1  3025 153 GENETICS AND PATHOPHYSIOLOGY OF GRANULOMATOSIS WITH POLYANGIITIS (GPA) AND ITS MAIN AUTOANTIGEN PROTEINASE 3. GRANULOMATOSIS WITH POLYANGIITIS (GPA) IS A SEVERE AUTOIMMUNE DISEASE AND ONE OF THE SMALL VESSEL ANTI-NEUTROPHIL CYTOPLASMIC ANTIBODY (ANCA)-ASSOCIATED VASCULITIDES. ALTHOUGH ITS ETIOLOGY AND PATHOPHYSIOLOGY ARE STILL WIDELY UNKNOWN, IT IS ACCEPTED THAT INFECTIONS, ENVIRONMENTAL FACTORS, EPIGENETIC MODIFICATIONS, AND A GENETIC PREDISPOSITION PROVIDE THE BASIS FOR THIS SYSTEMIC DISORDER. GPA TYPICALLY EVOLVES INTO TWO PHASES: AN INITIAL PHASE CHARACTERIZED BY EAR, NOSE AND THROAT (ENT) MANIFESTATIONS, SUCH AS CHRONIC SINUSITIS AND OTITIS, ULCERATION OF THE ORAL CAVITY AND PHARYNX, AS WELL AS PULMONARY NODULES AND A SEVERE GENERALIZED PHASE, DEFINED BY THE OCCURRENCE OF RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS, PULMONARY HEMORRHAGE, AND ARTHRITIS. ANCAS, DIRECTED AGAINST THE NEUTROPHILIC ENZYMES PROTEINASE 3 AND MYELOPEROXIDASE, ARE PRESENT IN UP TO 90% OF THE AFFECTED PATIENTS IN THE SYSTEMIC PHASE. AS THE HUMORAL IMMUNITY IS PREDOMINANTLY DIRECTED AGAINST NEUTROPHILIC ANTIGENS, IT IS APPARENT THAT NEUTROPHILS PLAY A CRITICAL ROLE IN GPA BOTH AS TARGET AND EFFECTOR CELLS. ALTHOUGH GPA PATHOGENESIS IS NOT WELL KNOWN, SOME SUSCEPTIBILITY GENES AND LOCI HAVE BEEN IDENTIFIED BY CANDIDATE GENE APPROACHES, GENOME-WIDE ASSOCIATION STUDIES, AND META-ANALYSES, AS WELL AS FAMILIAL ASSOCIATION STUDIES. SUCH GENES ARE CTLA4, PTPN22, COL11A2, SERPINA1, AND THE MHC CLASS II GENE CLUSTER. THIS REVIEW HIGHLIGHTS THE CLINICAL, PATHOPHYSIOLOGICAL, AND GENETIC BACKGROUND OF GPA AND AIMS TO GIVE AN OVERVIEW OF RECENT EFFORTS TO IDENTIFY GPA SUSCEPTIBILITY GENES. WE POINT OUT THE GENETIC BASIS OF THE MAIN AUTOANTIGEN PR3 AND WHY IT IS SO DIFFICULT TO ESTABLISH A MURINE GPA MODEL.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
2  6349  30 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  5610  29 S100A4/TCF COMPLEX TRANSCRIPTION REGULATION DRIVES EPITHELIAL-MESENCHYMAL TRANSITION IN CHRONIC SINUSITIS THROUGH WNT/GSK-3BETA/BETA-CATENIN SIGNALING. EPITHELIAL-MESENCHYMAL TRANSITION (EMT) IS THOUGHT TO BE INVOLVED IN THE TISSUE REMODELING AND LONG-TERM INFLAMMATORY PROCESS OF CHRONIC SINUSITIS (CRS), BUT THE DRIVING MECHANISM IS STILL UNCLEAR. USING HIGH-RESOLUTION MASS SPECTROMETRY, WE PERFORMED A PROTEOMIC SCREEN OF CRS NASAL MUCOSAL TISSUE TO IDENTIFY DIFFERENTIALLY EXPRESSED PROTEINS. DATA ARE AVAILABLE VIA PROTEOMEXCHANGE WITH IDENTIFIER PXD030884. SPECIFICALLY, WE IDENTIFIED S100 CALCIUM BINDING PROTEIN A4 (S100A4), AN EFFECTIVE FACTOR IN INFLAMMATION-RELATED DISEASES, AND ITS DOWNSTREAM PROTEIN CLOSELY RELATED TO TISSUE FIBROSIS COLLAGEN TYPE I ALPHA 1 CHAIN (COL1A1), WHICH SUGGESTED ITS INVOLVEMENT IN NASAL MUCOSAL TISSUE REMODELING. IN ADDITION, STIMULATION OF HUMAN NASAL EPITHELIAL CELLS (HNEPCS) WITH LIPOPOLYSACCHARIDE (LPS) MIMICKED THE INFLAMMATORY ENVIRONMENT OF CRS AND SHOWED THAT S100A4 IS INVOLVED IN REGULATING EMT AND THUS ACCELERATING TISSUE REMODELING IN THE NASAL MUCOSA, BOTH IN TERMS OF INCREASED CELL MOTILITY AND OVEREXPRESSION OF MESENCHYMAL-TYPE PROTEINS. ADDITIONALLY, WE FURTHER INVESTIGATED THE REGULATION MECHANISM OF S100A4 INVOLVED IN EMT IN CRS. OUR RESEARCH RESULTS SHOW THAT IN THE INFLAMMATORY ENVIRONMENT OF CRS NASAL MUCOSAL EPITHELIAL CELLS, TCF-4 WILL TARGET TO BIND TO S100A4 AND REGULATE ITS TRANSCRIPTION. THE TRANSCRIPTION OF S100A4 IN TURN AFFECTS THE EXECUTION OF THE IMPORTANT SIGNALING PATHWAY IN EMT, THE WNT/GSK-3BETA/BETA-CATENIN PATHWAY, THROUGH THE TCF-4/BETA-CATENIN COMPLEX. IN CONCLUSION, THIS STUDY CONFIRMED THAT THE EXPRESSION OF S100A4 WAS SIGNIFICANTLY INCREASED DURING THE PROGRESSIVE EMT PROCESS OF CRS MUCOSAL EPITHELIAL CELLS, AND REVEALED THAT THE TRANSCRIPTIONAL REGULATION OF S100A4 PLAYS AN IMPORTANT ROLE IN THE OCCURRENCE AND DEVELOPMENT OF EMT. THIS FINDING WILL HELP US TO BETTER UNDERSTAND THE PATHOGENESIS BEHIND THE REMODELING IN CRS PATIENTS, AND IDENTIFY TARGET MOLECULES FOR THE TREATMENT OF CRS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
