Functional characterization of cryptochromes CRY1 and CRY2 as metabolic sensors in the circadian regulation of mammalian physiology

• Applicant: Dr. Sabine Jordan
• Subject Area: Cell Biology
• Term: from 2011 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 213940697

Circadian clocks coordinate behavioral and physiological processes with day-night cycles through alternating actions of activators and repressors of gene expression. The transcriptional regulators BMAL1 and CLOCK activate expression of many genes including their own inhibitors period (PER1-3) and cryptochrome (CRY1&2), resulting in oscillating expression of target genes. For a long time mammalian clocks were thought to be confined to a small area of the hypothalamus that controls circadian rhythms in locomotor activity in relation to light stimuli. However, within the last decade, it has been shown that circadian clocks are widely distributed in mammalian tissues. The demonstration that feeding schedules determine the timing of peripheral clocks and the emerging evidence that dysregulation of circadian rhythms can contribute to obesity and diabetes, suggest that circadian regulation is intimately linked to metabolic homeostasis. The recent demonstration that AMPK, a central mediator of metabolic signaling, phosphorylates and thereby destabilizes CRY1 provides a molecular mechanism by which metabolic signals can reset the timing of circadian clocks. Moreover this finding suggests that, in addition to their role in clock function, CRYs may be important regulators of metabolism. This is further supported by the finding that CRYs physically interact with PPARs, a family of nuclear hormone receptors that regulates various essential metabolic processes.In the proposed study I will test the hypothesis that AMPK-mediated CRY1 phosphorylation plays a role in the transcriptional regulation of skeletal muscle metabolism and that CRYs interaction with PPARs is involved in these processes. These analyses hold the potential to further elucidate the molecular mechanisms by which CRYs regulate transcription in response to metabolic signals and will unravel their impact on skeletal muscle physiology, which plays a central role in mammalian metabolic homeostasis.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professorin Dr. Katja Lamia