The mammalian circadian clock system consists of inputs from light and feeding, a core pacemaker located in a paired nuclei, called suprachiasmatic nucleus (SCN), and outputs including, but not limited to, cycles of locomotor activity, sleep–awake, and hormonal secretion. Transcription–translation feedback loop WT,Ĭircadian rhythms with a period of approximately 24 h endow organisms with the ability to adapt to changes of solar light following earth's rotation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interests exist. NSF grant DMS-0931642 to the Mathematical Biosciences Institute (JKK). This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.įunding: Japan Society of Promotion of Science and Ministry of Education, Culture, Sports, Science, and Technology KAKENHI, Strategic International Coorperative Program and CREST, Japan Science and Technology Agency, Human Frontier Science Program (HFSP) grant RPG 24/2012, the Takeda Science Foundation, Mitsui Life Social Welfare Foundation, Sony Corporation, and Nippon Boehringer Ingelheim Co. Received: AugAccepted: MaPublished: April 15, 2014Ĭopyright: © 2014 Goriki et al. PLoS Biol 12(4):Īcademic Editor: Ueli Schibler, University of Geneva, Switzerland (2014) A Novel Protein, CHRONO, Functions as a Core Component of the Mammalian Circadian Clock. Our study suggests that Chrono functions as a clock repressor and reveals the molecular mechanisms underlying its function.Ĭitation: Goriki A, Hatanaka F, Myung J, Kim JK, Yoritaka T, Tanoue S, et al. We show that Chrono-mediated repression involves the suppression of BMAL1–CLOCK activity via an epigenetic mechanism and that it regulates metabolic pathways triggered by behavioral stress. Chrono knockout and Avp-neuron-specific knockout mice display longer circadian periods and altered expression of core clock genes. Chrono binds to the regulatory region of clock genes and its occupancy oscillates in a circadian manner. Here, we characterize a circadian gene renamed Chrono (Gm129) and show that it functions as a transcriptional repressor of the negative feedback loop in the mammalian clock. Although many of the clock genes comprising this circuit have been identified, there are still some critical components missing. The circadian clock has a fundamental role in regulating biological temporal rhythms in organisms, and it is tightly controlled by a molecular circuit consisting of positive and negative regulatory feedback loops. 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. CHRONO forms a complex with the glucocorticoid receptor and mediates glucocorticoid response. Chrono KO also alters the expression of core clock genes and impairs the response of the circadian clock to stress. In vivo loss-of-function studies of Chrono including Avp neuron-specific knockout (KO) mice display a longer circadian period of locomotor activity. Overexpression of Chrono leads to suppression of BMAL1–CLOCK activity in a histone deacetylase (HDAC) –dependent manner. Remarkably, endogenous CHRONO occupancy around E-boxes shows a circadian oscillation antiphasic to BMAL1. Here, we explore the role of Chrono in cellular timekeeping. We have recently identified Chrono as a robustly cycling transcript through genome-wide profiling of BMAL1 binding on the E-box. Although many genes have been implicated in these feedback loops, it is unclear whether our current list of clock genes is exhaustive. Circadian rhythms are controlled by a system of negative and positive genetic feedback loops composed of clock genes.
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