4  6662  26 UPREGULATION OF FZD5 IN EOSINOPHILIC CHRONIC RHINOSINUSITIS WITH NASAL POLYPS BY EPIGENETIC MODIFICATION. EOSINOPHILIC CHRONIC RHINOSINUSITIS WITH NASAL POLYPS (CRSWNP) IS ONE OF THE MOST CHALLENGING PROBLEMS IN CLINICAL RHINOLOGY. FZD5 IS A RECEPTOR FOR WNT5A, AND ITS COMPLEX WITH WNT5A CONTRIBUTES TO ACTIVATING INFLAMMATION AND TISSUE MODIFICATION. NASAL POLYPS AND EOSINOPHIL/NON-EOSINOPHIL COUNTS ARE REPORTED TO BE DIRECTLY CORRELATED. THIS STUDY INVESTIGATED THE EXPRESSION AND DISTRIBUTION OF FZD5, AND THE ROLE OF EOSINOPHIL INFILTRATION AND FZD5 IN EOSINOPHILIC CRSWNP PATHOGENESIS. THE PROGNOSTIC ROLE OF EOSINOPHIL LEVELS WAS EVALUATED IN SEVEN PATIENTS WITH CRSWNP. FIFTEEN PATIENTS WITH CRS WERE CLASSIFIED BASED ON THE PERCENTAGE OF EOSINOPHILS IN NASAL POLYP TISSUE. METHYLATED GENES WERE DETECTED USING METHYL-CPG-BINDING DOMAIN SEQUENCING, AND QRT-PCR AND IMMUNOHISTOCHEMISTRY WERE USED TO DETECT FZD5 EXPRESSION IN NASAL POLYP TISSUE SAMPLES. THE RESULTS SHOWED THAT MRNA EXPRESSION OF FZD5 WAS UPREGULATED IN NASAL POLYPS. FZD5 EXPRESSION WAS SIGNIFICANTLY HIGHER IN NASAL POLYP SAMPLES FROM PATIENTS WITH EOSINOPHILIC CRSWNP THAN IN THOSE FROM PATIENTS WITH NON-EOSINOPHILIC CRSWNP, AS INDICATED BY IMMUNOHISTOCHEMISTRY. FURTHERMORE, INFLAMMATORY CYTOKINE LEVELS WERE HIGHER IN EOSINOPHILIC CRSWNP-DERIVED EPITHELIAL CELLS THAN IN NORMAL TISSUES. IN CONCLUSION, FZD5 EXPRESSION IN NASAL MUCOSAL EPITHELIAL CELLS IS CORRELATED WITH INFLAMMATORY CELLS AND MIGHT PLAY A ROLE IN THE PATHOGENESIS OF EOSINOPHILIC CRSWNP.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
5  4964  41 PATHOGENETIC AND CLINICAL ASPECTS OF ANTI-NEUTROPHIL CYTOPLASMIC AUTOANTIBODY-ASSOCIATED VASCULITIDES. ANTI-NEUTROPHIL CYTOPLASMIC AUTOANTIBODIES (ANCA) TARGETING PROTEINASE 3 (PR3) AND MYELOPEROXIDASE EXPRESSED BY INNATE IMMUNE CELLS (NEUTROPHILS AND MONOCYTES) ARE SALIENT DIAGNOSTIC AND PATHOGENIC FEATURES OF SMALL VESSEL VASCULITIS, COMPRISING GRANULOMATOSIS WITH POLYANGIITIS (GPA), MICROSCOPIC POLYANGIITIS, AND EOSINOPHILIC GPA. GENETIC STUDIES SUGGEST THAT ANCA-ASSOCIATED VASCULITIDES (AAV) CONSTITUTE SEPARATE DISEASES, WHICH SHARE COMMON IMMUNOLOGICAL AND PATHOLOGICAL FEATURES, BUT ARE OTHERWISE HETEROGENEOUS. THE SUCCESSFUL THERAPEUTIC USE OF ANTI-CD20 ANTIBODIES EMPHASIZES THE PROMINENT ROLE OF ANCA AND POSSIBLY OTHER AUTOANTIBODIES IN THE PATHOGENESIS OF AAV. HOWEVER, TO ELUCIDATE CAUSAL EFFECTS IN AAV, A BETTER UNDERSTANDING OF THE COMPLEX INTERPLAY LEADING TO THE EMERGENCE OF B LYMPHOCYTES THAT PRODUCE PATHOGENIC ANCA REMAINS A CHALLENGE. DIFFERENT SCENARIOS SEEM POSSIBLE; E.G., THE BREAK OF TOLERANCE INDUCED BY A SHIFT FROM NON-PATHOGENIC TOWARD PATHOGENIC AUTOANTIGEN EPITOPES IN INFLAMED TISSUE. THIS REVIEW GIVES A BRIEF OVERVIEW ON CURRENT KNOWLEDGE ABOUT GENETIC AND EPIGENETIC FACTORS, BARRIER DYSFUNCTION AND CHRONIC NON-RESOLVING INFLAMMATION, NECRO-INFLAMMATORY AUTO-AMPLIFICATION OF CELLULAR DEATH AND INFLAMMATION, ALTERED AUTOANTIGEN PRESENTATION, ALTERNATIVE COMPLEMENT PATHWAY ACTIVATION, ALTERATIONS WITHIN PERIPHERAL AND INFLAMED TISSUE-RESIDING T- AND B-CELL POPULATIONS, ECTOPIC LYMPHOID TISSUE NEOFORMATION, THE CHARACTERIZATION OF PR3-SPECIFIC T-CELLS, PROPERTIES OF ANCA, LINKS BETWEEN AUTOIMMUNE DISEASE AND INFECTION-TRIGGERED PATHOLOGY, AND ANIMAL MODELS IN AAV.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
