Döhr S, Klingenhoff A, Maier H, Hrabé de Angelis M, Werner T, Schneider R
Institute of Experimental Genetics, GSF-National Research Center for Environment and Health Ingolstädter Landstrasse 1, D-85764 Neuherberg, Germany.
Nucleic Acids Res. 2005 Feb 8;33(3):864-72. doi: 10.1093/nar/gki230. Print 2005.
Pathway- or disease-associated genes may participate in more than one transcriptional co-regulation network. Such gene groups can be readily obtained by literature analysis or by high-throughput techniques such as microarrays or protein-interaction mapping. We developed a strategy that defines regulatory networks by in silico promoter analysis, finding potentially co-regulated subgroups without a priori knowledge. Pairs of transcription factor binding sites conserved in orthologous genes (vertically) as well as in promoter sequences of co-regulated genes (horizontally) were used as seeds for the development of promoter models representing potential co-regulation. This approach was applied to a Maturity Onset Diabetes of the Young (MODY)-associated gene list, which yielded two models connecting functionally interacting genes within MODY-related insulin/glucose signaling pathways. Additional genes functionally connected to our initial gene list were identified by database searches with these promoter models. Thus, data-driven in silico promoter analysis allowed integrating molecular mechanisms with biological functions of the cell.
与通路或疾病相关的基因可能参与不止一个转录共调控网络。此类基因群组可通过文献分析或高通量技术（如微阵列或蛋白质相互作用图谱）轻松获得。我们开发了一种策略，通过计算机模拟启动子分析来定义调控网络，在无需先验知识的情况下找到潜在的共调控亚组。直系同源基因（纵向）以及共调控基因的启动子序列（横向）中保守的转录因子结合位点对被用作开发代表潜在共调控的启动子模型的种子。该方法应用于青少年发病的成年型糖尿病（MODY）相关基因列表，产生了两个连接MODY相关胰岛素/葡萄糖信号通路中功能相互作用基因的模型。通过使用这些启动子模型进行数据库搜索，鉴定出了与我们最初基因列表功能相关的其他基因。因此，数据驱动的计算机模拟启动子分析能够将分子机制与细胞的生物学功能整合起来。
