Li Long, Zhu Qianqian, He Xin, Sinha Saurabh, Halfon Marc S
Department of Biochemistry, State University of New York at Buffalo, Buffalo, NY 14214, USA.
Genome Biol. 2007;8(6):R101. doi: 10.1186/gb-2007-8-6-r101.
Transcriptional cis-regulatory modules (for example, enhancers) play a critical role in regulating gene expression. While many individual regulatory elements have been characterized, they have never been analyzed as a class.
We have performed the first such large-scale study of cis-regulatory modules in order to determine whether they have common properties that might aid in their identification and contribute to our understanding of the mechanisms by which they function. A total of 280 individual, experimentally verified cis-regulatory modules from Drosophila were analyzed for a range of sequence-level and functional properties. We report here that regulatory modules do indeed share common properties, among them an elevated GC content, an increased level of interspecific sequence conservation, and a tendency to be transcribed into RNA. However, we find that dense clustering of transcription factor binding sites, especially homotypic clustering, which is commonly believed to be a general characteristic of regulatory modules, is rather a feature that belongs chiefly to a specific subclass. This has important implications for current computational approaches, many of which are biased toward this subset. We explore two new strategies to assess binding site clustering and gauge their performances with respect to their ability to detect all 280 modules and various functionally coherent subsets.
Our findings demonstrate that cis-regulatory modules share common features that help to define them as a class and that may lead to new insights into mechanisms of gene regulation. However, these properties alone may not be sufficient to reliably distinguish regulatory from non-regulatory sequences. We also demonstrate that there are distinct subclasses of cis-regulatory modules that are more amenable to in silico detection than others and that these differences must be taken into account when attempting genome-wide regulatory element discovery.
转录顺式调控模块（例如增强子）在调节基因表达中起关键作用。虽然许多单个调控元件已被表征，但从未将它们作为一个类别进行分析。
我们进行了首次此类大规模的顺式调控模块研究，以确定它们是否具有有助于其识别并增进我们对其功能机制理解的共同特性。对来自果蝇的总共280个经实验验证的单个顺式调控模块进行了一系列序列水平和功能特性分析。我们在此报告，调控模块确实具有共同特性，其中包括较高的GC含量、种间序列保守性增加以及转录为RNA的倾向。然而，我们发现转录因子结合位点的密集聚类，尤其是同型聚类，通常被认为是调控模块的一个普遍特征，实际上主要是特定子类的一个特征。这对当前的计算方法具有重要意义，其中许多方法偏向于这个子集。我们探索了两种评估结合位点聚类的新策略，并根据它们检测所有280个模块和各种功能相关子集的能力来衡量它们的性能。
我们的研究结果表明，顺式调控模块具有共同特征，这些特征有助于将它们定义为一个类别，并可能为基因调控机制带来新的见解。然而，仅这些特性可能不足以可靠地区分调控序列和非调控序列。我们还证明，顺式调控模块存在不同的子类，其中一些比其他子类更适合通过计算机检测，并且在尝试进行全基因组调控元件发现时必须考虑这些差异。
