Theoretical analysis of the stress induced B-Z transition in superhelical DNA.
Theoretical analysis of the stress induced B-Z transition in superhelical DNA.
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DOI：
10.1371/journal.pcbi.1001051
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发表时间：
2011-01-20
影响因子：
4.3
通讯作者：
Benham CJ
中科院分区：
文献类型：
--
作者：
Zhabinskaya D;Benham CJ
我们提出了一种方法来计算区域内的DNA分子从B-型过渡到Z-型负超螺旋应力下的倾向。我们使用统计力学分析的竞争，发生在所有敏感的Z-形成区域之间的热力学平衡在一个超螺旋强调指定序列的DNA。这种方法，我们称之为SIBZ，类似于之前开发的用于分析超螺旋双链体不稳定的SIDD算法。系统的状态是通过将每个碱基对分配为B-或Z-构象来确定的，考虑到Z-DNA的二核苷酸重复单元。一个状态的自由能由成核能、序列依赖的B-Z跃迁能和与由于跃迁而导致的扭曲变化后剩余的剩余超螺旋度相关的能量组成。使用这些信息，SIBZ计算序列中每个碱基对的平衡B-Z跃迁概率。这可以在任何生理上合理的负超螺旋度水平下进行。我们使用SIBZ来分析各种代表性的基因组DNA序列。我们发现，在一个序列中的优势Z-DNA形成区域可以竞争的超螺旋度水平的变化，在高度复杂的方式。尽管没有可调的参数，预测的SIBZ同意精确的实验结果，无论是在质粒中引入Z-形成序列和Z-形成区域的基因组序列中的位置的转变的开始。我们计算了从12，841个小鼠基因中的每一个中提取的5 kb区域的转换谱，并以转录起始位点（TSS）为中心。我们发现一个实质性的增加，在Z-形成区域的频率立即从TSS上游。这里开发的方法有可能照亮体内Z型区域的发生，以及这种转变可能在生物过程中发挥的作用。我们提出的SIBZ算法，计算的平衡性质的过渡，从右手的B-形式到左手的Z-形式的DNA序列，受到施加的应力。SIBZ计算用户定义序列中每个碱基对的转移概率。通过研究说明性的例子，我们表明，在一个序列中的所有Z-敏感区域的过渡行为耦合在一起的所施加的应力。我们表明，由SIBZ产生的结果与实验观察到的指定序列的分子中的转变和Z-形式网站的位置密切一致。通过分析12，841个小鼠基因，我们发现易受B-Z转换影响的位点聚集在基因起始位点的上游。由于这是由转录产生的压力积累的地方，当相关基因表达时，这些位点实际上可能会经历这种转变。这表明这些转变可能具有调节功能。
We present a method to calculate the propensities of regions within a DNA molecule to transition from B-form to Z-form under negative superhelical stresses. We use statistical mechanics to analyze the competition that occurs among all susceptible Z-forming regions at thermodynamic equilibrium in a superhelically stressed DNA of specified sequence. This method, which we call SIBZ, is similar to the SIDD algorithm that was previously developed to analyze superhelical duplex destabilization. A state of the system is determined by assigning to each base pair either the B- or the Z-conformation, accounting for the dinucleotide repeat unit of Z-DNA. The free energy of a state is comprised of the nucleation energy, the sequence-dependent B-Z transition energy, and the energy associated with the residual superhelicity remaining after the change of twist due to transition. Using this information, SIBZ calculates the equilibrium B-Z transition probability of each base pair in the sequence. This can be done at any physiologically reasonable level of negative superhelicity. We use SIBZ to analyze a variety of representative genomic DNA sequences. We show that the dominant Z-DNA forming regions in a sequence can compete in highly complex ways as the superhelicity level changes. Despite having no tunable parameters, the predictions of SIBZ agree precisely with experimental results, both for the onset of transition in plasmids containing introduced Z-forming sequences and for the locations of Z-forming regions in genomic sequences. We calculate the transition profiles of 5 kb regions taken from each of 12,841 mouse genes and centered on the transcription start site (TSS). We find a substantial increase in the frequency of Z-forming regions immediately upstream from the TSS. The approach developed here has the potential to illuminate the occurrence of Z-form regions in vivo, and the possible roles this transition may play in biological processes. We present the SIBZ algorithm that calculates the equilibrium properties of the transition from right-handed B-form to left-handed Z-form in a DNA sequence that is subjected to imposed stresses. SIBZ calculates the probability of transition of each base pair in a user-defined sequence. By examining illustrative examples, we show that the transition behaviors of all Z-susceptible regions in a sequence are coupled together by the imposed stresses. We show that the results produced by SIBZ agree closely with experimental observations of both the onset of transitions and the locations of Z-form sites in molecules of specified sequence. By analyzing 12,841 mouse genes, we show that sites susceptible to the B-Z transition cluster upstream from gene start sites. As this is where stresses generated by transcription accumulate, these sites may actually experience this transition when the genes involved are being expressed. This suggests that these transitions may serve regulatory functions.
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