Toward a Detailed Description of the Thermally Induced Dynamics of the Core Promoter
Toward a Detailed Description of the Thermally Induced Dynamics of the Core Promoter
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DOI：
10.1371/journal.pcbi.1000313
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发表时间：
2009-03-01
影响因子：
4.3
通讯作者：
Usheva, Anny
中科院分区：
文献类型：
--
作者：
Alexandrov, Boian S.;Gelev, Vladimir;Usheva, Anny
建立基因转录起始的一般和启动子特异性机制特征需要更好地理解启动子DNA的序列依赖性结构/动态特征。实验数据表明，在转录起始位点处的自发dsDNA链分离可能是几个启动子中转录起始的要求。在这里，我们使用Langevin分子动力学模拟的基础上的Peyrard-Bishop-Dauxois非线性模型的DNA（PBD LMD）分析链分离（气泡）动力学的80 bp长的启动子DNA序列。我们推导出三个动态标准，气泡概率，气泡寿命，平均链分离，表征气泡形成在8个哺乳动物基因启动子的转录起始位点。我们观察到，最稳定的双链DNA开口不一定与最可能的开口和最高的平均链置换相一致，强调了适当的分子动力学模拟的优点。所测试的哺乳动物启动子的动态概况在总体概况和气泡概率上显著不同，但转录起始位点通常通过双螺旋中的大（长于10 bp）和长寿命的瞬时开口来区分。支持这些结果的是我们的实验转录数据，证明了在没有任何其他转录因子的情况下，含有人工气泡的DNA模板仅由人RNA聚合酶双向转录。
Establishing the general and promoter-specific mechanistic features of gene transcription initiation requires improved understanding of the sequence-dependent structural/dynamic features of promoter DNA. Experimental data suggest that a spontaneous dsDNA strand separation at the transcriptional start site is likely to be a requirement for transcription initiation in several promoters. Here, we use Langevin molecular dynamic simulations based on the Peyrard-Bishop-Dauxois nonlinear model of DNA (PBD LMD) to analyze the strand separation (bubble) dynamics of 80-bp-long promoter DNA sequences. We derive three dynamic criteria, bubble probability, bubble lifetime, and average strand separation, to characterize bubble formation at the transcriptional start sites of eight mammalian gene promoters. We observe that the most stable dsDNA openings do not necessarily coincide with the most probable openings and the highest average strand displacement, underscoring the advantages of proper molecular dynamic simulations. The dynamic profiles of the tested mammalian promoters differ significantly in overall profile and bubble probability, but the transcriptional start site is often distinguished by large (longer than 10 bp) and long-lived transient openings in the double helix. In support of these results are our experimental transcription data demonstrating that an artificial bubble-containing DNA template is transcribed bidirectionally by human RNA polymerase alone in the absence of any other transcription factors.