6  1826  24 EFFECTS OF HISTONE DEACETYLASE INHIBITOR ON EXTRACELLULAR MATRIX PRODUCTION IN HUMAN NASAL POLYP ORGAN CULTURES. BACKGROUND: NASAL POLYPOSIS IS ASSOCIATED WITH A CHRONIC INFLAMMATORY CONDITION OF THE SINONASAL MUCOSA AND INVOLVES MYOFIBROBLAST DIFFERENTIATION AND EXTRACELLULAR MATRIX (ECM) ACCUMULATION. EPIGENETIC MODULATION BY HISTONE DEACETYLASE (HDAC) INHIBITORS INCLUDING TRICHOSTATIN A (TSA) HAS BEEN REPORTED TO HAVE INHIBITORY EFFECTS ON MYOFIBROBLAST DIFFERENTIATION IN LUNG AND RENAL FIBROBLASTS. THE PURPOSE OF THIS STUDY WAS TO INVESTIGATE THE INHIBITORY EFFECT OF TSA ON MYOFIBROBLAST DIFFERENTIATION AND ECM PRODUCTION IN NASAL POLYP ORGAN CULTURES. METHODS: NASAL POLYP TISSUES FROM 18 PATIENTS WERE ACQUIRED DURING ENDOSCOPIC SINUS SURGERY. AFTER ORGAN CULTURE, NASAL POLYPS WERE STIMULATED WITH TGF-BETA1 AND THEN TREATED WITH TSA. ALPHA-SMOOTH MUSCLE ACTIN (ALPHA-SMA), FIBRONECTIN, AND COLLAGEN TYPE I EXPRESSION LEVELS WERE EXAMINED BY REVERSE TRANSCRIPTION-POLYMERASE CHAIN REACTION (PCR), REAL-TIME PCR, WESTERN BLOT, AND IMMUNOFLUORESCENT STAINING. HDAC2, HDAC4, AND ACETYLATED H4 EXPRESSION LEVELS WERE ASSAYED BY WESTERN BLOT. CYTOTOXICITY WAS ANALYZED BY THE TERMINAL DEOXYNUCLEOTIDYL TRANSFERASE BIOTIN-DUTP NICK END LABELING ASSAY. RESULTS: THE EXPRESSION LEVELS OF ALPHA-SMA, FIBRONECTIN, AND COLLAGEN TYPE 1 WERE INCREASED IN NASAL POLYP AFTER TRANSFORMING GROWTH FACTOR (TGF) BETA1 TREATMENT. TSA-INHIBITED TGF-BETA1 INDUCED THESE GENE AND PROTEIN EXPRESSION LEVELS. FURTHERMORE, TSA SUPPRESSED PROTEIN EXPRESSION LEVELS OF HDAC2 AND HDAC4. HOWEVER, TSA INDUCED HYPERACETYLATION OF HISTONES H4. TREATMENT WITH TGF-BETA1 WITH OR WITHOUT TSA DID NOT HAVE CYTOTOXIC EFFECT. CONCLUSION: THESE FINDINGS PROVIDE NOVEL INSIGHTS INTO THE EPIGENETIC REGULATION IN MYOFIBROBLAST DIFFERENTIATION AND ECM PRODUCTION OF NASAL POLYP. TSA COULD BE A CANDIDATE OF A THERAPEUTIC AGENT FOR REVERSING THE TGF-BETA1-INDUCED ECM SYNTHESIS THAT LEADS TO NASAL POLYP DEVELOPMENT.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
7  1564  25 DNA METHYLATION OF PROXIMAL PLAT PROMOTER IN CHRONIC RHINOSINUSITIS WITH NASAL POLYPS. BACKGROUND NASAL POLYPS (NP) ARE CHARACTERIZED BY PSEUDOCYSTS DERIVED FROM STROMAL TISSUE EDEMA AND CAUSE PERSISTENT INFECTIONS IN PATIENTS WITH CHRONIC RHINOSINUSITIS (CRS). A LOW LEVEL OF TISSUE-TYPE PLASMINOGEN ACTIVATOR (GENE NAME PLAT) IS CONSIDERED A CAUSE OF STROMAL TISSUE EDEMA BECAUSE OF INSUFFICIENT PLASMIN ACTIVATION IN NP; HOWEVER, THE MECHANISM REGULATING PLAT GENE EXPRESSION LEVELS IS STILL UNCLEAR. THE EPIGENETIC MECHANISM REGULATING THE PLAT GENE EXPRESSION HAS BEEN STUDIED IN OTHER TISSUES. OBJECTIVE WE AIMED TO INVESTIGATE THE METHYLATION LEVELS IN THE PROXIMAL PLAT PROMOTER AND THEIR EFFECTS ON GENE EXPRESSION IN NP TISSUE. METHODS WE INVESTIGATED THE METHYLATION LEVELS AT 3 CPG SITES IN THE PROXIMAL PLAT PROMOTER REGIONS (-618, -121, AND -105 WITH RESPECT TO THE TRANSCRIPTION INITIATION SITE) BY BISULFITE PYROSEQUENCING AND THEIR EFFECTS ON THE GENE EXPRESSION BY QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION (QPCR) IN 20 PAIRED SAMPLES OF NP AND INFERIOR TURBINATE TISSUE (IT) FROM PATIENTS WITH CRS. RESULTS THE DNA METHYLATION LEVELS AT ALL CPG SITES WERE HIGHER ( P < .01), AND THE PLAT EXPRESSION WAS LOWER ( P < .001) IN NP COMPARED WITH IT. THE METHYLATION CHANGES AT THE -618 SITE SHOWED A NEGATIVE CORRELATION WITH THE GENE EXPRESSION CHANGES BETWEEN NP AND IT ( R = -.65, P < .01). CONCLUSIONS HYPERMETHYLATION OF PLAT PROMOTER MAY DOWNREGULATE THE GENE EXPRESSION IN NP, LEADING TO EXCESSIVE FIBRIN DEPOSITION BY ABERRANT COAGULATION CASCADE. DNA METHYLATION OF PROXIMAL PLAT PROMOTER MAY CONTRIBUTE TO NP GROWTH AND HAVE A POTENTIAL AS A NEW THERAPEUTIC TARGET.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
