DISEASE AND OPENS NEW AVENUES FOR TARGETED THERAPY. FIBROMYALGIA IS A CHRONIC DISORDER CHARACTERIZED BY WIDESPREAD PAIN AND BY SEVERAL NON-PAIN SYMPTOMS. AUTOIMMUNITY, SMALL FIBER NEUROPATHY AND NEUROINFLAMMATION HAVE BEEN SUGGESTED TO BE INVOLVED IN THE PATHOGENESIS OF THE DISEASE. WE HAVE INVESTIGATED THE GENE EXPRESSION PROFILE IN PERIPHERAL BLOOD MONONUCLEAR CELLS OBTAINED FROM TEN PATIENTS AND TEN HEALTHY SUBJECTS. OF THE 545,500 TRANSCRIPTS ANALYZED, 1673 RESULTED MODULATED IN FIBROMYALGIC PATIENTS. THE MAJORITY OF THESE GENES ARE INVOLVED IN BIOLOGICAL PROCESSES AND PATHWAYS LINKED TO THE CLINICAL MANIFESTATIONS OF THE DISEASE. MOREOVER, GENES INVOLVED IN IMMUNOLOGICAL PATHWAYS CONNECTED TO INTERLEUKIN-17 AND TO TYPE I INTERFERON SIGNATURES WERE ALSO MODULATED, SUGGESTING THAT AUTOIMMUNITY PLAYS A ROLE IN THE DISEASE. WE THEN AIMED AT IDENTIFYING DIFFERENTIALLY EXPRESSED LONG NON-CODING RNAS (LNCRNAS) FUNCTIONALLY CONNECTED TO MODULATED GENES BOTH DIRECTLY AND VIA MICRORNA TARGETING. ONLY TWO LNCRNAS OF THE 298 FOUND MODULATED IN PATIENTS, WERE ABLE TO TARGET THE MOST HIGHLY CONNECTED GENES IN THE FIBROMYALGIA INTERACTOME, SUGGESTING THEIR INVOLVEMENT IN CRUCIAL GENE REGULATION. OUR GENE EXPRESSION DATA WERE CONFIRMED BY REAL TIME PCR, BY AUTOANTIBODY TESTING, DETECTION OF SOLUBLE MEDIATORS AND TH-17 POLARIZATION IN A VALIDATION COHORT OF 50 PATIENTS. OUR RESULTS INDICATE THAT GENETIC AND EPIGENETIC MECHANISMS AS WELL AS AUTOIMMUNITY PLAY A PIVOTAL ROLE IN THE PATHOGENESIS OF FIBROMYALGIA.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
13 1551  39 DNA METHYLATION IS GLOBALLY DISRUPTED AND ASSOCIATED WITH EXPRESSION CHANGES IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE SMALL AIRWAYS. DNA METHYLATION IS AN EPIGENETIC MODIFICATION THAT IS HIGHLY DISRUPTED IN RESPONSE TO CIGARETTE SMOKE AND INVOLVED IN A WIDE SPECTRUM OF MALIGNANT AND NONMALIGNANT DISEASES, BUT SURPRISINGLY NOT PREVIOUSLY ASSESSED IN SMALL AIRWAYS OF PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). SMALL AIRWAYS ARE THE PRIMARY SITES OF AIRFLOW OBSTRUCTION IN COPD. WE SOUGHT TO DETERMINE WHETHER DNA METHYLATION PATTERNS ARE DISRUPTED IN SMALL AIRWAY EPITHELIA OF PATIENTS WITH COPD, AND EVALUATE WHETHER CHANGES IN GENE EXPRESSION ARE ASSOCIATED WITH THESE DISRUPTIONS. GENOME-WIDE METHYLATION AND GENE EXPRESSION ANALYSIS WERE PERFORMED ON SMALL AIRWAY EPITHELIAL DNA AND RNA OBTAINED FROM THE SAME PATIENT DURING BRONCHOSCOPY, USING ILLUMINA'S INFINIUM HM27 AND AFFYMETRIX'S GENECHIP HUMAN GENE 1.0 ST ARRAYS. TO CONTROL FOR KNOWN EFFECTS OF CIGARETTE SMOKING ON DNA METHYLATION, METHYLATION AND GENE EXPRESSION PROFILES WERE COMPARED BETWEEN FORMER SMOKERS WITH AND WITHOUT COPD MATCHED FOR AGE, PACK-YEARS, AND YEARS OF SMOKING CESSATION. OUR RESULTS INDICATE THAT ABERRANT DNA METHYLATION IS (1) A