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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.

SUBMITTER: Bhattacharya S

PROVIDER: S-EPMC4280157 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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The genome-wide transcriptional response to neonatal hyperoxia identifies Ahr as a key regulator.

Bhattacharya Soumyaroop S Zhou Zhongyang Z Yee Min M Chu Chin-Yi CY Lopez Ashley M AM Lunger Valerie A VA Solleti Siva Kumar SK Resseguie Emily E Buczynski Bradley B Mariani Thomas J TJ O'Reilly Michael A MA

American journal of physiology. Lung cellular and molecular physiology 20140822 7

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 fo ...[more]

PMID: 25150061

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Project description:Pasteurella multocida is a Gram-negative capsulated bacterium responsible for a range of diseases that cause severe morbidity and mortality in livestock animals. The hyaluronic acid (HA) capsule produced by P. multocida serogroup A strains is a critical virulence factor. In this study, we utilized transposon-directed insertion site sequencing (TraDIS) to identify genes essential for in vitro growth of P. multocida and combined TraDIS with discontinuous density gradients (TraDISort) to identify genes required for HA capsule production and regulation in this pathogen. Analysis of mutants with a high cell density phenotype, indicative of the loss of extracellular capsule, led to the identification of 69 genes important for capsule production. These genes included all previously characterized genes in the capsule biosynthesis locus and fis and hfq, which encode known positive regulators of P. multocida capsule. Many of the other capsule-associated genes identified in this study were involved in regulation or activation of the stringent response, including spoT and relA, which encode proteins that regulate the concentration of guanosine alarmones. Disruption of the autoregulatory domains in the C-terminal half of SpoT using insertional mutagenesis resulted in reduced expression of capsule biosynthesis genes and an acapsular phenotype. Overall, these findings have greatly increased the understanding of hyaluronic acid capsule production and regulation in P. multocida. IMPORTANCE The bacterial pathogen P. multocida can cause serious disease in production animals, including fowl cholera in poultry, hemorrhagic septicemia in cattle and buffalo, atrophic rhinitis in pigs, and respiratory diseases in a range of livestock. P. multocida produces a capsule that is essential for systemic disease, but the complete mechanisms underlying synthesis and regulation of capsule production are not fully elucidated. A whole-genome analysis using TraDIS was undertaken to identify genes essential for growth in rich media and to obtain a comprehensive characterization of capsule production. Many of the capsule-associated genes identified in this study were involved in the stringent response to stress, a novel finding for this important animal pathogen.

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The genome-wide transcriptional response to neonatal hyperoxia identifies Ahr as a key regulator.

Publications

The genome-wide transcriptional response to neonatal hyperoxia identifies Ahr as a key regulator.

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