Abstract
Author SummaryMost organisms show daily rhythms in physiology, behavior, and metabolism, which may be advantageous because they anticipate environmental changes thus optimize energy metabolism. These rhythms are controlled by the circadian clock, which produces cyclic expression of thousands of output genes. More than a dozen components of the circadian clock are called clock genes, and the proteins they encode form a transcription factor network that generates rhythmic gene expression. In this study, we set out to control the function of the circadian clock and to identify new clock proteins by means of chemical tools. We tested the effects on the clock in human cells of around 120,000 uncharacterized compounds. Here we describe identification of a novel compound “longdaysin” that markedly slows the circadian clock both in cultured mammalian cells and in living zebrafish. By using longdaysin as a chemical probe, we found new proteins that modulate clock function. Because defects of clock function have been linked to numerous diseases, longdaysin may form the basis for therapeutic strategies directed towards circadian rhythm-related disorders, shift-work fatigue, and jet lag.
Highlights
A variety of physiological processes such as sleep/wake behavior, body temperature, hormone secretion, and metabolism show daily rhythms under the control of the circadian clock which is intrinsic to the organism
We identified a number of compounds with different scaffolds that lengthened the circadian period of cellular luminescence rhythms
We further investigated the effect of longdaysin (Figure 1C–E) by using primary cells and tissues isolated from mPer2Luc knockin mice harboring a mPer2Luc reporter [45,46] as an additional clock-controlled reporter different from Bmal1-dLuc used in the screen
Summary
A variety of physiological processes such as sleep/wake behavior, body temperature, hormone secretion, and metabolism show daily rhythms under the control of the circadian clock which is intrinsic to the organism. The manifestation of circadian disorders at the level of the whole organism can be caused by dysfunction of the clock at the level of intracellular networks, as single cells exhibit circadian rhythms in a cell-autonomous manner [5,6]. In mammals, these cellular oscillators are organized in a hierarchy, in which the suprachiasmatic nucleus (SCN) of the hypothalamus constitutes the central circadian pacemaker controlling behavioral rhythms, while peripheral clocks in other tissues control local rhythmic outputs [1,3,7]. In the intracellular circadian network, the clock genes and their protein products form transcriptional feedback loops: CLOCK and BMAL1 transcription factors activate expression of Per and Cry genes, and PER and CRY proteins (PER1, PER2, CRY1, and CRY2) in turn inhibit their own transcription to generate rhythmic gene expression [3,8]
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