Identifying gene regulatory modules of heat shock response in yeast.
Identifying gene regulatory modules of heat shock response in yeast.
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DOI：
10.1186/1471-2164-9-439
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发表时间：
2008-09-23
期刊：
影响因子：
4.4
通讯作者：
Li WH
中科院分区：
文献类型：
--
作者：
Wu WS;Li WH
基因调控模块(GRM)是由同一组转录因子(TF)调控的一组基因。通过将基因组组织成GRM，活细胞可以协调许多基因的活动，以响应各种内部和外部刺激。因此，鉴定GRMS有助于理解基因调控。结合转录因子结合位点(TFBS)、突变体、芯片和热休克时间序列基因表达数据，我们开发了一种重建酵母热休克反应GRM的方法，称为热诱导模块识别算法(HIMIA)。与以前的基于静态统计的模块推理工具不同，HIMIA是一种基于动态系统模型的方法，它利用了时间序列基因表达数据的动态性质。HIMIA鉴定了29个GRM，它们总共包含182个热诱导基因，由12个热响应因子调控。利用各种类型的已发表数据，我们验证了已识别的GRM的生物学相关性。我们的分析表明，相当少量的热响应因子的不同组合调控着大量参与热休克反应的基因，热休克反应与其他细胞过程之间可能存在串扰。利用HIMIA，我们确定了68个可能参与热休克反应的未鉴定基因，并确定了它们可能的热反应调节因子。此外，HIMIA能够分配调控GRMS的转录因子的调节角色，Cst6、HSF1、MSN2、MSN4和YAP1被发现是几个GRMS的激活剂。此外，HIMIA提炼了两组与热休克反应有关的基因，并更好地了解了热休克反应的复杂表达程序是如何调控的。最后，我们证明了HIMIA的性能优于当前的四种模块推理工具(GRAM、MOFA、ReMoDisvovery和Samba)，并进行了两次随机化测试，表明HIMIA的输出具有统计意义。HIMIA可以有效地重建酵母热休克反应的GRM。事实上，许多重建的GRM与之前的研究是一致的。此外，HIMIA预测了几个有趣的新模块和新的Tf组合。我们的研究表明，整合多种类型的数据是研究复杂生物系统的有力途径。
A gene regulatory module (GRM) is a set of genes that is regulated by the same set of transcription factors (TFs). By organizing the genome into GRMs, a living cell can coordinate the activities of many genes in response to various internal and external stimuli. Therefore, identifying GRMs is helpful for understanding gene regulation. Integrating transcription factor binding site (TFBS), mutant, ChIP-chip, and heat shock time series gene expression data, we develop a method, called Heat-Inducible Module Identification Algorithm (HIMIA), for reconstructing GRMs of yeast heat shock response. Unlike previous module inference tools which are static statistics-based methods, HIMIA is a dynamic system model-based method that utilizes the dynamic nature of time series gene expression data. HIMIA identifies 29 GRMs, which in total contain 182 heat-inducible genes regulated by 12 heat-responsive TFs. Using various types of published data, we validate the biological relevance of the identified GRMs. Our analysis suggests that different combinations of a fairly small number of heat-responsive TFs regulate a large number of genes involved in heat shock response and that there may exist crosstalk between heat shock response and other cellular processes. Using HIMIA, we identify 68 uncharacterized genes that may be involved in heat shock response and we also identify their plausible heat-responsive regulators. Furthermore, HIMIA is capable of assigning the regulatory roles of the TFs that regulate GRMs and Cst6, Hsf1, Msn2, Msn4, and Yap1 are found to be activators of several GRMs. In addition, HIMIA refines two clusters of genes involved in heat shock response and provides a better understanding of how the complex expression program of heat shock response is regulated. Finally, we show that HIMIA outperforms four current module inference tools (GRAM, MOFA, ReMoDisvovery, and SAMBA), and we conduct two randomization tests to show that the output of HIMIA is statistically meaningful. HIMIA is effective for reconstructing GRMs of yeast heat shock response. Indeed, many of the reconstructed GRMs are in agreement with previous studies. Further, HIMIA predicts several interesting new modules and novel TF combinations. Our study shows that integrating multiple types of data is a powerful approach to studying complex biological systems.
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