GENOME-WIDE PHENOMENON IN SMALL AIRWAYS OF PATIENTS WITH COPD, AND (2) ASSOCIATED WITH ALTERED EXPRESSION OF GENES AND PATHWAYS IMPORTANT TO COPD, SUCH AS THE NF-E2-RELATED FACTOR 2 OXIDATIVE RESPONSE PATHWAY. DNA METHYLATION IS LIKELY AN IMPORTANT MECHANISM CONTRIBUTING TO MODULATION OF GENES IMPORTANT TO COPD PATHOLOGY. BECAUSE THESE METHYLATION EVENTS MAY UNDERLIE DISEASE-SPECIFIC GENE EXPRESSION CHANGES, THEIR CHARACTERIZATION IS A CRITICAL FIRST STEP TOWARD THE DEVELOPMENT OF EPIGENETIC MARKERS AND AN OPPORTUNITY FOR DEVELOPING NOVEL EPIGENETIC THERAPEUTIC INTERVENTIONS FOR COPD.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
14 5418  44 REGULATION OF DNA METHYLATION SIGNATURES ON NF-KAPPAB AND STAT3 PATHWAY GENES AND TET ACTIVITY IN CIGARETTE SMOKE EXTRACT-CHALLENGED CELLS/COPD EXACERBATION MODEL IN VITRO. BACKGROUND: CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A GLOBAL HEALTH PROBLEM. CURRENTLY, THERE IS A LACK OF KNOWLEDGE ABOUT THE PATHOBIOLOGY OF THIS DISEASE AND AVAILABLE THERAPIES ARE INEFFECTIVE. CIGARETTE SMOKING IS THE LEADING CAUSE OF COPD; HOWEVER, NOT ALL SMOKERS DEVELOP COPD. EXACERBATIONS OF COPD CAUSED BY MICROBES ARE COMMON AND DETRIMENTAL. APPROXIMATELY 20-50% OF PATIENT EXACERBATIONS ARE CAUSED BY BACTERIAL COLONIZATION IN THE LOWER AIRWAYS. IT IS GENERALLY ACCEPTED THAT EPIGENETIC MECHANISMS, ESPECIALLY DNA METHYLATION, PLAY AN IMPORTANT ROLE DURING PROGRESSION OF COPD. THUS, WE HYPOTHESIZED THAT DNA METHYLATION PATTERNS VARY SIGNIFICANTLY FOLLOWING SMOKE EXPOSURE AND DURING EXACERBATIONS CAUSED BY BACTERIAL INFECTIONS. TO TEST OUR HYPOTHESIS, WE USED AN IN VITRO STUDY MODEL THAT MIMICS COPD EXACERBATIONS AND PERFORMED EXTENSIVE STUDIES TO UNDERSTAND THE ROLE OF CPG PROMOTER METHYLATION OF NF-KAPPAB AND STAT3-MEDIATED PATHWAY GENES. BOTH NF-KAPPAB AND STAT3 TRANSCRIPTION FACTORS PLAY CRITICAL ROLES IN ORCHESTRATING INFLAMMATORY RESPONSES DURING CIGARETTE SMOKE EXPOSURE. IN BRIEF, HUMAN LUNG ADENOCARCINOMA CELLS WITH TYPE II ALVEOLAR EPITHELIUM CHARACTERISTICS (A549) WERE CHALLENGED WITH CIGARETTE SMOKE EXTRACT (CSE) OR DMSO (CONTROL) FOLLOWED BY A 3-H CHALLENGE WITH BACTERIAL LIPOPOLYSACCHARIDE (LPS; FROM PSEUDOMONAS AERUGINOSA) PRIOR TO THE TERMINATION OF CSE EXPOSURE (COPD EXACERBATION GROUP). THE PRODUCTION OF CYTOKINES/CHEMOKINES, REGULATION OF TRANSCRIPTION FACTORS, AND DNA METHYLATION OF SPECIFIC GENES WERE THEN ASSESSED. WE ALSO STUDIED CHANGES IN THE EXPRESSION AND ACTIVITY OF TEN-ELEVEN TRANSLOCASES (TETS), THE ENZYMES RESPONSIBLE FOR DNA DEMETHYLATION, AND ASSESSED THEIR ROLE IN REGULATING DNA METHYLATION IN THE CSE-CHALLENGED GROUP. RESULTS: THERE WAS A SIGNIFICANT INCREASE IN THE RELEASE OF CYTOKINES/CHEMOKINES (IL-8, MCP-1, IL-6 AND CCL5) IN THE COPD EXACERBATION GROUP AS COMPARED TO THE CONTROL GROUP. HYPOMETHYLATION OF NF-KAPPAB-MEDIATED