8  3019  39 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
9  3758  30 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
10  5553  32 ROLE OF EPIGENETICS IN THE PATHOGENESIS OF CHRONIC RHINOSINUSITIS WITH NASAL POLYPS. CHRONIC RHINOSINUSITIS (CRS) IS A HIGHLY PREVALENT DISEASE CHARACTERIZED BY MUCOSAL INFLAMMATION OF THE NOSE AND PARANASAL SINUSES. CRS CAN BE DIVIDED INTO TWO MAIN CATEGORIES, CRS WITH NASAL POLYPS (NPS; CRSWNP) AND CRS WITHOUT NPS (CRSSNP). ALTHOUGH THE PATHOPHYSIOLOGY OF CRS REMAINS UNCLEAR, DNA METHYLATION HAS BEEN IMPLICATED IN THE ETIOLOGY OF CRSWNP. THE AIM OF THE PRESENT STUDY WAS TO ELUCIDATE WHETHER DNA METHYLATION OF SPECIFIC GENES IS INVOLVED IN THE DEVELOPMENT OF NPS. IN TOTAL, 18 INDIVIDUALS WERE INCLUDED IN THE PRESENT STUDY, AND WERE DIVIDED INTO THREE GROUPS: CRSWNP (N=7), CRSSNP (N=7) AND HEALTHY CONTROLS (N=4). NP TISSUES WERE OBTAINED FROM THE SEVEN PATIENTS WITH CRSWNP AND BIOPSIES OF THE INFERIOR TURBINATE MUCOSA FROM ALL THREE GROUPS WERE USED AS CONTROLS. METHYLATED GENES DETECTED BY METHYL?CPG?BINDING DOMAIN SEQUENCING WERE VALIDATED BY METHYLATION?SPECIFIC POLYMERASE CHAIN REACTION (PCR), BISULFITE SEQUENCING, AND REVERSE TRANSCRIPTION?QUANTITATIVE PCR (RT?QPCR). METHYL?CPG?BINDING DOMAIN SEQUENCING IDENTIFIED 43,674 CPG ISLANDS IN 518 GENES. THE PROMOTOR REGIONS OF 10 AND 30 GENES WERE HYPERMETHYLATED AND HYPOMETHYLATED, RESPECTIVELY, IN NP SAMPLES COMPARED WITH CONTROLS. THE TOP FOUR GENES WITH ALTERED HYPOMETHYLATION IN NP TISSUES WERE, KERATIN 19 (KRT19), NUCLEAR RECEPTOR SUBFAMILY 2 GROUP F MEMBER 2 (NR2F2), A DISINTEGRIN?LIKE AND METALLOPEPTIDASE (REPROLYSIN TYPE) WITH THROMBOSPONDIN TYPE 1 MOTIF 1 (ADAMTS1) AND ZINC FINGER PROTEIN 222 (ZNF222). RT?QPCR DEMONSTRATED THAT THE EXPRESSION LEVELS OF KRT19, NR2F2 AND ADAMTS1 WERE SIGNIFICANTLY INCREASED IN NP TISSUES; HOWEVER, THERE WAS NO DIFFERENCE IN THE LEVELS OF ZNF222 BETWEEN NP AND CONTROL TISSUES. FURTHER STUDIES ARE REQUIRED TO CONFIRM THE RELEVANCE OF THESE EPIGENETIC MODIFICATIONS IN THE MECHANISMS UNDERLYING NP FORMATION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
11  1632  23 DNMTS ARE INVOLVED IN TGF-BETA1-INDUCED EPITHELIAL-MESENCHYMAL TRANSITIONS IN AIRWAY EPITHELIAL CELLS. CHRONIC RHINOSINUSITIS (CRS) PATHOGENESIS IS CLOSELY RELATED TO TISSUE REMODELING, INCLUDING EPITHELIAL-MESENCHYMAL TRANSITION (EMT). EPIGENETIC MECHANISMS PLAY KEY ROLES IN EMT. DNA METHYLATION, MEDIATED BY DNA METHYLTRANSFERASES (DNMTS), IS AN EPIGENETIC MARKER THAT IS CRITICAL TO EMT. THE GOAL OF THIS STUDY WAS TO DETERMINE WHETHER DNMTS WERE INVOLVED IN TGF-BETA1-INDUCED EMT AND ELUCIDATE THE UNDERLYING MECHANISMS IN NASAL EPITHELIAL CELLS AND AIR-LIQUID INTERFACE CULTURES. GLOBAL DNA METHYLATION AND DNMT ACTIVITY WERE QUANTIFIED. DNMT EXPRESSION WAS MEASURED USING REAL-TIME PCR (QRT-PCR) IN HUMAN CRS TISSUES. MRNA AND PROTEIN LEVELS OF DNMTS, E-CADHERIN, VIMENTIN, ALPHA-SMA, AND FIBRONECTIN WERE DETERMINED USING RT-PCR AND WESTERN BLOTTING, RESPECTIVELY. DNMT1, DNMT3A, AND DNMT3B GENE EXPRESSION WERE KNOCKED DOWN USING SIRNA TRANSFECTION. MAPK PHOSPHORYLATION AND EMT-RELATED TRANSCRIPTION FACTOR LEVELS WERE DETERMINED USING WESTERN