EGR1 regulates hepatic clock gene amplitude by activating Per1 transcription

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.

Prefrontal Cortex and Dorsomedial Hypothalamus Mediate Food Reward-Induced Effects via npas2 and egr1 Expression in Rat

“…We observed a pronounced daily rhythm in per2, npas2 and egr1 expression in the liver with the maximum as was reported before (Damiola et al 2000, Tao et al 2015. per2 and npas2 expression was not influenced by food reward; however, food reward caused a diminishing of egr1 rhythmic expression.…”

“…per2 and npas2 expression was not influenced by food reward; however, food reward caused a diminishing of egr1 rhythmic expression. Food reward with food restriction caused a pronounced phase shift in gene expression as was reported earlier (Damiola et al 2000, Tao et al 2015.…”

“…While npas2 is known for its role in the circadian oscillator function, egr1 is known mainly as an immediate early gene involved in neural development, cell differentiation, memory and learning (Beckmann and Wilce 1997). Its direct connection to the circadian system was recently established when functional E-box was identified in its sequence (Tao et al 2015). In spite of the presence of functional E-box, egr1 shows surprising variability in its acrophase in tissues with similar expression of the BMAL1 (NPAS2)/CLOCK heterodimer.…”

Sea cucumber genome provides insights into saponin biosynthesis and aestivation regulation

“…4b ). Egr1 and members of the Klf family are known to participate in biorhythm regulation 55 – 58 , e. g., Egr1 can regulate the clock gene Cry1 55 , the key repressor gene that can propel the animal into sleep phase (through the inhibition of key activators Clock and Bmal1 59 ). We therefore investigated the expression patterns of clock-related genes during the aestivation of sea cucumber.…”

REV‑ERBα reduction is associated with clinicopathological features and prognosis in human gastric cancer

“…It has also been demonstrated that the REV-ERBα expression leading to apoptosis was affected by circadian rhythms ( 22 ). REV-ERBα controls the circadian clock genes and regulates Early growth response 1 expression, causing extensive expression of Tumor protein p73 (p73) ( 23 ). p73 activates the transcription of Bax and Bcl-2, causing the release of cytochrome c from the mitochondria ( 24 ).…”