EGR1 regulates hepatic clock gene amplitude by activating Per1 transcription

• Published in: Scientific reports 2015-10, Vol.5 (1), p.15212-15212, Article 15212
• Main Authors: Tao, Weiwei, Wu, Jing, Zhang, Qian, Lai, Shan-Shan, Jiang, Shan, Jiang, Chen, Xu, Ying, Xue, Bin, Du, Jie, Li, Chao-Jun
• Format: Article
• Language: English
• Subjects: 13/1; 13/89; 38/109; 38/15; 631/208/200; 631/80/105; 64/110; 82/80; 96/95; Animals; ARNTL Transcription Factors - deficiency; ARNTL Transcription Factors - genetics; ARNTL Transcription Factors - metabolism; Biological clocks; BMAL1 protein; Chromatin Immunoprecipitation; Circadian rhythm; Circadian rhythms; Clock gene; CLOCK Proteins - chemistry; CLOCK Proteins - genetics; CLOCK Proteins - metabolism; Early Growth Response Protein 1 - antagonists & inhibitors; Early Growth Response Protein 1 - genetics; Early Growth Response Protein 1 - metabolism; EGR-1 protein; Feedback; Feedback, Physiological; Feeding behavior; Genes; Hepatocytes; Humanities and Social Sciences; Liver; Liver - metabolism; Mice; Mice, Knockout; multidisciplinary; Oscillators; Period 1 protein; Period 2 protein; Period Circadian Proteins - antagonists & inhibitors; Period Circadian Proteins - genetics; Period Circadian Proteins - metabolism; Promoter Regions, Genetic; Protein Binding; Response Elements; RNA Interference; RNA, Messenger - metabolism; RNA, Small Interfering - metabolism; Rodents; Science; Transcription; Transcriptional Activation; Transposition
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep15212

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.