BLOTTING. SIGNALING PATHWAYS WERE ANALYZED USING SPECIFIC INHIBITORS OF MAPK. WE DEMONSTRATED THESE DATA IN PRIMARY NASAL EPITHELIAL CELLS AND AIR-LIQUID INTERFACE CULTURES. GLOBAL DNA METHYLATION, DNMT ACTIVITY, AND DNMT EXPRESSION INCREASED IN CRS TISSUES. DNMT EXPRESSION WAS POSITIVELY CORRELATED WITH LUND-MCKAY CT SCORES. TGF-BETA1 DOSE-DEPENDENTLY INDUCED DNMT EXPRESSION. FURTHER, 5-AZA INHIBITED TGF-BETA1-INDUCED DNMT, SNAIL, AND SLUG EXPRESSION RELATED TO EMT, AS WELL AS P38 AND JNK PHOSPHORYLATION IN A549 CELLS AND TGF-BETA1-INDUCED DNMT EXPRESSION AND EMT IN PRIMARY NASAL EPITHELIAL CELLS AND AIR-LIQUID INTERFACE CULTURES. TGF-BETA1-INDUCED DNMT EXPRESSION LEADS TO DNA METHYLATION AND EMT VIA P38, JNK, SNAIL, AND SLUG SIGNALING PATHWAYS. INHIBITION OF DNMT SUPPRESSED THE EMT PROCESS AND THEREFORE IS POTENTIALLY A CRS THERAPEUTIC STRATEGY.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
12  3746  41 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	

13  4300  33 MICRORNA-19A CONTRIBUTES TO THE EPIGENETIC REGULATION OF TISSUE FACTOR IN DIABETES. BACKGROUND: DIABETES MELLITUS IS CHARACTERIZED BY CHRONIC VASCULAR DISORDER AND PRESENTS A MAIN RISK FACTOR FOR CARDIOVASCULAR MORTALITY. IN PARTICULAR, HYPERGLYCAEMIA AND INFLAMMATORY CYTOKINES INDUCE VASCULAR CIRCULATING TISSUE FACTOR (TF) THAT PROMOTES PRO-THROMBOTIC CONDITIONS IN DIABETES. IT HAS RECENTLY BECOME EVIDENT THAT ALTERATIONS OF THE POST-TRANSCRIPTIONAL REGULATION OF TF VIA SPECIFIC MICRORNA(MIR)S, SUCH AS MIR-126, CONTRIBUTE TO THE PATHOGENESIS OF DIABETES AND ITS COMPLICATIONS. THE ENDOTHELIAL MIR-19A IS INVOLVED IN VASCULAR HOMEOSTASIS AND ATHEROPROTECTION. HOWEVER, ITS ROLE IN DIABETES-RELATED THROMBOGENICITY IS UNKNOWN. UNDERSTANDING MIR-NETWORKS REGULATING PROCOAGULABILITY IN DIABETES MAY HELP TO DEVELOP NEW TREATMENT OPTIONS PREVENTING VASCULAR COMPLICATIONS. METHODS AND RESULTS: PLASMA OF 44 PATIENTS WITH KNOWN DIABETES WAS ASSESSED FOR THE EXPRESSION OF MIR-19A, TF PROTEIN, TF ACTIVITY, AND MARKERS FOR VASCULAR INFLAMMATION. HIGH MIR-19A EXPRESSION WAS ASSOCIATED WITH REDUCED TF PROTEIN, TF-MEDIATED PROCOAGULABILITY, AND VASCULAR INFLAMMATION BASED ON EXPRESSION OF VASCULAR ADHESION MOLECULE-1 AND LEUKOCYTE COUNT. WE FOUND PLASMA EXPRESSION OF MIR-19A TO STRONGLY CORRELATE WITH MIR-126. MIR-19A REDUCED THE TF EXPRESSION ON MRNA AND PROTEIN LEVEL IN HUMAN MICROVASCULAR ENDOTHELIAL CELLS (HMEC) AS WELL AS TF ACTIVITY IN HUMAN MONOCYTES (THP-1), WHILE ANTI-MIR-19A INCREASED THE TF EXPRESSION. INTERESTINGLY, MIR-19A INDUCED VCAM EXPRESSION IN HMEC. HOWEVER, MIR-19A AND MIR-126 CO-TRANSFECTION REDUCED TOTAL ENDOTHELIAL VCAM EXPRESSION AND EXHIBITED ADDITIVE INHIBITION OF A LUCIFERASE REPORTER CONSTRUCT CONTAINING THE F3 3'UTR. CONCLUSIONS: WHILE BOTH MIRS HAVE DIFFERENTIAL FUNCTIONS ON ENDOTHELIAL VCAM EXPRESSION, MIR-19A AND MIR-126 COOPERATE TO EXHIBIT ANTI-THROMBOTIC PROPERTIES VIA REGULATING VASCULAR TF EXPRESSION. MODULATING THE POST-TRANSCRIPTIONAL CONTROL OF TF IN DIABETES MAY PROVIDE A FUTURE ANTI-THROMBOTIC AND ANTI-INFLAMMATORY THERAPY.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
14  2406  27 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
