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Posttranscriptional Gene Regulatory Networks in Chronic Airway Inflammatory Diseases: In silico Mapping of RNA-Binding Protein Expression in Airway Epithelium.
Ricciardi, Luca; Giurato, Giorgio; Memoli, Domenico; Pietrafesa, Mariagrazia; Dal Col, Jessica; Salvato, Ilaria; Nigro, Annunziata; Vatrella, Alessandro; Caramori, Gaetano; Casolaro, Vincenzo; Stellato, Cristiana.
Afiliación
  • Ricciardi L; Department of Medicine, Surgery and Dentistry Scuola Medica Salernitana, University of Salerno, Salerno, Italy.
  • Giurato G; Department of Medicine, Surgery and Dentistry Scuola Medica Salernitana, University of Salerno, Salerno, Italy.
  • Memoli D; Department of Medicine, Surgery and Dentistry Scuola Medica Salernitana, University of Salerno, Salerno, Italy.
  • Pietrafesa M; Department of Medicine, Surgery and Dentistry Scuola Medica Salernitana, University of Salerno, Salerno, Italy.
  • Dal Col J; Department of Medicine, Surgery and Dentistry Scuola Medica Salernitana, University of Salerno, Salerno, Italy.
  • Salvato I; Pulmonology, Department of Biomedical Sciences, Dentistry and Morphological and Functional Imaging (BIOMORF), University of Messina, Messina, Italy.
  • Nigro A; Department of Medicine, Surgery and Dentistry Scuola Medica Salernitana, University of Salerno, Salerno, Italy.
  • Vatrella A; Department of Medicine, Surgery and Dentistry Scuola Medica Salernitana, University of Salerno, Salerno, Italy.
  • Caramori G; Pulmonology, Department of Biomedical Sciences, Dentistry and Morphological and Functional Imaging (BIOMORF), University of Messina, Messina, Italy.
  • Casolaro V; Department of Medicine, Surgery and Dentistry Scuola Medica Salernitana, University of Salerno, Salerno, Italy.
  • Stellato C; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
Front Immunol ; 11: 579889, 2020.
Article en En | MEDLINE | ID: mdl-33178205
Background: Posttranscriptional gene regulation (PTGR) contributes to inflammation through alterations in messenger RNA (mRNA) turnover and translation rates. RNA-binding proteins (RBPs) coordinate these processes but their role in lung inflammatory diseases is ill-defined. We evaluated the expression of a curated list of mRNA-binding RBPs (mRBPs) in selected Gene Expression Omnibus (GEO) transcriptomic databases of airway epithelium isolated from chronic obstructive pulmonary disease (COPD), severe asthma (SA) and matched control subjects, hypothesizing that global changes in mRBPs expression could be used to infer their pathogenetic roles and identify novel disease-related regulatory networks. Methods: A published list of 692 mRBPs [Nat Rev Genet 2014] was searched in GEO datasets originated from bronchial brushings of stable COPD patients (C), smokers (S), non-smokers (NS) controls with normal lung function (n = 6/12/12) (GEO ID: GSE5058) and of (SA) and healthy control (HC) (n = 6/12) (GSE63142). Fluorescence intensity data were extracted and normalized on the medians for fold change (FC) comparisons. FCs were set at ≥ |1.5| with a false discovery rate (FDR) of ≤ 0.05. Pearson correlation maps and heatmaps were generated using tMEV tools v4_9_0.45. DNA sequence motifs were searched using PScan-ChIP. Gene Ontology (GO) was performed with Ingenuity Pathway Analysis (IPA) tool. Results: Significant mRBP expression changes were detected for S/NS, COPD/NS and COPD/S (n = 41, 391, 382, respectively). Of those, 32% of genes changed by FC ≥ |1.5| in S/NS but more than 60% in COPD/NS and COPD/S (n = 13, 267, 257, respectively). Genes were predominantly downregulated in COPD/NS (n = 194, 73%) and COPD/S (n = 202, 79%), less so in S/NS (n = 4, 31%). Unsupervised cluster analysis identified in 4 out of 12 S the same mRBP pattern seen in C, postulating subclinical COPD. Significant DNA motifs enrichment for transcriptional regulation was found for downregulated RBPs. Correlation analysis identified five clusters of co-expressed mRBPs. GO analysis revealed significant enrichments in canonical pathways both specific and shared among comparisons. Unexpectedly, no significant mRBPs modulation was found in SA compared to controls. Conclusions: Airway epithelial mRBPs profiling reveals a COPD-specific global downregulation of RBPs shared by a subset of control smokers, the potential of functional cooperation by coexpressed RBPs and significant impact on relevant pathogenetic pathways in COPD. Elucidation of PTGR in COPD could identify disease biomarkers or pathways for therapeutic targeting.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sistema Respiratorio / Asma / Proteínas de Unión al ARN / Mucosa Respiratoria / Enfermedad Pulmonar Obstructiva Crónica / Inflamación Límite: Humans Idioma: En Revista: Front Immunol Año: 2020 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Suiza

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sistema Respiratorio / Asma / Proteínas de Unión al ARN / Mucosa Respiratoria / Enfermedad Pulmonar Obstructiva Crónica / Inflamación Límite: Humans Idioma: En Revista: Front Immunol Año: 2020 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Suiza