Abstract
The mammalian clock system is composed of a master clock and peripheral clocks. At the molecular level, the rhythm-generating mechanism is controlled by a molecular clock composed of positive and negative feedback loops. However, the underlying mechanisms for molecular clock regulation that affect circadian clock function remain unclear. Here, we show that Egr1 (early growth response 1), an early growth response gene, is expressed in mouse liver in a circadian manner. Consistently, Egr1 is transactivated by the CLOCK/BMAL1 heterodimer through a conserved E-box response element. In hepatocytes, EGR1 regulates the transcription of several core clock genes, including Bmal1, Per1, Per2, Rev-erbα and Rev-erbβ, and the rhythm amplitude of their expression is dependent on EGR1’s transcriptional function. Further mechanistic studies indicated that EGR1 binds to the proximal region of the Per1 promoter to activate its transcription directly. When the peripheral clock is altered by light or feeding behavior transposition in Egr1-deficient mice, the expression phase of hepatic clock genes shifts normally, but the amplitude is also altered. Our data reveal a critical role for EGR1 in the regulation of hepatic clock circuitry, which may contribute to the rhythm stability of peripheral clock oscillators.
Highlights
The mammalian clock system is composed of a master clock and peripheral clocks
A master clock that generates circadian rhythms is located in the suprachiasmatic nucleus (SCN) and drives the slave oscillators that are distributed in various peripheral tissues using autonomic innervation and behavioral and neuroendocrine signals[6,7,8]
At the mRNA level, we found that Egr[1] expression had a diurnal rhythm that peaked at ZT5 (ZT0 is the onset at hour 0 of the subjective light period), gradually declined thereafter, and reached a nadir at ZT21 in mouse liver (Fig. 1a)
Summary
The mammalian clock system is composed of a master clock and peripheral clocks. At the molecular level, the rhythm-generating mechanism is controlled by a molecular clock composed of positive and negative feedback loops. Most living organisms exhibit behavioral and physiological rhythms, including sleep-wake, rest-activity, blood pressure, hormone secretion and energy metabolism[1,2,3,4,5,6] This diurnal oscillation is regulated by circadian clocks, which respond to light and feeding cycles. Bmal[1] transcription is regulated both positively and negatively by the orphan nuclear receptors RORs and REV-ERBs13,14 This core feedback loop requires approximately 24 h to complete a cycle and constitutes a circadian oscillation of the molecular clock. Previous reports have shown that EGR1 can regulate the expression of certain clock genes in cell lines[26,27,28] Based on these findings, we hypothesize that EGR1 may play a potential role in the regulation of the hepatic circadian clock in response to feeding/fasting or other signals
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