Short-term exposure to intermittent hypoxia leads to changes in gene expression seen in chronic pulmonary disease
- Cincinnati Children's Hospital Medical Center, United States
- University of Cincinnati College of Medicine, United States
Abstract
Obstructive sleep apnea (OSA) results from episodes of airway collapse and intermittent hypoxia (IH) and is associated with a host of health complications. Although the lung is the first organ to sense changes in oxygen levels, little is known about the consequences of IH to the lung hypoxia-inducible factor- (HIF)-responsive pathways. We hypothesized that exposure to IH would lead to cell-specific up and downregulation of diverse expression pathways. We identified changes in circadian and immune pathways in lungs from mice exposed to IH. Among all cell types, endothelial cells showed the most prominent transcriptional changes. Upregulated genes in myofibroblast cells were enriched for genes associated with pulmonary hypertension and included targets of several drugs currently used to treat chronic pulmonary diseases. A better understanding of the pathophysiologic mechanisms underlying diseases associated with OSA could improve our therapeutic approaches, directing therapies to the most relevant cells and molecular pathways.
Data availability
Sequencing data has been uploaded to GEO (GSE145436), as mentioned in the manuscript 'Data and Materials Availability' section.
Article and author information
Author details
Funding
National Institutes of Health (5K08HL148551-02)
- David F Smith
American Laryngological, Rhinological and Otological Society (2017 Career Development Award)
- David F Smith
American Society of Pediatric Otolaryngology (2016 Basic Research Award)
- David F Smith
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Anurag Agrawal, CSIR Institute of Genomics and Integrative Biology, India
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#2019-0028) of the Cincinnati Children's Hospital Medical Center.
Version history
- Received: September 11, 2020
- Accepted: February 17, 2021
- Accepted Manuscript published: February 18, 2021 (version 1)
- Accepted Manuscript updated: February 19, 2021 (version 2)
- Version of Record published: February 26, 2021 (version 3)
Copyright
© 2021, Wu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 3,139
- views
-
- 408
- downloads
-
- 22
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Short-term exposure to intermittent hypoxia leads to changes in gene expression seen in chronic pulmonary disease
eLife 10:e63003.
https://doi.org/10.7554/eLife.63003
Further reading
-
- Chromosomes and Gene Expression
RNA polymerase II (RNAPII) transcription initiates bidirectionally at many human protein-coding genes. Sense transcription usually dominates and leads to messenger RNA production, whereas antisense transcription rapidly terminates. The basis for this directionality is not fully understood. Here, we show that sense transcriptional initiation is more efficient than in the antisense direction, which establishes initial promoter directionality. After transcription begins, the opposing functions of the endonucleolytic subunit of Integrator, INTS11, and cyclin-dependent kinase 9 (CDK9) maintain directionality. Specifically, INTS11 terminates antisense transcription, whereas sense transcription is protected from INTS11-dependent attenuation by CDK9 activity. Strikingly, INTS11 attenuates transcription in both directions upon CDK9 inhibition, and the engineered recruitment of CDK9 desensitises transcription to INTS11. Therefore, the preferential initiation of sense transcription and the opposing activities of CDK9 and INTS11 explain mammalian promoter directionality.
-
- Chromosomes and Gene Expression
Tiny animals known as tardigrades use a combination of DNA repair machinery and a novel protein to mend their genome after intense ionizing radiation.
