title: The genome-wide transcriptional response to neonatal hyperoxia identifies Ahr as a key regulator.
abstract: Premature infants requiring supplemental oxygen are at increased risk for developing bronchopulmonary dysplasia (BPD). Rodent models involving neonatal exposure to excessive oxygen concentrations (hyperoxia) have helped to identify mechanisms of BPD-associated pathology. Genome-wide assessments of the effects of hyperoxia in neonatal mouse lungs could identify novel BPD-related genes and pathways. Newborn C57BL/6 mice were exposed to 100% oxygen for 10 days, and whole lung tissue RNA was used for high-throughput, sequencing-based transcriptomic analysis (RNA-Seq). Significance Analysis of Microarrays and Ingenuity Pathway Analysis were used to identify genes and pathways affected. Expression patterns for selected genes were validated by qPCR. Mechanistic relationships between genes were further tested in cultured mouse lung epithelial cells. We identified 300 genes significantly and substantially affected following acute neonatal hyperoxia. Canonical pathways dysregulated in hyperoxia lungs included nuclear factor (erythryoid-derived-2)-like 2-mediated oxidative stress signaling, p53 signaling, eNOS signaling, and aryl hydrocarbon receptor (Ahr) pathways. Cluster analysis identified Ccnd1, Cdkn1a, and Ahr as critical regulatory nodes in the response to hyperoxia, with Ahr serving as the major effector node. A mechanistic role for Ahr was assessed in lung epithelial cells, and we confirmed its ability to regulate the expression of multiple hyperoxia markers, including Cdkn1a, Pdgfrb, and A2m. We conclude that a global assessment of gene regulation in the acute neonatal hyperoxia model of BPD-like pathology has identified Ahr as one driver of gene dysregulation.
authors.affiliation: Division of Neonatology, Department of Pediatrics, University of Rochester Medical Center, Rochester, New York; Pediatric Molecular and Personalized Medicine Program, Department of Pediatrics, University of Rochester Medical Center, Rochester, New York; and.
authors.forename: Soumyaroop
authors.initials: S
authors.lastname: Bhattacharya
authors.affiliation: Division of Neonatology, Department of Pediatrics, University of Rochester Medical Center, Rochester, New York;
authors.forename: Zhongyang
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Division of Neonatology, Department of Pediatrics, University of Rochester Medical Center, Rochester, New York; Perinatal and Pediatric Origins of Disease Program, Department of Pediatrics, University of Rochester Medical Center, Rochester, New York.
authors.forename: Min
authors.initials: M
authors.lastname: Yee
authors.affiliation: Division of Neonatology, Department of Pediatrics, University of Rochester Medical Center, Rochester, New York; Pediatric Molecular and Personalized Medicine Program, Department of Pediatrics, University of Rochester Medical Center, Rochester, New York; and.
authors.forename: Chin-Yi
authors.initials: CY
authors.lastname: Chu
authors.affiliation: Division of Neonatology, Department of Pediatrics, University of Rochester Medical Center, Rochester, New York; Pediatric Molecular and Personalized Medicine Program, Department of Pediatrics, University of Rochester Medical Center, Rochester, New York; and.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Lopez
authors.affiliation: Division of Neonatology, Department of Pediatrics, University of Rochester Medical Center, Rochester, New York; Pediatric Molecular and Personalized Medicine Program, Department of Pediatrics, University of Rochester Medical Center, Rochester, New York; and.
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Lunger
authors.affiliation: Division of Neonatology, Department of Pediatrics, University of Rochester Medical Center, Rochester, New York; Pediatric Molecular and Personalized Medicine Program, Department of Pediatrics, University of Rochester Medical Center, Rochester, New York; and.
authors.forename: Siva Kumar
authors.initials: SK
authors.lastname: Solleti
authors.affiliation: Division of Neonatology, Department of Pediatrics, University of Rochester Medical Center, Rochester, New York; Perinatal and Pediatric Origins of Disease Program, Department of Pediatrics, University of Rochester Medical Center, Rochester, New York.
authors.forename: Emily
authors.initials: E
authors.lastname: Resseguie
authors.affiliation: Division of Neonatology, Department of Pediatrics, University of Rochester Medical Center, Rochester, New York; Perinatal and Pediatric Origins of Disease Program, Department of Pediatrics, University of Rochester Medical Center, Rochester, New York.
authors.forename: Bradley
authors.initials: B
authors.lastname: Buczynski
authors.affiliation: Division of Neonatology, Department of Pediatrics, University of Rochester Medical Center, Rochester, New York; Pediatric Molecular and Personalized Medicine Program, Department of Pediatrics, University of Rochester Medical Center, Rochester, New York; and Tom_Mariani@URMC.rochester.edu.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Mariani
authors.affiliation: Division of Neonatology, Department of Pediatrics, University of Rochester Medical Center, Rochester, New York; Perinatal and Pediatric Origins of Disease Program, Department of Pediatrics, University of Rochester Medical Center, Rochester, New York.
authors.forename: Michael A
authors.initials: MA
authors.lastname: O'Reilly
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D001997:Bronchopulmonary Dysplasia / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D016000:Cluster Analysis; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D016678:Genome; D006801:Humans; D018496:Hyperoxia / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018336:Receptors, Aryl Hydrocarbon; C484722:Ahr protein, mouse
keywords: aryl hydrocarbon receptor; bronchopulmonary dysplasia; high-throughput sequencing-based transcriptional profiling