Researchers from RIKEN, Hiroshima University, and the University of Michigan report the discovery of a gene that plays a key role in influencing circadian rhythms. In their study (“A Novel Protein, CHRONO, Functions as a Core Component of the Mammalian Circadian Clock”), which appears in PLOS Biology, the team performed a genome-wide chromatin immunoprecipitation analysis for genes that were the target of BMAL1, a core clock component that binds to many other circadian clock genes, regulating their transcription.

The authors, who call the new gene they found Chrono, show that it functions as a transcriptional repressor of the negative feedback loop in the mammalian clock. The Chrono protein binds to the regulatory region of clock genes, with its repressor function oscillating in a circadian manner. The expression of core clock genes is altered in mice lacking the Chrono gene, and the mice have longer circadian cycles.

“In vivo loss-of-function studies of Chrono including Avp neuron-specific knockout (KO) mice display a longer circadian period of locomotor activity. Chrono KO also alters the expression of core clock genes and impairs the response of the circadian clock to stress,” write the investigators. “Chrono forms a complex with the glucocorticoid receptor and mediates glucocorticoid response. Our comprehensive study spotlights a previously unrecognized clock component of an unsuspected negative circadian feedback loop that is independent of another negative regulator, Cry2, and that integrates behavioral stress and epigenetic control for efficient metabolic integration of the clock.”

According to the scientists, “These results suggest that Chrono functions as a core clock repressor.”

All organisms, from mammals to fungi, have daily cycles controlled by a tightly regulated internal circadian clock. The whole-body circadian clock, influenced by the exposure to light, dictates the wake-sleep cycle. By obtaining a deeper understanding of the functioning of these circadian rhythms, the researchers hope to gain better insights into their impact on the physiology of humans and other mammals.

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