title: Whole transcriptome analysis reveals a role for OGG1-initiated DNA repair signaling in airway remodeling.
abstract: Reactive oxygen species (ROS) generated by environmental exposures, and endogenously as by-products of respiration, oxidatively modify biomolecules including DNA. Accumulation of ROS-induced DNA damage has been implicated in various diseases that involve inflammatory processes, and efficient DNA repair is considered critical in preventing such diseases. One of the most abundant DNA base lesions is 7,8-dihydro-8-oxoguanine (8-oxoG), which is repaired by the 8-oxoguanine DNA glycosylase 1 (OGG1)-initiated base-excision repair (OGG1-BER) pathway. Recent studies have shown that the OGG1-BER by-product 8-oxoG base forms a complex with cytosolic OGG1, activating small GTPases and downstream cell signaling in cultured cells and lungs. This implies that persistent OGG1-BER could result in signaling leading to histological changes in airways. To test this, we mimicked OGG1-BER by repeatedly challenging airways with its repair product 8-oxoG base. Gene expression was analyzed by RNA sequencing (RNA-Seq) and qRT-PCR, and datasets were evaluated by gene ontology and statistical tools. RNA-Seq analysis identified 3252 differentially expressed transcripts (2435 up- and 817 downregulated, ≥ 3-fold change). Among the upregulated transcripts, 2080 mRNAs were identified whose encoded protein products were involved in modulation of the actin family cytoskeleton, extracellular matrix, cell adhesion, cadherin, and cell junctions, affecting biological processes such as tissue development, cell-to-cell adhesion, cell communication, and the immune system. These data are supported by histological observations showing epithelial alterations, subepithelial fibrosis, and collagen deposits in the lungs. These data imply that continuous challenge by the environment and consequent OGG1-BER-driven signaling trigger gene expression consistent with airway remodeling.
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Leopoldo
authors.initials: L
authors.lastname: Aguilera-Aguirre
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Koa
authors.initials: K
authors.lastname: Hosoki
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Attila
authors.initials: A
authors.lastname: Bacsi
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Radák
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA; Sealy Center for Molecular Medicine, and, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Sur
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Muralidhar L
authors.initials: ML
authors.lastname: Hegde
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA; Sealy Center for Molecular Medicine, and, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Tian
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Saavedra-Molina
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA; Sealy Center for Molecular Medicine, and, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Allan R
authors.initials: AR
authors.lastname: Brasier
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Ba
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; Sealy Center for Molecular Medicine, and, University of Texas Medical Branch, Galveston, TX 77555, USA. Electronic address: sboldogh@utmb.edu.
authors.forename: Istvan
authors.initials: I
authors.lastname: Boldogh
mesh_terms: D056151:Airway Remodeling / Q000235:genetics*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D063990:Gene Ontology; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018384:Oxidative Stress
chemical_list: D015415:Biomarkers; C024829:8-hydroxyguanine; D006147:Guanine; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human
keywords: 8-Oxoguanine; Airway remodeling; OGG1-BER