Modeling co-expression across species for complex traits: insights to the difference of human and mouse embryonic stem cells.
Modeling co-expression across species for complex traits: insights to the difference of human and mouse embryonic stem cells.
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DOI：
10.1371/journal.pcbi.1000707
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发表时间：
2010-03-12
影响因子：
4.3
通讯作者：
Zhong S
中科院分区：
文献类型：
--
作者：
Cai J;Xie D;Fan Z;Chipperfield H;Marden J;Wong WH;Zhong S
基因或蛋白质之间复杂的相互作用在很大程度上促进了表型进化。我们提出了一种概率模型和最大似然方法，用于跨物种聚类分析和鉴定保守的以及物种特异性的共表达模块。该模型通过鼓励但不强制同源基因被归为同一类，实现了“软”跨物种聚类（SCSC）方法。因此，SCSC在模糊同源关系方面具有很强的稳健性，可以反映不同物种中同源基因的不同功能作用。我们建立了小鼠胚胎干细胞（ES）分化的时间序列基因表达数据集，并编译了已发表的人类胚胎干细胞分化的基因表达数据集。应用SCSC分析这些数据集，我们确定了保守的和物种特异性的基因调控模块。结合蛋白- dna结合数据，在小鼠胚胎干细胞中特异性诱导的SCSC簇表明，KLF2/4/5转录因子虽然对维持小鼠胚胎干细胞的多能表型至关重要，但与人类胚胎干细胞中的OCT4/SOX2/NANOG调节模块解耦。小鼠KLF2/4/5的两个靶基因LIN28和NODAL在人ES细胞中被重新连接为OCT4/SOX2/NANOG的靶基因。此外，通过将SCSC簇映射到KEGG信号通路，我们确定了在多能胚胎干细胞中以保守或物种特异性方式诱导的信号转导成分。这些结果表明多能性细胞身份可以通过多个基因调控网络建立和维持。生物学的一个主要目标是了解复杂性状的进化，例如多细胞机体结构的发展。复杂性状在一定程度上受调控基因表达的支配。物种间的比较表达数据比序列比较需要额外的考虑，因为基因表达不是静态的，表达水平受外界条件的影响。考虑到物种间的共表达模式通常具有可比性，我们开发了一个跨物种聚类分析的统计模型。该模型允许每个物种创造自己的基因簇，但也鼓励物种从彼此的同源基因簇中借用力量。结果是成对的集群，每个物种一个，其中成对的集群共享许多但不一定全部的同源基因。基于模型的方法不仅减少了主观影响，而且能够有效地利用进化依赖。应用该模型分析人和小鼠胚胎干细胞数据，我们确定了在人和小鼠胚胎干细胞中特异性表达的转录因子和信号蛋白。这些结果表明多能性细胞身份可以通过多个基因调控网络建立和维持。
Complex interactions between genes or proteins contribute substantially to phenotypic evolution. We present a probabilistic model and a maximum likelihood approach for cross-species clustering analysis and for identification of conserved as well as species-specific co-expression modules. This model enables a “soft” cross-species clustering (SCSC) approach by encouraging but not enforcing orthologous genes to be grouped into the same cluster. SCSC is therefore robust to obscure orthologous relationships and can reflect different functional roles of orthologous genes in different species. We generated a time-course gene expression dataset for differentiating mouse embryonic stem (ES) cells, and compiled a dataset of published gene expression data on differentiating human ES cells. Applying SCSC to analyze these datasets, we identified conserved and species-specific gene regulatory modules. Together with protein-DNA binding data, an SCSC cluster specifically induced in murine ES cells indicated that the KLF2/4/5 transcription factors, although critical to maintaining the pluripotent phenotype in mouse ES cells, were decoupled from the OCT4/SOX2/NANOG regulatory module in human ES cells. Two of the target genes of murine KLF2/4/5, LIN28 and NODAL, were rewired to be targets of OCT4/SOX2/NANOG in human ES cells. Moreover, by mapping SCSC clusters onto KEGG signaling pathways, we identified the signal transduction components that were induced in pluripotent ES cells in either a conserved or a species-specific manner. These results suggest that the pluripotent cell identity can be established and maintained through more than one gene regulatory network. A major goal in biology is to understand the evolution of complex traits, such as the development of multicellular body plans. To a certain extent, complex traits are governed by regulated gene expression. The comparison expression data between species requires extra considerations than sequence comparison, because gene expression is not static and the level of expression is influenced by external conditions. Considering that co-expression patterns are often comparable across species, we developed a statistical model for cross-species clustering analysis. The model allows each species to create its own clusters of the genes but also encourages the species to borrow strength from each others' clusters of orthologous genes. The result is a pairing of clusters, one from each species, where the paired clusters share many but not necessarily all orthologous genes. The model-based approach not only reduces subjective influence but also enables effective use of evolutionary dependence. Applying this model to analyze human and mouse embryonic stem (ES) cell data, we identified the transcription factors and the signaling proteins that are specifically expressed in either human or mouse ES cells. These results suggest that the pluripotent cell identity can be established and maintained through more than one gene regulatory network.
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DOI：
10.1073/pnas.011404098
发表时间：
2001-01-02
影响因子：
11.1
作者：
Li, C;Wong, WH
通讯作者：
Wong, WH
影响因子：
64.8
作者：
Brons, I. Gabrielle M.;Smithers, Lucy E.;Vallier, Ludovic
通讯作者：
Vallier, Ludovic
影响因子：
64.5
作者：
Lee, TI;Jenner, RG;Young, RA
通讯作者：
Young, RA
影响因子：
9.8
作者：
Gasch AP;Moses AM;Chiang DY;Fraser HB;Berardini M;Eisen MB
通讯作者：
Eisen MB
影响因子：
9.8
作者：
Bergmann S;Ihmels J;Barkai N
通讯作者：
Barkai N