15  2349  26 EPIGENETIC REGULATION OF MYOFIBROBLAST DIFFERENTIATION AND EXTRACELLULAR MATRIX PRODUCTION IN NASAL POLYP-DERIVED FIBROBLASTS. BACKGROUND: NASAL POLYPOSIS IS A MULTI-FACTORIAL DISEASE ASSOCIATED WITH CHRONIC INFLAMMATORY CONDITION OF THE PARANASAL SINUSES. MYOFIBROBLAST DIFFERENTIATION AND EXTRACELLULAR MATRIX (ECM) ACCUMULATION ARE INVOLVED IN THE PATHOGENESIS OF NASAL POLYPOSIS. OBJECTIVE: THE AIM OF THIS STUDY WAS TO STUDY THE EFFECT OF TRICHOSTATIN A (TSA), A HISTONE DEACETYLASE (HDAC) INHIBITOR, ON TRANSFORMING GROWTH FACTOR (TGF)-BETA1-INDUCED MYOFIBROBLAST DIFFERENTIATION AND ECM ACCUMULATION IN NASAL POLYP-DERIVED FIBROBLASTS (NPDFS). METHODS: NASAL POLYP-DERIVED FIBROBLASTS WERE ISOLATED FROM NASAL POLYPS OF PATIENTS WHO HAVE CHRONIC RHINOSINUSITIS WITH NASAL POLYP. TSA WAS TREATED IN TGF-BETA1-INDUCED NPDFS. EXPRESSION LEVELS OF HDAC2, ALPHA-SMOOTH MUSCLE ACTIN (SMA), TGF-BETA1, COLLAGEN TYPE I, ACETYLATED HISTONE H3, ACETYLATED HISTONE H4, PHOSPHORYLATED SMAD2/3 AND SMAD7 WERE DETERMINED BY RT-PCR, WESTERN BLOT AND/OR IMMUNOFLUORESCENT STAINING. THE TOTAL COLLAGEN AMOUNT PRODUCTION WAS ANALYSED BY SIRCOL SOLUBLE COLLAGEN ASSAY AND CONTRACTILE ACTIVITY WAS MEASURED BY COLLAGEN GEL CONTRACTION ASSAY. HDAC2 INHIBITION BY TSA OR HDAC2 SILENCING WAS ESTABLISHED BY RT-PCR AND WESTERN BLOT. THE EPIGENETIC EFFECT ON ALPHA-SMA GENE INACTIVATION WAS EXAMINED BY CHROMATIN IMMUNOPRECIPITATION ASSAY. PROLIFERATION WAS DETERMINED BY KI67-POSITIVE CELL STAINING AND CYTOTOXICITY WAS ASSESSED BY 3-(4,5- DIMETHYLTHIAZOL-2YL)-2,5-DIPHENYL-2H-TETRAZOLIUM BROMIDE (MTT) ASSAY. RESULTS: THE EXPRESSION LEVELS OF HDAC2, ALPHA-SMA AND TGF-BETA1 WERE INCREASED IN NASAL POLYP TISSUES COMPARED TO NORMAL INFERIOR TURBINATE TISSUES. TSA AND HDAC2 SILENCING INHIBITED EXPRESSION LEVELS ALPHA-SMA, COLLAGEN AND HDAC2. TSA INDUCED HYPERACETYLATION OF HISTONE AND SUPPRESSED OPENING OF ALPHA-SMA GENE PROMOTER IN TGF-BETA1-INDUCED NPDFS. TSA INHIBITED TGF-BETA1-INDUCED SMAD 2/3 AND RESCUED TGF-BETA1-SUPPRESSED SMAD7 SIGNALLING PATHWAY. FINALLY, TSA BLOCKED PROLIFERATION IN TGF-BETA1-INDUCED NPDFS AND HAS NO CYTOTOXIC EFFECT IN NPDFS. CONCLUSIONS AND CLINICAL RELEVANCE: THESE RESULTS SUGGEST THAT HDAC INHIBITION IS ASSOCIATED WITH MYOFIBROBLAST DIFFERENTIATION AND EXTRACELLUAR MATRIX ACCUMULATION IN NASAL POLYPOSIS. TSA MAY BE USEFUL AS AN INHIBITOR OF NASAL POLYP GROWTH, AND THUS HAS POTENTIAL TO BE USED AS A NOVEL TREATMENT OPTION FOR NASAL POLYPOSIS.	2012	
                                                                                                                                                                                                                                                                                                                                                                    
16  5850  27 SUBEROYLANILIDE HYDROXAMIC ACID (SAHA) REDUCES FIBROSIS MARKERS AND DEACTIVATES HUMAN STELLATE CELLS VIA THE EPITHELIAL-MESENCHYMAL TRANSITION (EMT). HEPATIC FIBROSIS IS KNOWN AS THE ACCUMULATION OF CONNECTIVE TISSUE SECONDARY TO CHRONIC DAMAGE TO THE LIVER. EPITHELIAL-MESENCHYMAL TRANSITION (EMT) CORRESPONDING INCREASE IN LIVER FIBROGENESIS WAS SHOWN WITH IMMUNOHISTOCHEMISTRY AND PCR-BASED STUDIES. SUBEROYLANILIDE HYDROXAMIC ACID (SAHA), A SYNTHETIC COMPOUND APPROVED AS A HISTONE DEACETYLASE INHIBITOR (HDAC) BY THE FDA TO TREAT CUTANEOUS T-CELL LYMPHOMA IS UNDER INVESTIGATION FOR THE TREATMENT OF LUNG AND RENAL FIBROSIS. EXPERIMENTAL MODELING FOR HEPATIC FIBROSIS CAN BE CONSTRUCTED WITH AN LX2 CELL LINE ISOLATED FROM HUMAN HEPATIC STELLATE CELLS (HSCS). IN THIS STUDY, WE AIMED TO INVESTIGATE THE MODULATION OF SAHA IN THE PATHOGENESIS OF LIVER FIBROSIS BY DETECTING THE LEVELS OF PROTEINS; (E-CADHERIN (E-CAD), N-CADHERIN (N-CAD), VIMENTIN (VIM), AND GENES; E-CAD, N-CAD, VIM, TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA), ALPHA-SMOOTH MUSCLE ACTIN (ALPHA-SMA), TYPE 1 COLLAGEN (COL1A1), TYPE 3 COLLAGEN (COL3A1)) THAT PLAY A SIGNIFICANT ROLE IN EMT WITH THE LX2 