Deb Arindam, Kundu Sudip
Department of Biophysics Molecular Biology and Bioinformatics, University of Calcutta, Kolkata, West Bengal, India.
Department of Biophysics Molecular Biology and Bioinformatics, University of Calcutta, Kolkata, West Bengal, India; Center of Excellence in Systems Biology and Biomedical Engineering (TEQIP Phase II), University of Calcutta, Kolkata, West Bengal, India.
PLoS One. 2015 Sep 1;10(9):e0137295. doi: 10.1371/journal.pone.0137295. eCollection 2015.
Combinations of cis-regulatory elements (CREs) present at the promoters facilitate the binding of several transcription factors (TFs), thereby altering the consequent gene expressions. Due to the eminent complexity of the regulatory mechanism, the combinatorics of CRE-mediated transcriptional regulation has been elusive. In this work, we have developed a new methodology that quantifies the co-occurrence tendencies of CREs present in a set of promoter sequences; these co-occurrence scores are filtered in three consecutive steps to test their statistical significance; and the significantly co-occurring CRE pairs are presented as networks. These networks of co-occurring CREs are further transformed to derive higher order of regulatory combinatorics. We have further applied this methodology on the differentially up-regulated gene-sets of rice tissues under fungal (Magnaporthe) infected conditions to demonstrate how it helps to understand the CRE-mediated combinatorial gene regulation. Our analysis includes a wide spectrum of biologically important results. The CRE pairs having a strong tendency to co-occur often exhibit very similar joint distribution patterns at the promoters of rice. We couple the network approach with experimental results of plant gene regulation and defense mechanisms and find evidences of auto and cross regulation among TF families, cross-talk among multiple hormone signaling pathways, similarities and dissimilarities in regulatory combinatorics between different tissues, etc. Our analyses have pointed a highly distributed nature of the combinatorial gene regulation facilitating an efficient alteration in response to fungal attack. All together, our proposed methodology could be an important approach in understanding the combinatorial gene regulation. It can be further applied to unravel the tissue and/or condition specific combinatorial gene regulation in other eukaryotic systems with the availability of annotated genomic sequences and suitable experimental data.
启动子处存在的顺式作用元件（CRE）组合有助于几种转录因子（TF）的结合，从而改变后续的基因表达。由于调控机制极为复杂，CRE介导的转录调控的组合方式一直难以捉摸。在这项工作中，我们开发了一种新方法，该方法可量化一组启动子序列中存在的CRE的共现趋势；这些共现分数经过三个连续步骤进行筛选，以检验其统计显著性；并且将显著共现的CRE对呈现为网络。这些共现CRE的网络进一步转化以推导更高阶的调控组合方式。我们进一步将此方法应用于真菌（稻瘟病菌）感染条件下水稻组织中差异上调的基因集，以证明它如何有助于理解CRE介导的组合基因调控。我们的分析包括一系列广泛的生物学重要结果。具有强烈共现趋势的CRE对在水稻启动子处通常表现出非常相似的联合分布模式。我们将网络方法与植物基因调控和防御机制的实验结果相结合，发现了TF家族之间的自调控和交叉调控、多种激素信号通路之间的相互作用、不同组织之间调控组合方式的异同等等证据。我们的分析指出了组合基因调控的高度分布式性质，有助于对真菌攻击做出有效改变。总之，我们提出的方法可能是理解组合基因调控的重要途径。随着注释基因组序列和合适实验数据的可得，它可以进一步应用于揭示其他真核系统中组织和/或条件特异性的组合基因调控。
