Curtis Anne M, Seo Sang-beom, Westgate Elizabeth J, Rudic Radu Daniel, Smyth Emer M, Chakravarti Debabrata, FitzGerald Garret A, McNamara Peter
Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
J Biol Chem. 2004 Feb 20;279(8):7091-7. doi: 10.1074/jbc.M311973200. Epub 2003 Nov 26.
Rhythmic gene expression is central to the circadian control of physiology in mammals. Transcriptional activation of Per and Cry genes by heterodimeric bHLH-PAS proteins is a key event in the feedback loop that drives rhythmicity; however, the mechanism is not clearly understood. Here we show the transcriptional coactivators and histone acetyltransferases, p300/CBP, PCAF, and ACTR associate with the bHLH-PAS proteins, CLOCK and NPAS2, to regulate positively clock gene expression. Furthermore, Cry2 mediated repression of NPAS2:BMAL1 is overcome by overexpression of p300 in transactivation assays. Accordingly, p300 exhibits a circadian time-dependent association with NPAS2 in the vasculature, which precedes peak expression of target genes. In addition, a rhythm in core histone H3 acetylation on the mPer1 promoter in vivo correlates with the cyclical expression of their mRNAs. Temporal coactivator recruitment and HAT-dependent chromatin remodeling on the promoter of clock controlled genes in the vasculature permits the mammalian clock to orchestrate circadian gene expression.
节律性基因表达是哺乳动物生理昼夜节律控制的核心。异二聚体bHLH-PAS蛋白对Per和Cry基因的转录激活是驱动节律性的反馈回路中的关键事件；然而，其机制尚不清楚。在此我们表明，转录共激活因子和组蛋白乙酰转移酶p300/CBP、PCAF和ACTR与bHLH-PAS蛋白CLOCK和NPAS2结合，以正向调节生物钟基因表达。此外，在反式激活试验中，p300的过表达可克服Cry2介导的对NPAS2:BMAL1的抑制作用。相应地，p300在脉管系统中与NPAS2呈现出昼夜时间依赖性结合，这发生在靶基因表达峰值之前。此外，体内mPer1启动子上核心组蛋白H3乙酰化的节律与它们mRNA的周期性表达相关。脉管系统中生物钟控制基因启动子上的时间性共激活因子募集和HAT依赖性染色质重塑使得哺乳动物生物钟能够协调昼夜节律基因表达。