CELL LINE. WE ALSO EVALUATED THE ACTION OF SAHA WITH CELL PROLIFERATION, CLONOGENIC, AND MIGRATION ASSAY. CELL PROLIFERATION WAS PERFORMED BY FLOW CYTOMETRY. ALL THE PROTEIN LEVELS WERE DETERMINED BY WESTERN BLOT ANALYSIS, AND GENE EXPRESSION LEVELS WERE MEASURED BY REAL-TIME PCR. OUR STUDY OBSERVED THAT SAHA TREATMENT DECREASED CELL VIABILITY, COLONY FORMATION AND MIGRATION IN LX2 CELLS. WE FOUND THAT SAHA INCREASED E-CAD EXPRESSION LEVEL, WHILE IT DECREASED N-CAD, VIM, COL1A1, COL3A1, ALPHA-SMA TGF-BETA GENES EXPRESSION LEVELS. SAHA DECREASED THE LEVEL OF E-CAD, N-CAD, AND VIM PROTEIN LEVELS. WE THOUGHT THAT SAHA POSSESSES POTENT ANTIFIBROTIC AND ANTI-EMT PROPERTIES IN LX2.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
17  4358  28 MIR-338-3P BLOCKS TGFBETA-INDUCED MYOFIBROBLAST DIFFERENTIATION THROUGH THE INDUCTION OF PTEN. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC INTERSTITIAL LUNG DISEASE. THE PATHOGENESIS OF IPF IS NOT COMPLETELY UNDERSTOOD. HOWEVER, NUMEROUS GENES ARE ASSOCIATED WITH THE DEVELOPMENT AND PROGRESSION OF PULMONARY FIBROSIS, INDICATING THERE IS A SIGNIFICANT GENETIC COMPONENT TO THE PATHOGENESIS OF IPF. EPIGENETIC INFLUENCES ON THE DEVELOPMENT OF HUMAN DISEASE, INCLUDING PULMONARY FIBROSIS, REMAIN TO BE FULLY ELUCIDATED. IN THIS PAPER, WE IDENTIFY MIR-338-3P AS A MICRORNA SEVERELY DOWNREGULATED IN THE LUNGS OF PATIENTS WITH PULMONARY FIBROSIS AND IN EXPERIMENTAL MODELS OF PULMONARY FIBROSIS. TREATMENT OF PRIMARY HUMAN LUNG FIBROBLASTS WITH MIR-338-3P INHIBITS MYOFIBROBLAST DIFFERENTIATION AND MATRIX PROTEIN PRODUCTION. PUBLISHED AND PROPOSED TARGETS OF MIR-338-3P SUCH AS TGFBETA RECEPTOR 1, MEK/ERK 1/2, CDK4, AND CYCLIN D ARE ALSO NOT RESPONSIBLE FOR THE REGULATION OF PULMONARY FIBROBLAST BEHAVIOR BY MIR-338-3P. MIR-338-3P INHIBITS MYOFIBROBLAST DIFFERENTIATION BY PREVENTING TGFBETA-MEDIATED DOWNREGULATION OF PHOSPHATASE AND TENSIN HOMOLOG (PTEN), A KNOWN ANTIFIBROTIC MEDIATOR.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
18  5227  22 PRMT6 MEDIATES INFLAMMATION VIA ACTIVATION OF THE NF-KAPPAB/P65 PATHWAY ON A CIGARETTE SMOKE EXTRACT-INDUCED MURINE EMPHYSEMA MODEL. INTRODUCTION: SMOKE-DRIVEN LUNG INFLAMMATION IS CONSIDERED TO BE THE MAJOR PATHOPHYSIOLOGY MECHANISM OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)/EMPHYSEMA. PROTEIN ARGININE METHYLTRANSFERASE 6 (PRMT6) IS A KEY EPIGENETIC ENZYME, WHICH IS RELATED TO PROTECTING THE TRI-METHYLATION OF H3K4 (H3K4ME3). WE HYPOTHESIZED THAT PTMT6 PROTECTS LUNG INFLAMMATION THROUGH THE NUCLEAR FACTOR KAPPA B (NF-KAPPAB) PATHWAY. METHODS: MICE WERE INJECTED WITH CIGARETTE SMOKE EXTRACT (CSE) OR PBS TO ESTABLISH A MICE MODEL, INTRATRACHEALLY INSTILLED WITH OVEREXPRESSED PRMT6 OR NEGATIVE CONTROL VECTOR. MORPHOMETRY OF LUNG SLIDES AND LUNG FUNCTION WERE MEASURED. WE DETERMINED THE PROTEIN EXPRESSION OF PRMT6 AND ITS RELATED HISTONE TARGETS, THE ACTIVATION OF NF-KAPPAB PATHWAY, THE LEVEL OF TUMOR NECROSIS FACTOR ALPHA (TNFALPHA) AND INTERLEUKIN-1BETA (IL-1BETA). RESULTS: AFTER PRMT6 OVEREXPRESSION, THE MORPHOMETRY INDEXES AND LUNG FUNCTION WERE IMPROVED. ALSO, THE EXPRESSION OF H3K4ME3 WAS DECREASED. OVEREXPRESSED PRMT6 COULD SUPPRESS CSE-INDUCED NF-KAPPAB ACTIVATION AND PRO-INFLAMMATION GENES EXPRESSION. CONCLUSIONS: THE OVEREXPRESSED PRMT6 COULD SERVE AS AN INFLAMMATION INHIBITOR, POTENTIALLY THROUGH BLOCKING THE NF-KAPPAB/P65 PATHWAY IN THE MURINE EMPHYSEMA MODEL.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
