Abstract
Author SummaryThe 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. Although many of the clock genes comprising this circuit have been identified, there are still some critical components missing. 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. Chrono binds to the regulatory region of clock genes and its occupancy oscillates in a circadian manner. Chrono knockout and Avp-neuron-specific knockout mice display longer circadian periods and altered expression of core clock genes. 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. Our study suggests that Chrono functions as a clock repressor and reveals the molecular mechanisms underlying its function.
Highlights
Circadian rhythms with a period of approximately 24 h endow organisms with the ability to adapt to changes of solar light following earth’s rotation
When the transcription of Chrono is inhibited in the model, the model predicts that Chrono KO lengthens the period (Figure 4D, right), which indicates that the biochemical mechanisms we have identified for Chrono-mediated repression of BMAL1– CLOCK (Figure 2D) are expected to cause the Chrono KO phenotypes
Our results suggest that CHRONO operates as a repressor of the core circadian feedback loop through the recruitment of histone deacetylase (HDAC)
Summary
Circadian 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 clock gene, period, was first identified in fly [6,7,8] and later in various organisms [9]. The complex of positive elements BMAL–CLOCK (NPAS2) activates PER and CRY that repress their own transcription to form a negative feedback loop. An accessory feedback loop involves ROR and REV–ERBa, which regulate BMAL1 transcription positively and negatively, respectively, whereas BMAL1 activates REV–ERBa expression. Because of the complexity of circadian timekeeping, mathematical modeling has emerged as an important tool to understand data and make novel predictions [17,18,19]. A recently published mathematical model reproduces much of the known data on circadian timekeeping (e.g., mutant phenotypes) and correctly predicts the pharmacological manipulation of circadian rhythms [20,21]
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