Editors' ChoiceCircadian Biology

Daily oxygen rhythms

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Sci. Signal.  31 Jan 2017:
Vol. 10, Issue 464, eaam8695
DOI: 10.1126/scisignal.aam8695

The hypoxia response system and circadian clock system are interconnected.

Hypoxia occurs when cells or animals experience reduced oxygen availability, and it induces an adaptive transcriptional response through stabilization of the transcription factor hypoxia-inducible factor (HIF)–1α. Circadian physiology is the daily fluctuations in biological processes that are coordinated by the light-dark cycles, which are controlled by a transcriptional circuit involving the transcription factors BMAL and CLOCK, which are the positive regulators, and PER and CRY, which are the negative regulators. Three papers explore the connection between these two aspects of biology.

Wu et al. injected mice with a chemical (DMOG) to induce the accumulation of HIF-1α and found that DMOG-induced gene expression was impaired in mice with mutations in or genetic deficiency of the genes that regulate the circadian clock. Experiments measuring promoter occupancy, endogenous gene expression, and reporter gene induction in various mutant backgrounds and under conditions in which HIF-1α was chemically stabilized to mimic hypoxia indicated that BMAL1 stimulated, whereas PER2 inhibited, HIF1A expression, and that HIF-1α and BMAL1 coregulated multiple genes, including PER2. Additionally, injecting the mice at different times during the daily cycle with a drug in clinical trials that stabilizes HIF-1α resulted in differences in the induction of EPO, which is encoded by a HIF-1α target gene, suggesting that clinical effectiveness could be influenced by the time of day at which the drug is administered. Furthermore, in a mouse model of heart attack, Per2–/– mice exhibited a greater region of damage than did wild-type mice and showed increased transcripts of HIF-1α target genes, especially the proapoptotic gene Bnip3, which may contribute to the enhanced damage in the Per2–/– mice. Thus, the authors propose that the effect of circadian rhythms be considered when treating patients, especially when using drugs that affect HIF-1α–regulated processes or when treating conditions related to hypoxia.

Peek et al. examined the connection between circadian signaling and hypoxia in skeletal muscle. Although the central clock is in the brain, peripheral tissues and even cells in culture exhibit circadian fluctuations in behavior. Analysis of wild-type and Bmal1–/– C2C12 myotubes revealed circadian variations in metabolism such that the cells shifted between oxidative and glycolytic metabolism in a BMAL1-dependent manner. Many of the genes that enable glycolytic metabolism are regulated by HIF-1α, and Bmal1–/– myotubes had reduced Hif1a mRNA and increased HIF-1α turnover. Similar to the results of Wu et al., conditions that affected HIF-1α stability altered oscillations in a PER2-controlled reporter or endogenous clock-regulating genes. Analysis of the muscles of mice that had performed strenuous exercise at different times in the circadian cycle revealed that HIF-1α target genes exhibited minimal induction during the resting part of the cycle. The authors proposed that clock-dependent regulation of HIF-1α in skeletal muscle primes the tissue to enable the best performance during the time of day when activity is likely to be the greatest.

Adamovich et al. found that oxygen consumption throughout the daily cycle in mice was highest during the active period, and that the amount of oxygen in the blood and kidney exhibited circadian fluctuations. However, individual organs showed differences in the peak of nuclear HIF-1α, with the kidney exhibiting a peak that occurred 4 hours before that in the brain. This difference correlated with the abundance of the clock-regulating transcription factor REV-ERBα. Exposing two different human cultured cell lines to 12-hour cycles of 5% O2 followed by 12-hour cycles of 8% O2 (to mimic physiological O2 rhythms) followed by continuous culture in 8% O2 resulted in the rhythmic expression of clock-regulating genes, and this response depended on HIF-1α. Decreased O2 increased the expression of some negative regulatory clock genes, and the regulation of Cry2 and Per1 by changes in O2 required HIF-1α. Mice that had been exposed to a sleep-wake cycle that mimics jet lag adapted more quickly when exposed to a 2-hour period of low oxygen (14%) before the shift in lighting. This response was absent in mice heterozygous for Hif1a, confirming that oxygen affected the circadian clock through the hypoxia pathway.

Transcription is not the only process affected by circadian rhythms. As Robles et al. showed, mouse livers exhibited daily oscillations in the abundances of thousands of phosphorylated proteins, including the clock-regulating transcription factors. Bioinformatic analysis matched kinases with substrates, enabling the authors to generate a temporal map of the daily rhythms in kinase-mediated signaling in mouse liver. This set of papers illustrates the complexity in organismal physiology and indicates the importance of considering circadian biology in investigating normal and pathophysiological processes and pharmacological intervention.

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