Reciprocal Regulation between the Circadian Clock and Hypoxia Signaling at the Genome Level in Mammals

Abstract

Circadian regulation is critically important in maintaining metabolic and physiological homeostasis. However, little is known about the possible influence of the clock on physiological abnormalities occurring under pathological conditions. Here, we report the discovery that hypoxia, a condition that causes catastrophic bodily damage, is gated by the circadian clock in vivo. Hypoxia signals conversely regulate the clock by slowing the circadian cycle and dampening the amplitude of oscillations in a dose-dependent manner. ChIP-seq analyses of hypoxia-inducible factor HIF1A and the core clock component BMAL1 revealed crosstalk between hypoxia and the clock at the genome level. Further, severe consequences caused by acute hypoxia, such as those that occur with heart attacks, were correlated with defects in circadian rhythms. We propose that the clock plays functions in fine-tuning hypoxic responses under pathophysiological conditions. We argue that the clock can, and likely should, be exploited therapeutically to reduce the severity of fatal hypoxia-related diseases.

Metabolic Plasticity Enables Circadian Adaptation to Acute Hypoxia in Zebrafish Cells

“…As a consequence, the NAD + /NADH ratio oscillation aligns with the hypoxia induced high amplitude rhythm of the NADP + /NADPH ratio and nocturnal Prx ox , leading to highly oxidized states of the cells during the night periods. While oscillations of canonical clock genes are already dampened after short time hypoxic incubation as it is also known from experiments with chronic hypoxia [10, 14, 15, 28, 30], circadian rhythms of cytosolic H 2 O 2 remain absolutely unaffected by the hypoxia induced metabolic and transcriptional changes, implicating that a cellular timekeeping mechanism apart from the transcriptional clock is quite robust against the stress of reduced oxygen tensions. The hypoxia-induced and mostly Hif-1α driven response observed in cellular metabolic rhythms might thus form the basis for the observed hypoxia induced attenuation of the TTFL, against the background of the reduced binding affinity of the CLOCK/BMAL1 complex to DNA in a highly oxidized cellular environment.…”

“…The reciprocal interaction between the hypoxic signaling pathway and the circadian clock was described for the first time in the vertebrate model zebrafish [10, 28] and only recently also found and characterized in more detail in mammals [5, 14, 15], which stresses the translational potential of the findings and the essential nature of the observed link, representing a fundamental aspect of eukaryotic cell biology. In this context, reduced oxygen tensions were found to dampen oscillation amplitudes of core clock genes in vertebrates including mammals through direct binding of Hypoxia Inducible Factor 1α (Hif-1α) to E-boxes of the genes period1, period2 and cryptochrome1 , all members of the negative limb of the core transcriptional translational feedback loop (TTFL) [10, 14, 15, 28, 30].…”

“…In this context, reduced oxygen tensions were found to dampen oscillation amplitudes of core clock genes in vertebrates including mammals through direct binding of Hypoxia Inducible Factor 1α (Hif-1α) to E-boxes of the genes period1, period2 and cryptochrome1 , all members of the negative limb of the core transcriptional translational feedback loop (TTFL) [10, 14, 15, 28, 30]. In turn, the expression of Hif-1α protein was shown to be clock controlled, and examples for the physiological relevance of the observed link between both pathways was likewise illustrated in zebrafish [28] and in mice [5, 15]. …”

“…The cellular system to cope with reduced oxygen levels, the hypoxic signaling pathway with its major transcription factor Hypoxia Inducible Factor-1 α (HIF-1α) and its isoforms has thus been extensively studied from invertebrates to humans [1-4]. Besides, oxygen deficiency has also been shown to affect another essential pathway, the circadian clock, an interplay which meanwhile has been explored in a couple of physiological and molecular studies [5-15]. …”

“…The influence of hypoxia on the TTFL has been investigated in several vertebrate studies [5, 7, 10, 14, 15] and the HIF-1α mediated dampening of specific core clock gene oscillation amplitudes, first described in zebrafish [10, 28] was specified recently also in mice [14, 15]. Similarly, consequences of the reported link between both pathways for organismic physiology were illustrated in both models, in zebrafish [28] and in mice [5, 15], which stresses the translational impact of the findings and the essential nature of the mutual interaction between the circadian clock and oxygen metabolism.…”