Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824-1319, USA.
Mol Syst Biol. 2010;6:341. doi: 10.1038/msb.2009.97. Epub 2010 Jan 19.
Systems biology seeks a genomic-level interpretation of transcriptional regulatory information represented by patterns of protein-binding sites. Obtaining this information without direct experimentation is challenging; minor alterations in binding sites can have profound effects on gene expression, and underlie important aspects of disease and evolution. Quantitative modeling offers an alternative path to develop a global understanding of the transcriptional regulatory code. Recent studies have focused on endogenous regulatory sequences; however, distinct enhancers differ in many features, making it difficult to generalize to other cis-regulatory elements. We applied a systematic approach to simpler elements and present here the first quantitative analysis of short-range transcriptional repressors, which have central functions in metazoan development. Our fractional occupancy-based modeling uncovered unexpected features of these proteins' activity that allow accurate predictions of regulation by the Giant, Knirps, Krüppel, and Snail repressors, including modeling of an endogenous enhancer. This study provides essential elements of a transcriptional regulatory code that will allow extensive analysis of genomic information in Drosophila melanogaster and related organisms.
系统生物学旨在从蛋白质结合位点模式所代表的转录调控信息中，进行基因组水平的解读。在不进行直接实验的情况下获取这些信息具有挑战性；结合位点的微小改变可能对基因表达产生深远影响，并构成疾病和进化的重要方面。定量建模为全面了解转录调控密码提供了另一种途径。最近的研究集中在内源性调控序列上；然而，不同的增强子在许多方面存在差异，因此难以推广到其他顺式调控元件。我们应用了一种系统的方法来研究更简单的元件，并在此首次对短程转录抑制剂进行了定量分析，这些抑制剂在后生动物发育中具有核心功能。我们基于部分占据的建模揭示了这些蛋白质活性的意外特征，从而能够准确预测 Giant、Knirps、Krüppel 和 Snail 抑制剂的调控作用，包括对一个内源性增强子的建模。这项研究提供了转录调控密码的基本要素，这将允许对黑腹果蝇和相关生物的基因组信息进行广泛分析。
