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A Novel Protein, CHRONO, Functions as a Core Component of the Mammalian Circadian Clock

2014; Public Library of Science; Volume: 12; Issue: 4 Linguagem: Inglês

10.1371/journal.pbio.1001839

1545-7885

Akihiro Goriki, Fumiyuki Hatanaka, Jihwan Myung, Jae Kyoung Kim, Takashi Yoritaka, Shintaro Tanoue, Takaya Abe, Hiroshi Kiyonari, Katsumi Fujimoto, Yukio Kato, Takashi Todo, Akio Matsubara, Daniel B. Forger, Toru Takumi,

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Circadian rhythms are controlled by a system of negative and positive genetic feedback loops composed of clock genes. Although many genes have been implicated in these feedback loops, it is unclear whether our current list of clock genes is exhaustive. We have recently identified Chrono as a robustly cycling transcript through genome-wide profiling of BMAL1 binding on the E-box. Here, we explore the role of Chrono in cellular timekeeping. Remarkably, endogenous CHRONO occupancy around E-boxes shows a circadian oscillation antiphasic to BMAL1. Overexpression of Chrono leads to suppression of BMAL1–CLOCK activity in a histone deacetylase (HDAC) –dependent manner. 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. 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.