PATHWAY GENES CORRELATED WITH THEIR INDUCTION IN OUR COPD EXACERBATION STUDY MODEL. FURTHER, WE OBSERVED AN IMPORTANT ROLE OF TET1/2 IN REGULATING THE DNA METHYLATION OF NF-KAPPAB, STAT3, IKK, AND NIK GENES AND CYTOKINE/CHEMOKINE PRODUCTION BY A549 CELLS DURING CSE CHALLENGE. CONCLUSIONS: STUDIES TO FURTHER DEFINE THE ROLE OF TETS IN CSE-MEDIATED EPIGENETIC REGULATION MAY LEAD TO THE DEVELOPMENT OF BETTER AND MORE EFFECTIVE THERAPEUTIC INTERVENTION STRATEGIES FOR COPD.	2020	
                                                                                                                                                                         
15 6431  38 THE USE OF TARGETED NEXT GENERATION SEQUENCING TO EXPLORE CANDIDATE REGULATORS OF TGF-BETA1'S IMPACT ON KIDNEY CELLS. AIMS/HYPOTHESIS: TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA1) PLAYS AN IMPORTANT REGULATORY ROLE IN THE PROGRESSION OF CHRONIC KIDNEY FAILURE. FURTHER, DAMAGE TO KIDNEY GLOMERULAR MESANGIAL CELLS IS CENTRAL TO THE PROGRESSION OF DIABETIC NEPHROPATHY. THE AIM OF THIS STUDY WAS TO EXPLORE THE GENETIC ASSOCIATIONS BETWEEN MRNA, MICRORNA, AND EPIGENETICS IN MESANGIAL CELLS IN RESPONSE TO TGF-BETA1. METHODS: THE REGULATORY EFFECTS OF TGF-BETA1 ON MESANGIAL CELLS WERE INVESTIGATED AT DIFFERENT MOLECULAR LEVELS BY TREATING MESANGIAL CELLS WITH TGF-BETA1 FOR 3 DAYS FOLLOWED BY GENOME-WIDE MIRNA, RNA, DNA METHYLATION, AND H3K27ME3 EXPRESSION PROFILING USING NEXT GENERATION SEQUENCING (NGS). RESULTS: OUR RESULTS PROVIDE THE FIRST COMPREHENSIVE, COMPUTATIONALLY INTEGRATED REPORT OF RNA-SEQ, MIRNA-SEQ, AND EPIGENOMIC ANALYSES ACROSS ALL GENETIC VARIATIONS, CONFIRMING THE OCCURRENCE OF DNA METHYLATION AND H3K27ME3 IN RESPONSE TO TGF-BETA1. OUR FINDINGS SHOW THAT THE EXPRESSION OF KLF7 AND GJA4 ARE INVOLVED IN TGF-BETA1 REGULATED DNA METHYLATION. OUR DATA ALSO PROVIDE EVIDENCE OF THE ASSOCIATION BETWEEN EPIGENETIC CHANGES AND THE EXPRESSION OF GENES CLOSELY RELATED TO TGF-BETA1 REGULATION. CONCLUSION: THIS STUDY HAS ADVANCED OUR CURRENT KNOWLEDGE OF MECHANISMS THAT CONTRIBUTE TO THE EXPRESSION OF TGF-BETA1-REGULATED GENES INVOLVED IN THE PATHOGENESIS OF KIDNEY DISEASE. THE MOLECULAR UNDERPINNINGS OF TGF-BETA1 STIMULATION OF KIDNEY CELLS WAS DETERMINED, THEREBY PROVIDING A ROBUST PLATFORM FOR FURTHER TARGET EXPLORATION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
16 3308  32 HIGH-RESOLUTION TRANSCRIPTOMIC AND EPIGENETIC PROFILING IDENTIFIES NOVEL REGULATORS OF COPD. PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) ARE STILL WAITING FOR CURATIVE TREATMENTS. CONSIDERING ITS ENVIRONMENTAL CAUSE, WE HYPOTHESIZED THAT COPD WILL BE ASSOCIATED WITH ALTERED EPIGENETIC SIGNALING IN LUNG CELLS. WE GENERATED GENOME-WIDE DNA METHYLATION MAPS AT SINGLE CPG RESOLUTION OF PRIMARY HUMAN LUNG FIBROBLASTS (HLFS) ACROSS COPD