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Science Translational Medicine  28 Jun 2017:
Vol. 9, Issue 396, eaan6728
DOI: 10.1126/scitranslmed.aan6728


A new type of biological clock regulates the unfolded protein response.

Daily (circadian) rhythms are a dominant feature of biology, extending from behavior and physiology down to gene expression. However, there are other important rhythms in nature, from longer duration seasonal rhythms to faster (ultradian) rhythms like your heartbeat. We now know that circadian rhythms in gene expression are driven by a molecular clock present in most cells. However, a proportion of genes exhibit ultradian rather than circadian variation, and we know less about the significance of these rhythms and how they come about. Using a new method for detecting rhythmic gene expression, Zhu et al. present evidence for a new biological clock that is responsible for generating ultradian gene expression rhythms. This new clock appears to be genetically distinct from the circadian clock, runs on a 12-hour cycle (rather than 24), and resembles a system previously seen only in crustaceans that live in tidal pools. Many of the genes entrained by this 12-hour clock are involved in the unfolded protein response and have been implicated in fatty liver disease in humans, suggesting that the system has translational relevance. More broadly, the paper challenges a popular assumption of homeostasis: that most genes have a constant “set point” of expression that deviates only when an organism is challenged with a stimulus. However, if the authors are right, then the vast majority of transcripts have no homeostatic set point of expression even in mammals but rather oscillate at some dominant frequency. One caveat about this study is that the results depend heavily on a new methodology for analyzing gene expression, which is laid out in the paper but is unorthodox and will need to be validated. Nevertheless, Zhu et al. raise the exciting possibility of a new biological clock that potentially could be harnessed to develop new therapies.

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