The Edison Family Center for Genome Sciences and Systems Biology, School of Medicine, Washington University in St. Louis, Saint Louis, Missouri 63110, USA.
Department of Genetics, School of Medicine, Washington University in St. Louis, Saint Louis, Missouri 63110, USA.
Genome Res. 2022 Jan;32(1):85-96. doi: 10.1101/gr.276025.121. Epub 2021 Dec 27.
A classical model of gene regulation is that enhancers provide specificity whereas core promoters provide a modular site for the assembly of the basal transcriptional machinery. However, examples of core promoter specificity have led to an alternate hypothesis in which specificity is achieved by core promoters with different sequence motifs that respond differently to genomic environments containing different enhancers and chromatin landscapes. To distinguish between these models, we measured the activities of hundreds of diverse core promoters in four different genomic locations and, in a complementary experiment, six different core promoters at thousands of locations across the genome. Although genomic locations had large effects on expression, the intrinsic activities of different classes of promoters were preserved across genomic locations, suggesting that core promoters are modular regulatory elements whose activities are independently scaled up or down by different genomic locations. This scaling of promoter activities is nonlinear and depends on the genomic location and the strength of the core promoter. Our results support the classical model of regulation in which diverse core promoter motifs set the intrinsic strengths of core promoters, which are then amplified or dampened by the activities of their genomic environments.
经典的基因调控模型认为，增强子提供特异性，而核心启动子则为基础转录机制的组装提供一个模块化的位点。然而，核心启动子特异性的例子导致了另一种假设，即特异性是通过具有不同序列基序的核心启动子实现的，这些基序对含有不同增强子和染色质景观的基因组环境的反应不同。为了区分这些模型，我们在四个不同的基因组位置测量了数百种不同的核心启动子的活性，在一个互补的实验中，在基因组上的数千个位置测量了六个不同的核心启动子的活性。尽管基因组位置对表达有很大的影响，但不同类别的启动子的固有活性在基因组位置之间是保持不变的，这表明核心启动子是模块化的调节元件，其活性通过不同的基因组位置独立地放大或减弱。这种启动子活性的缩放是非线性的，取决于基因组位置和核心启动子的强度。我们的结果支持了经典的调控模型，即不同的核心启动子基序设定了核心启动子的固有强度，然后通过它们的基因组环境的活性被放大或减弱。