STAGES. WE SHOW THAT THE EPIGENETIC LANDSCAPE IS CHANGED EARLY IN COPD, WITH DNA METHYLATION CHANGES OCCURRING PREDOMINANTLY IN REGULATORY REGIONS. RNA SEQUENCING OF MATCHED FIBROBLASTS DEMONSTRATED DYSREGULATION OF GENES INVOLVED IN PROLIFERATION, DNA REPAIR, AND EXTRACELLULAR MATRIX ORGANIZATION. DATA INTEGRATION IDENTIFIED 110 CANDIDATE REGULATORS OF DISEASE PHENOTYPES THAT WERE LINKED TO FIBROBLAST REPAIR PROCESSES USING PHENOTYPIC SCREENS. OUR STUDY PROVIDES HIGH-RESOLUTION MULTI-OMIC MAPS OF HLFS ACROSS COPD STAGES. WE REVEAL NOVEL TRANSCRIPTOMIC AND EPIGENETIC SIGNATURES ASSOCIATED WITH COPD ONSET AND PROGRESSION AND IDENTIFY NEW CANDIDATE REGULATORS INVOLVED IN THE PATHOGENESIS OF CHRONIC LUNG DISEASES. THE PRESENCE OF VARIOUS EPIGENETIC FACTORS AMONG THE CANDIDATES DEMONSTRATES THAT EPIGENETIC REGULATION IN COPD IS AN EXCITING RESEARCH FIELD THAT HOLDS PROMISE FOR NOVEL THERAPEUTIC AVENUES FOR PATIENTS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
17 1500  38 DNA METHYLATION ANALYSIS OF CD4+ T CELLS IN PATIENTS WITH PSORIASIS. PSORIASIS IS A CHRONIC INFLAMMATORY SKIN DISEASE THAT IS CHARACTERIZED BY ABERRANT CROSS-TALK BETWEEN KERATINOCYTES AND IMMUNE CELLS SUCH AS CD4+ T CELLS, RESULTING IN KERATINOCYTE HYPERPROLIFERATION IN THE EPIDERMIS. DNA METHYLATION, ONE OF SEVERAL EPIGENETIC MECHANISMS, PLAYS AN IMPORTANT ROLE IN GENE EXPRESSION WITHOUT CHANGING THE DNA SEQUENCE. SEVERAL STUDIES HAVE SUGGESTED THE INVOLVEMENT OF EPIGENETIC REGULATION IN SKIN LESIONS FROM PATIENTS WITH PSORIASIS. IN THIS STUDY, WE INVESTIGATED THE GENOME-WIDE DNA METHYLATION STATUS OF CD4+ T CELLS IN PATIENTS WITH PSORIASIS COMPARED WITH HEALTHY SUBJECTS USING METHYLATED DNA IMMUNOPRECIPITATION SEQUENCING (MEDIP-SEQ). THE RESULTS OF MEDIP-SEQ SHOWED THAT THE GLOBAL METHYLATION VALUES OF CD4+ T CELLS ARE HIGHER IN PATIENTS WITH PSORIASIS THAN IN HEALTHY CONTROLS, PARTICULARLY IN THE PROMOTER REGIONS. AMONG THE MOST HYPERMETHYLATED GENES IN THE PROMOTER REGIONS, WE SELECTED THE GENES WHOSE EXPRESSION IS SIGNIFICANTLY REDUCED IN THE CD4+ T CELLS OF PSORIASIS PATIENTS. STUDIES USING THE METHYLATION INHIBITOR 5-AZACYTIDINE IN VITRO METHYLATION ASSAYS HAVE SHOWN THAT THE DIFFERENTIAL EXPRESSION LEVELS WERE ASSOCIATED WITH THE METHYLATION STATUS OF EACH GENE. BISULFITE SEQUENCING OF THE TRANSCRIPTION START REGION OF PHOSPHATIDIC ACID PHOSPHATASE TYPE 2 DOMAIN CONTAINING 3 (PPAPDC3), ONE OF THE SELECTED GENES, SHOWED HYPERMETHYLATION IN THE CD4+ T CELLS OF PSORIASIS PATIENTS. THESE RESULTS SUGGESTED THAT THE METHYLATION STATUS, WHICH IS IDENTIFIED BY MEDIP-SEQ OF THE GENES, WAS CORRELATED WITH THE MRNA EXPRESSION LEVEL OF THE GENES. COLLECTIVELY, THE DNA METHYLATION STATUS IN CD4+ T CELLS MIGHT BE ASSOCIATED WITH THE PATHOGENESIS OF PSORIASIS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
