Editors' ChoiceCircadian Rhythms

Resetting a Lagging Body Clock

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Sci. Signal.  10 Sep 2013:
Vol. 6, Issue 292, pp. ec215
DOI: 10.1126/scisignal.2004707

Traveling across time zones or to latitudinal extremes can severely compromise sleep patterns, metabolism, and cognition. Also known as jet lag, this can take multiple days to overcome as the circadian rhythm (or clock) is adjusted in response to the new light cycle. In mammals, the circadian clock is controlled by a 24-hour transcriptional-translational feedback loop. Light-sensitive proteins, such as opsins, reset the clock. Jagannath et al. found that a protein within this loop, salt-inducible kinase 1 (SIK1), functions as a negative feedback inhibitor in the circadian cycle and that inhibiting Sik1 in mice hastened resetting of the clock. Whole-genome exon arrays performed after a 2-hour exposure to nocturnal light in wild-type or Opn4–/– mice revealed a large set of light- and OPN4 (opsin 4, also known as melanopsin)–regulated genes in cells of the suprachiasmatic nuclei. In addition to known clock-related genes, such as Crtc1 [encoding c-AMP response element binding protein (CREB)–regulated transcription coactivator 1] and Per1 (encoding period circadian clock 1), the expression of Sik1 was increased after light stimuli. The promoters of Per1 and Sik1 contain CREB-binding sites, suggesting that they are direct CREB targets. The circadian clock can also be manipulated by factors in serum, and serum-induced clock models in human cell lines confirmed the immediate induction of CRTC1, PER1, and SIK1 expression, as well as that of EGR1 and NR4A1 (other light-induced genes). At later time points, the expression of PER1, EGR1, and NR4A1 returned to that seen prestimulus. The peak mRNA abundance of each was decreased in CRTC1-knockdown cells and was increased in SIK1-knockdown cells. CRTC1 was phosphorylated and inactivated by SIK1 both in vitro and in cell lysates, and its phosphorylation increased after serum-induced SIK1 expression in wild-type but not SIK1-knockdown cells, suggesting that SIK1 is both a downstream transcriptional target and a feedback inhibitor of CRTC1. In mice, knockdown of Sik1 through intracranial siRNA injection increased the speed of circadian adjustment to shifted, extended, or shortened light periods. The findings indicate that because SIK1 represses the effects of light on the circadian clock, it may be a target for treating jet lag and other circadian rhythm disruption disorders.

A. Jagannath, R. Butler, S. I. H. Godinho, Y. Couch, L. A. Brown, S. R. Vasudevan, K. C. Flanagan, D. Anthony, G. C. Churchill, M. J. A. Wood, G. Steiner, M. Ebeling, M. Hossbach, J. G. Wettstein, G. E. Duffield, S. Gatti, M. W. Hankins, R. G. Foster, S. N. Peirson, The CRTC1-SIK1 pathway regulates entrainment of the circadian clock. Cell 154, 1100–1111 (2013). [PubMed]