Doctoral thesis

The cold-inducible RNA-binding protein CIRP regulates circadian gene expression

ContributorsMorf, Jörg
Defense date2011-11-07

Virtually all light-sensitive organisms, ranging from bacteria to human, anticipate and adapt to daily changes in luminosity and/or temperature caused by the rotation of the earth around its own axis. Endogenous circadian clocks synchronize to such external cues and regulate many aspects of behavior and physiology. In mammals, the circadian timing system comprises the master clock in the suprachiasmatic nuclei (SCN) in the brain and subsidiary clocks in most cells of the body. The SCN is reset by light in a daily fashion and in turn ensures phase coherence of subsidiary oscillators in the periphery. The master clock synchronizes peripheral oscillators by diverse means. These include hormone secretion, neuronal cues, rest-activity and feeding-fasting cycles of the animal as well as circadian fluctuations in body temperature. In order to gain insights into how SCN-emitted cues are integrated into peripheral oscillators, we attempted to characterize the function of Cold-inducible RNA-binding protein (CIRP) and to examine its effect on circadian rhythms. CIRP belongs to a group of genes, which are expressed in a circadian manner in mouse liver irrespective of whether local hepatocyte clocks are functional or not. These genes must therefore be regulated by oscillating systemic signals under the direct control of the master clock in the SCN. Conversely, if systemically driven genes, such as Cirp, were involved in the regulation of peripheral core clock components, this would provide a plausible mechanism to relay cyclic SCN signals to the circadian clock circuitry. Indeed, loss-of-function experiments demonstrated that CIRP is required for high-amplitude circadian gene expression and thereby confers robustness to oscillators. We aimed at identifying the molecular interactions between CIRP and circadian clocks. For this purpose, we, purified CIRP–RNA complexes and analyzed CIRP-interacting RNAs through high-throughput sequencing (CLIP-seq). We furthermore deep-sequenced whole transcriptomes (RNA-seq) from control and CIRP-depleted cells, respectively. We thereby identified transcripts associated with and regulated by CIRP. These experiments revealed Clock and several additional core clock components as targets of CIRP and therefore established a molecular link between CIRP and the core clock. Using cultured fibroblasts, a clock model devoid of complex SCN signals, we were able to reconstitute the rhythmic expression of CIRP by imposed circadian temperature fluctuations, suggesting that body temperature cycles act as the systemic signal that regulates CIRP abundance. Thus, CIRP might participate in a pathway, which relays temperature cues to circadian oscillators.

Citation (ISO format)
MORF, Jörg. The cold-inducible RNA-binding protein CIRP regulates circadian gene expression. 2011. doi: 10.13097/archive-ouverte/unige:21635
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