18 2217  24 EPIGENETIC MODIFICATIONS IN CHRONIC RHINOSINUSITIS WITH AND WITHOUT NASAL POLYPS. CHRONIC RHINOSINUSITIS (CRS) HAS BROUGHT A HUGE SOCIOECONOMIC BURDEN. HOWEVER, ITS MECHANISM IS STILL ELUSIVE, WHICH MAY INVOLVE GENETIC, ENVIRONMENTAL AND SOME OTHER FACTORS. EPIGENETIC ANALYSES HAVE BEEN CONDUCTED TO EXPLORE THE MECHANISMS UNDERLYING CRS. HERE, WE REVIEWED THE FRUITS IN THE EPIGENETIC STUDIES ON DNA METHYLATION, HISTONE MODIFICATION, AND NON-CODING RNA REGULATION. WE CONCLUDED THAT THE EPIGENETIC RESEARCH ON CRS HAS MADE GREAT BREAKTHROUGHS, ESPECIALLY IN THE PAST 5 YEARS AND THE FIELD OF MICRORNAS. "EPIGENETIC THERAPIES" ARE EXPECTED TO BE DESIGNED TO TREAT CRS IN THE FUTURE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
19 3503  30 IDENTIFICATION OF POTENTIAL DIFFERENTIALLY METHYLATED GENE-RELATED BIOMARKERS IN ENDOMETRIOSIS. AIM: TO IDENTIFY EPIGENETIC ALTERATIONS OF DIFFERENTIALLY EXPRESSED GENES AND SCREEN OUT TARGETED THERAPEUTIC DRUGS IN ENDOMETRIOSIS. METHODS: BASED ON THE GENE EXPRESSION OMNIBUS DATABASE AND A SERIES OF BIOLOGICAL INFORMATION ANALYSIS TOOLS, SUPPLEMENTED BY VALIDATION OF CLINICAL SAMPLES, ABERRANT DNA METHYLATION-DRIVEN GENES AND THEIR FUNCTIONS WERE EXPLORED, AS WELL AS POSSIBLE TARGETED DRUGS. RESULTS: THIS STUDY SCREENED OUT A RANGE OF DNA METHYLATION-DRIVEN GENES THAT WERE ASSOCIATED WITH POWERFUL PROPERTIES AND CORRESPONDING PATHWAYS. AMONG THEM, BDNF AND CCL2 WERE KEY GENES IN THE DEVELOPMENT OF ENDOMETRIOSIS. FOUR CHEMICAL AGENTS HAVE BEEN FLAGGED AS POTENTIAL TREATMENTS FOR ENDOMETRIOSIS. CONCLUSION: THESE CANDIDATE GENES AND SMALL-MOLECULE AGENTS MAY BE FURTHER EXPLORED AS POTENTIAL TARGETS AND DRUGS FOR ENDOMETRIOSIS DIAGNOSIS AND THERAPY, RESPECTIVELY.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
20 5157  31 PRE-NEOPLASTIC EPIGENETIC DISRUPTION OF TRANSCRIPTIONAL ENHANCERS IN CHRONIC INFLAMMATION. CHRONIC PERIODONTITIS (CP) IS A CHRONIC INFLAMMATORY DISEASE INDEPENDENTLY ASSOCIATED WITH HIGHER INCIDENCE OF ORAL CAVITY SQUAMOUS CELL CARCINOMA (OSCC). HOWEVER, THE MOLECULAR MECHANISM RESPONSIBLE FOR THIS INCREASED INCIDENCE IS UNKNOWN. HERE WE PROFILED THE DNA METHYLOME OF CP PATIENTS AND HEALTHY CONTROLS AND COMPARED TO A LARGE SET OF OSCC SAMPLES FROM TCGA. WE OBSERVED A SIGNIFICANT OVERLAP BETWEEN THE ALTERED DNA METHYLATION PATTERNS IN CP AND IN OSCC, SUGGESTING AN EMERGENCE OF A PRE-NEOPLASTIC EPIGENOME IN CP. REMARKABLY, THE HYPERMETHYLATED CPGS IN CP WERE SIGNIFICANTLY ENRICHED FOR ENHANCER ELEMENTS. THIS ABERRANT ENHANCER METHYLATION IS FUNCTIONAL AND ABLE TO DISRUPT ENHANCER ACTIVITY BY PREVENTING THE BINDING OF CHROMATIN LOOPING FACTORS. THIS STUDY PROVIDES NEW INSIGHTS ON THE MOLECULAR MECHANISMS LINKING CHRONIC INFLAMMATION AND TUMOR PREDISPOSITION, HIGHLIGHTING THE ROLE OF EPIGENETIC DISRUPTION OF TRANSCRIPTIONAL ENHANCERS.	2016