Obstructive sleep apnea disrupts all-day gene activity in mice

Low blood oxygen levels from obstructive sleep apnea lead to widespread changes in gene activity throughout the day, according to a new study in the open access journal PLOS Biology by David Smith of Cincinnati Children’s Hospital Medical Center, US, and colleagues. These findings could lead to tools for early diagnosis and tracking of the disorder.

Obstructive sleep apnea (OSA) occurs when the airway is blocked (usually by soft tissue, related to snoring and impaired breathing at night), resulting in intermittent hypoxia (low blood oxygen) and disturbed sleep. It affects more than one billion people worldwide and costs $150 billion annually in direct medical costs in the United States alone. OSA increases the risk of cardiovascular, respiratory, metabolic and neurological complications.

The activity of many genes varies naturally throughout the day, in part in response to the activity of circadian clock genes, whose regular oscillations drive circadian variation up to half the genome. Gene activity also varies in response to external factors, including decreased oxygen levels, leading to the production of “hypoxia inducible factors”, which affect the activity of many genes, including clock genes. To better understand how OSA might influence gene activity throughout the day, the authors exposed mice to intermittent hypoxic conditions and examined whole-genome transcription in six tissues—lung, liver, kidney, muscle, heart, and cerebellum—throughout the day. The authors then evaluated circadian timing variations of gene expression in these same tissues.

The largest changes were found in the lung, where intermittent hypoxia affected the transcription of nearly 16% of all genes, most of which were upregulated. Less than 5% of genes are affected in the heart, liver and cerebellum. The subset of genes that normally display circadian rhythms was even more strongly affected by intermittent hypoxia, with significant changes seen in 74% of the genes in the lung and 66.9% of the genes in the heart. Among the genes affected in each network were known clock genes, effects of which likely contributed to the large changes in the circadian activity of other genes seen in this network.

“Our findings provide new insights into the pathophysiological mechanisms that may be associated with end organ damage in patients with chronic exposure to intermittent hypoxia,” said Smith, “and may be useful for identifying targets for future mechanistic studies evaluating diagnostic or therapeutic approaches; for example, through a blood test that traces one of the disordered gene products to detect OSA early.

Bala SC Koritala added, “Our research using the animal model of Obstructive Sleep Apnea uncovered time- and tissue-specific variations of the entire genome transcriptome and associated trait pathways. This unique finding sheds light on the early biological changes associated with this disorder, which occur in multiple organ systems.”

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Quote: Koritala BSC, Lee YY, Gaspar LS, Bhadri SS, Su W, Wu G, et al. (2023) Obstructive sleep apnea in a mouse model is associated with tissue-specific transcriptomic changes in circadian rhythms and average 24-hour gene expression. PLoS Biol 21(5): e3002139. https://doi.org/10.1371/journal.pbio.3002139

Author’s Country: United States, Portugal

Funding: see manuscript