A novel protein, CHRONO, functions as a core component of the mammalian circadian clock

• Published in: PLoS biology Vol. 12; no. 4; p. e1001839
• Main Authors: Goriki, Akihiro, Hatanaka, Fumiyuki, Myung, Jihwan, Kim, Jae Kyoung, Yoritaka, Takashi, Tanoue, Shintaro, Abe, Takaya, Kiyonari, Hiroshi, Fujimoto, Katsumi, Kato, Yukio, Todo, Takashi, Matsubara, Akio, Forger, Daniel, Takumi, Toru
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.04.2014; Public Library of Science (PLoS)
• Subjects: 3T3 Cells; Amino Acid Sequence; Animals; ARNTL Transcription Factors - metabolism; Biological clocks; Biology and Life Sciences; Cell Line; Chlorocebus aethiops; Circadian Clocks - genetics; Circadian Clocks - physiology; Circadian rhythm; Circadian Rhythm - genetics; Circadian Rhythm - physiology; Circadian Rhythm Signaling Peptides and Proteins - biosynthesis; Circadian Rhythm Signaling Peptides and Proteins - genetics; Circadian Rhythm Signaling Peptides and Proteins - metabolism; COS Cells; Cryptochromes - genetics; Cryptochromes - metabolism; Genes; Histone Deacetylases - metabolism; Mammals; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Sequence Data; Receptors, Glucocorticoid - metabolism; Repressor Proteins - biosynthesis; Repressor Proteins - genetics; Repressor Proteins - metabolism; Rodents; Sequence Alignment; Transcription, Genetic - genetics
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.1001839

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.