Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
BMC Bioinformatics. 2009 Dec 22;10:442. doi: 10.1186/1471-2105-10-442.
The relative preference of nucleosomes to form on individual DNA sequences plays a major role in genome packaging. A wide variety of DNA sequence features are believed to influence nucleosome formation, including periodic dinucleotide signals, poly-A stretches and other short motifs, and sequence properties that influence DNA structure, including base content. It was recently shown by Kaplan et al. that a probabilistic model using composition of all 5-mers within a nucleosome-sized tiling window accurately predicts intrinsic nucleosome occupancy across an entire genome in vitro. However, the model is complicated, and it is not clear which specific DNA sequence properties are most important for intrinsic nucleosome-forming preferences.
We find that a simple linear combination of only 14 simple DNA sequence attributes (G+C content, two transformations of dinucleotide composition, and the frequency of eleven 4-bp sequences) explains nucleosome occupancy in vitro and in vivo in a manner comparable to the Kaplan model. G+C content and frequency of AAAA are the most important features. G+C content is dominant, alone explaining approximately 50% of the variation in nucleosome occupancy in vitro.
Our findings provide a dramatically simplified means to predict and understand intrinsic nucleosome occupancy. G+C content may dominate because it both reduces frequency of poly-A-like stretches and correlates with many other DNA structural characteristics. Since G+C content is enriched or depleted at many types of features in diverse eukaryotic genomes, our results suggest that variation in nucleotide composition may have a widespread and direct influence on chromatin structure.
核小体在单个 DNA 序列上的相对偏好性在基因组包装中起着重要作用。人们认为，各种 DNA 序列特征都会影响核小体的形成，包括周期性二核苷酸信号、多 A 延伸和其他短基序，以及影响 DNA 结构的序列特性，包括碱基组成。最近，Kaplan 等人表明，使用核小体大小平铺窗口内所有 5 个核苷酸组成的概率模型，可以准确预测整个基因组在体外的固有核小体占有率。然而，该模型较为复杂，目前尚不清楚哪些特定的 DNA 序列特性对固有核小体形成偏好最重要。
我们发现，仅由 14 种简单 DNA 序列属性（G+C 含量、二核苷酸组成的两种转换以及 11 种 4 个碱基序列的频率）组成的简单线性组合，以类似于 Kaplan 模型的方式解释了体外和体内的核小体占有率。G+C 含量和 AAAA 的频率是最重要的特征。G+C 含量占主导地位，单独解释了体外核小体占有率变化的约 50%。
我们的研究结果为预测和理解固有核小体占有率提供了一种大大简化的方法。G+C 含量可能占主导地位，因为它既能降低类似 poly-A 的延伸频率，又与许多其他 DNA 结构特征相关。由于在不同真核生物基因组的许多类型特征中存在 G+C 含量的富集或缺失，我们的结果表明，核苷酸组成的变化可能对染色质结构有广泛而直接的影响。