19  3323  30 HISTONE DEACETYLASE 1 (HDAC1): A KEY PLAYER OF T CELL-MEDIATED ARTHRITIS. RHEUMATOID ARTHRITIS (RA) REPRESENTS A CHRONIC T CELL-MEDIATED INFLAMMATORY AUTOIMMUNE DISEASE. STUDIES HAVE SHOWN THAT EPIGENETIC MECHANISMS CONTRIBUTE TO THE PATHOGENESIS OF RA. HISTONE DEACETYLASES (HDACS) REPRESENT ONE IMPORTANT GROUP OF EPIGENETIC REGULATORS. HOWEVER, THE ROLE OF INDIVIDUAL HDAC MEMBERS FOR THE PATHOGENESIS OF ARTHRITIS IS STILL UNKNOWN. IN THIS STUDY WE DEMONSTRATE THAT MICE WITH A T CELL-SPECIFIC DELETION OF HDAC1 (HDAC1-CKO) ARE RESISTANT TO THE DEVELOPMENT OF COLLAGEN-INDUCED ARTHRITIS (CIA), WHEREAS THE ANTIBODY RESPONSE TO COLLAGEN TYPE II WAS UNDISTURBED, INDICATING AN UNALTERED T CELL-MEDIATED B CELL ACTIVATION. THE INFLAMMATORY CYTOKINES IL-17 AND IL-6 WERE SIGNIFICANTLY DECREASED IN SERA OF HDAC1-CKO MICE. IL-6 TREATED HDAC1-DEFICIENT CD4(+) T CELLS SHOWED AN IMPAIRED UPREGULATION OF CCR6. SELECTIVE INHIBITION OF CLASS I HDACS WITH THE HDAC INHIBITOR MS-275 UNDER TH17-SKEWING CONDITIONS INHIBITED THE UPREGULATION OF CHEMOKINE RECEPTOR 6 (CCR6) IN MOUSE AND HUMAN CD4(+) T CELLS. ACCORDINGLY, ANALYSIS OF HUMAN RNA-SEQUENCING (RNA-SEQ) DATA AND HISTOLOGICAL ANALYSIS OF SYNOVIAL TISSUE SAMPLES FROM HUMAN RA PATIENTS REVEALED THE EXISTENCE OF CD4(+)CCR6(+) CELLS WITH ENHANCED HDAC1 EXPRESSION. OUR DATA INDICATE A KEY ROLE FOR HDAC1 FOR THE PATHOGENESIS OF CIA AND SUGGEST THAT HDAC1 AND OTHER CLASS I HDACS MIGHT BE PROMISING TARGETS OF SELECTIVE HDAC INHIBITORS (HDACI) FOR THE TREATMENT OF RA.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
20  3075  26 GENOME-WIDE EPIGENETIC STUDY OF CHRONIC RHINOSINUSITIS TISSUES REVEALS DYSREGULATED INFLAMMATORY, IMMUNOLOGIC AND REMODELING PATHWAYS. BACKGROUND: EPIGENETICS STUDIES MECHANISMS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS, NON-CODING RNAS, AND ALTERNATIVE POLYADENYLATION THAT CAN MODIFY GENE ACTIVITY WITHOUT CHANGING THE UNDERLYING DNA NUCLEOTIDE BASE-PAIR STRUCTURE. BECAUSE THESE CHANGES ARE REVERSIBLE, THEY HAVE POTENTIAL IN DEVELOPING NOVEL THERAPEUTICS. CURRENTLY, SEVEN PHARMACEUTICAL AGENTS TARGETING EPIGENETIC CHANGES ARE FDA APPROVED AND COMMERCIALLY AVAILABLE FOR TREATMENT OF CERTAIN CANCERS. HOWEVER, STUDIES INVESTIGATING EPIGENETICS IN CHRONIC RHINOSINUSITIS (CRS) HAVE NOT BEEN UNDERTAKEN PREVIOUSLY IN THE UNITED STATES. OBJECTIVES: THE GOAL OF THIS STUDY WAS TO INVESTIGATE SINONASAL DNA METHYLATION PATTERNS IN CRS VERSUS CONTROLS, TO DISCERN ENVIRONMENTALLY-INDUCED EPIGENETIC CHANGES IMPACTING CRS SUBJECTS. METHODS AND RESULTS: ETHMOIDAL SAMPLES FROM CRS AND INFERIOR TURBINATE MUCOSAL TISSUE SAMPLES FROM CONTROLS WITHOUT CRS WERE STUDIED. DNA METHYLATION WAS STUDIED BY REDUCED REPRESENTATION BISULFITE SEQUENCING. RADMETH(R) BIOSTATISTICAL PACKAGE WAS USED TO IDENTIFY DIFFERENTIALLY METHYLATED REGIONS (DMRS) BETWEEN CRS AND CONTROLS. INGENUITY PATHWAY ANALYSIS OF DMRS WAS PERFORMED TO IDENTIFY TOP UPSTREAM REGULATORS AND CANONICAL PATHWAYS. NINETY-THREE SAMPLES FROM 64 CRS SUBJECTS (36 CRSWNP; 28 CRSSNP) AND 29 CONTROLS WERE STUDIED. CRS AND CONTROL SAMPLES DIFFERED IN 13 662 CPGS SITES AND 1381 DMRS. TOP UPSTREAM REGULATORS IDENTIFIED INCLUDED: 1. CRS VERSUS CONTROLS: TGFB1, TNF, TP53, DGCR8, AND BETA-ESTRADIOL. 2. CRSWNP VERSUS CONTROLS: TGFB1, CTNNB1, LIPOPOLYSACCHARIDE, ID2, AND TCF7L2. 3. CRSSNP VERSUS CONTROLS: MYOD1, ACETONE, ID2, ST8SIA4, AND LEPR. CONCLUSIONS: DIFFERENTIAL PATTERNS OF METHYLATION WERE IDENTIFIED BETWEEN CONTROLS AND CRS, CRSWNP, AND CRSSNP. EPIGENETIC, ENVIRONMENTALLY-INDUCED CHANGES RELATED TO NOVEL, INFLAMMATORY, IMMUNOLOGIC, AND REMODELING PATHWAYS APPEAR TO AFFECT EPITHELIAL INTEGRITY, CELL PROLIFERATION, HOMEOSTASIS, VASCULAR PERMEABILITY, AND OTHER YET UNCHARACTERIZED PATHWAYS AND GENES.	2023