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Transcriptional Programs Controlling Perinatal Lung Maturation

The timing of lung maturation is controlled precisely by complex genetic and cellular programs. Lung immaturity following preterm birth frequently results in Respiratory Distress Syndrome (RDS) and Broncho-Pulmonary Dysplasia (BPD), which are leading causes of mortality and morbidity in preterm infa...

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Autores principales: Xu, Yan, Wang, Yanhua, Besnard, Valérie, Ikegami, Machiko, Wert, Susan E., Heffner, Caleb, Murray, Stephen A., Donahue, Leah Rae, Whitsett, Jeffrey A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3423373/
https://www.ncbi.nlm.nih.gov/pubmed/22916088
http://dx.doi.org/10.1371/journal.pone.0037046
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author Xu, Yan
Wang, Yanhua
Besnard, Valérie
Ikegami, Machiko
Wert, Susan E.
Heffner, Caleb
Murray, Stephen A.
Donahue, Leah Rae
Whitsett, Jeffrey A.
author_facet Xu, Yan
Wang, Yanhua
Besnard, Valérie
Ikegami, Machiko
Wert, Susan E.
Heffner, Caleb
Murray, Stephen A.
Donahue, Leah Rae
Whitsett, Jeffrey A.
author_sort Xu, Yan
collection PubMed
description The timing of lung maturation is controlled precisely by complex genetic and cellular programs. Lung immaturity following preterm birth frequently results in Respiratory Distress Syndrome (RDS) and Broncho-Pulmonary Dysplasia (BPD), which are leading causes of mortality and morbidity in preterm infants. Mechanisms synchronizing gestational length and lung maturation remain to be elucidated. In this study, we designed a genome-wide mRNA expression time-course study from E15.5 to Postnatal Day 0 (PN0) using lung RNAs from C57BL/6J (B6) and A/J mice that differ in gestational length by ∼30 hr (B6<A/J). Comprehensive bioinformatics and functional genomics analyses were used to identify key regulators, bioprocesses and transcriptional networks controlling lung maturation. We identified both temporal and strain dependent gene expression patterns during lung maturation. For time dependent changes, cell adhesion, vasculature development, and lipid metabolism/transport were major bioprocesses induced during the saccular stage of lung development at E16.5–E17.5. CEBPA, PPARG, VEGFA, CAV1 and CDH1 were found to be key signaling and transcriptional regulators of these processes. Innate defense/immune responses were induced at later gestational ages (E18.5–20.5), STAT1, AP1, and EGFR being important regulators of these responses. Expression of RNAs associated with the cell cycle and chromatin assembly was repressed during prenatal lung maturation and was regulated by FOXM1, PLK1, chromobox, and high mobility group families of transcription factors. Strain dependent lung mRNA expression differences peaked at E18.5. At this time, mRNAs regulating surfactant and innate immunity were more abundantly expressed in lungs of B6 (short gestation) than in A/J (long gestation) mice, while expression of genes involved in chromatin assembly and histone modification were expressed at lower levels in B6 than in A/J mice. The present study systemically mapped key regulators, bioprocesses, and transcriptional networks controlling lung maturation, providing the basis for new therapeutic strategies to enhance lung function in preterm infants.
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spelling pubmed-34233732012-08-22 Transcriptional Programs Controlling Perinatal Lung Maturation Xu, Yan Wang, Yanhua Besnard, Valérie Ikegami, Machiko Wert, Susan E. Heffner, Caleb Murray, Stephen A. Donahue, Leah Rae Whitsett, Jeffrey A. PLoS One Research Article The timing of lung maturation is controlled precisely by complex genetic and cellular programs. Lung immaturity following preterm birth frequently results in Respiratory Distress Syndrome (RDS) and Broncho-Pulmonary Dysplasia (BPD), which are leading causes of mortality and morbidity in preterm infants. Mechanisms synchronizing gestational length and lung maturation remain to be elucidated. In this study, we designed a genome-wide mRNA expression time-course study from E15.5 to Postnatal Day 0 (PN0) using lung RNAs from C57BL/6J (B6) and A/J mice that differ in gestational length by ∼30 hr (B6<A/J). Comprehensive bioinformatics and functional genomics analyses were used to identify key regulators, bioprocesses and transcriptional networks controlling lung maturation. We identified both temporal and strain dependent gene expression patterns during lung maturation. For time dependent changes, cell adhesion, vasculature development, and lipid metabolism/transport were major bioprocesses induced during the saccular stage of lung development at E16.5–E17.5. CEBPA, PPARG, VEGFA, CAV1 and CDH1 were found to be key signaling and transcriptional regulators of these processes. Innate defense/immune responses were induced at later gestational ages (E18.5–20.5), STAT1, AP1, and EGFR being important regulators of these responses. Expression of RNAs associated with the cell cycle and chromatin assembly was repressed during prenatal lung maturation and was regulated by FOXM1, PLK1, chromobox, and high mobility group families of transcription factors. Strain dependent lung mRNA expression differences peaked at E18.5. At this time, mRNAs regulating surfactant and innate immunity were more abundantly expressed in lungs of B6 (short gestation) than in A/J (long gestation) mice, while expression of genes involved in chromatin assembly and histone modification were expressed at lower levels in B6 than in A/J mice. The present study systemically mapped key regulators, bioprocesses, and transcriptional networks controlling lung maturation, providing the basis for new therapeutic strategies to enhance lung function in preterm infants. Public Library of Science 2012-08-20 /pmc/articles/PMC3423373/ /pubmed/22916088 http://dx.doi.org/10.1371/journal.pone.0037046 Text en © 2012 Xu et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Xu, Yan
Wang, Yanhua
Besnard, Valérie
Ikegami, Machiko
Wert, Susan E.
Heffner, Caleb
Murray, Stephen A.
Donahue, Leah Rae
Whitsett, Jeffrey A.
Transcriptional Programs Controlling Perinatal Lung Maturation
title Transcriptional Programs Controlling Perinatal Lung Maturation
title_full Transcriptional Programs Controlling Perinatal Lung Maturation
title_fullStr Transcriptional Programs Controlling Perinatal Lung Maturation
title_full_unstemmed Transcriptional Programs Controlling Perinatal Lung Maturation
title_short Transcriptional Programs Controlling Perinatal Lung Maturation
title_sort transcriptional programs controlling perinatal lung maturation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3423373/
https://www.ncbi.nlm.nih.gov/pubmed/22916088
http://dx.doi.org/10.1371/journal.pone.0037046
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