title: 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.
authors.affiliation: MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center (MARC) and the School of Medicine, Nanjing University, Nanjing 210093, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Tao
authors.affiliation: MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center (MARC) and the School of Medicine, Nanjing University, Nanjing 210093, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.affiliation: MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center (MARC) and the School of Medicine, Nanjing University, Nanjing 210093, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center (MARC) and the School of Medicine, Nanjing University, Nanjing 210093, China.
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Lai
authors.affiliation: MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center (MARC) and the School of Medicine, Nanjing University, Nanjing 210093, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Jiang
authors.affiliation: MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center (MARC) and the School of Medicine, Nanjing University, Nanjing 210093, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Jiang
authors.affiliation: MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center (MARC) and the School of Medicine, Nanjing University, Nanjing 210093, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
authors.affiliation: MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center (MARC) and the School of Medicine, Nanjing University, Nanjing 210093, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Xue
authors.affiliation: Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Du
authors.affiliation: MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center (MARC) and the School of Medicine, Nanjing University, Nanjing 210093, China.
authors.forename: Chao-Jun
authors.initials: CJ
authors.lastname: Li
mesh_terms: D056930:ARNTL Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000818:Animals; D056926:CLOCK Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D051766:Early Growth Response Protein 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D056950:Period Circadian Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D020218:Response Elements; D015533:Transcriptional Activation
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D051766:Early Growth Response Protein 1; C539023:Per1 protein, mouse; D056950:Period Circadian Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D056926:CLOCK Proteins