Edited by Joseph S. Takahashi, The University of Texas Southwestern Medical Center, Dallas, TX, and approved November 20, 2019 (received for review August 14, 2019)
Circadian clocks are present in most cells of the body and act in concert to coordinate our daily physiology and behavior with the environment. Circadian misalignment between body clocks and the environment has been implicated in various pathologies. Here, we show that circadian misalignment can also occur between clocks of different peripheral tissues following exposure to hypoxia and that it stems from the differential response of core clock components to hypoxia. Intertissue circadian misalignment also occurs upon intermittent hypoxia, a model for obstructive sleep apnea (OSA). Our findings highlight the potential role of internal circadian misalignment in the pathophysiology of OSA and potentially other hypoxia-related diseases.
The occurrence and sequelae of disorders that lead to hypoxic spells such as asthma, chronic obstructive pulmonary disease, and obstructive sleep apnea (OSA) exhibit daily variance. This prompted us to examine the interaction between the hypoxic response and the circadian clock in vivo. We found that the global transcriptional response to acute hypoxia is tissue-specific and time-of-day–dependent. In particular, clock components differentially responded at the transcriptional and posttranscriptional level, and these responses depended on an intact circadian clock. Importantly, exposure to hypoxia phase-shifted clocks in a tissue-dependent manner led to intertissue circadian clock misalignment. This differential response relied on the intrinsic properties of each tissue and could be recapitulated ex vivo. Notably, circadian misalignment was also elicited by intermittent hypoxia, a widely used model for OSA. Given that phase coherence between circadian clocks is considered favorable, we propose that hypoxia leads to circadian misalignment, contributing to the pathophysiology of OSA and potentially other diseases that involve hypoxia.
Author contributions: G.M. and G.A. designed research; G.M., R.A., N.B., S.M., and M.G. performed research; D.F.S. contributed new reagents/analytic tools; G.M. analyzed data; and G.M. and G.A. wrote the paper.
The authors declare no competing interest.
This article is a PNAS Direct Submission.
Data disposition: RNA-Seq data, including fastq files and raw counts, have been uploaded to the Gene Expression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo, under accession number GSE130613; the analyzed data are provided in Datasets S1 and S2.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1914112117/-/DCSupplemental.
Published under the PNAS license.
