Department of Biology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland.
Laboratory of Cardiovascular and Aging Research, Department of Endocrinology, Metabolism, Cardiovascular System, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland.
Sci Rep. 2021 Nov 5;11(1):21766. doi: 10.1038/s41598-021-01178-6.
Light affects many physiological processes in mammals such as entrainment of the circadian clock, regulation of mood, and relaxation of blood vessels. At the molecular level, a stimulus such as light initiates a cascade of kinases that phosphorylate CREB at various sites, including serine 133 (S133). This modification leads CREB to recruit the co-factor CRCT1 and the histone acetyltransferase CBP to stimulate the transcription of genes containing a CRE element in their promoters, such as Period 1 (Per1). However, the details of this pathway are poorly understood. Here we provide evidence that PER2 acts as a co-factor of CREB to facilitate the formation of a transactivation complex on the CRE element of the Per1 gene regulatory region in response to light or forskolin. Using in vitro and in vivo approaches, we show that PER2 modulates the interaction between CREB and its co-regulator CRTC1 to support complex formation only after a light or forskolin stimulus. Furthermore, the absence of PER2 abolished the interaction between the histone acetyltransferase CBP and CREB. This process was accompanied by a reduction of histone H3 acetylation and decreased recruitment of RNA Pol II to the Per1 gene. Collectively, our data show that PER2 supports the stimulus-dependent induction of the Per1 gene via modulation of the CREB/CRTC1/CBP complex.
光是影响哺乳动物许多生理过程的因素之一，例如生物钟的同步、情绪的调节和血管的松弛。在分子水平上，光等刺激会引发一系列激酶的级联反应，使 CREB 在多个位点磷酸化，包括丝氨酸 133（S133）。这种修饰使 CREB 招募辅助因子 CRCT1 和组蛋白乙酰转移酶 CBP，以刺激其启动子中含有 CRE 元件的基因的转录，如 Period 1（Per1）。然而，该途径的细节尚不清楚。在这里，我们提供的证据表明 PER2 作为 CREB 的辅助因子，在光或 forskolin 刺激下，促进了 PER1 基因调控区 CRE 元件上的转录激活复合物的形成。通过体外和体内方法，我们表明 PER2 调节 CREB 与其共调节剂 CRTC1 之间的相互作用，仅在光或 forskolin 刺激后支持复合物的形成。此外，PER2 的缺失消除了组蛋白乙酰转移酶 CBP 与 CREB 之间的相互作用。这一过程伴随着组蛋白 H3 乙酰化的减少和 RNA Pol II 向 Per1 基因的募集减少。总的来说，我们的数据表明，PER2 通过调节 CREB/CRTC1/CBP 复合物，支持 Per1 基因的刺激依赖性诱导。
