Low nucleosome occupancy is encoded around functional human transcription factor binding sites.
Low nucleosome occupancy is encoded around functional human transcription factor binding sites.
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DOI：
10.1186/1471-2164-9-332
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发表时间：
2008-07-15
期刊：
影响因子：
4.4
通讯作者：
De Bleser PJ
中科院分区：
文献类型：
--
作者：
Daenen F;van Roy F;De Bleser PJ
真核生物中基因的转录调控是通过多个转录因子与DNA上的转录因子结合位点（TFBSs）阵列以及彼此之间的相互作用来实现的。鉴定这些TFBSs是我们理解基因调控网络的重要一步，但使用共识模型或常用的随机模型（如位置特异性评分矩阵（PSSMs））对TFBSs进行计算预测的结果是，由少数真正的功能结合位点和大量虚假的非功能结合位点组成的高命中数令人无法接受。这是由于模型无法纳入序列的高阶特性，包括围绕TFBSs的序列和影响核小体定位和/或转录因子之间可能发生的相互作用。通过开发一个明确考虑这些高阶序列属性的TFBSs建模和预测的新框架，可以预期显著的改进。在新的建模框架中包含围绕TFBSs的核小体定位序列（nps）中存在的信息将是特别有趣的，因为可以假设基因组使用这些信息编码非功能位点上稳定核小体的形成，而功能位点具有更开放的染色质配置。在本报告中，我们通过比较实验验证的人类TFBSs周围的核小体占用概率与假阳性TFBSs周围的核小体占用概率和随机序列来评估后一特征的有用性。我们提供的证据表明，与非功能性人类TFBSs相比，真正功能性人类TFBSs周围的核小体占用率显著低于非功能性人类TFBSs，这支持使用这一特征来改进当前高等真核生物中TFBS的预测方法。
Transcriptional regulation of genes in eukaryotes is achieved by the interactions of multiple transcription factors with arrays of transcription factor binding sites (TFBSs) on DNA and with each other. Identification of these TFBSs is an essential step in our understanding of gene regulatory networks, but computational prediction of TFBSs with either consensus or commonly used stochastic models such as Position-Specific Scoring Matrices (PSSMs) results in an unacceptably high number of hits consisting of a few true functional binding sites and numerous false non-functional binding sites. This is due to the inability of the models to incorporate higher order properties of sequences including sequences surrounding TFBSs and influencing the positioning of nucleosomes and/or the interactions that might occur between transcription factors. Significant improvement can be expected through the development of a new framework for the modeling and prediction of TFBSs that considers explicitly these higher order sequence properties. It would be particularly interesting to include in the new modeling framework the information present in the nucleosome positioning sequences (NPSs) surrounding TFBSs, as it can be hypothesized that genomes use this information to encode the formation of stable nucleosomes over non-functional sites, while functional sites have a more open chromatin configuration. In this report we evaluate the usefulness of the latter feature by comparing the nucleosome occupancy probabilities around experimentally verified human TFBSs with the nucleosome occupancy probabilities around false positive TFBSs and in random sequences. We present evidence that nucleosome occupancy is remarkably lower around true functional human TFBSs as compared to non-functional human TFBSs, which supports the use of this feature to improve current TFBS prediction approaches in higher eukaryotes.
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