Mapping pathways and phenotypes by systematic gene overexpression
Mapping pathways and phenotypes by systematic gene overexpression
复制标题
DOI：
10.1016/j.molcel.2005.12.011
复制
发表时间：
2006-02-03
期刊：
影响因子：
16
通讯作者：
Andrews, B
中科院分区：
文献类型：
--
作者：
Sopko, R;Huang, DQ;Andrews, B
许多疾病状态是由基因过度表达引起的，通常是在特定的遗传背景下。为了系统地探索基因过表达表型，我们组装了5280个酵母菌株的阵列，每个酵母菌株含有S.酿酒酵母基因，覆盖> 80%的基因组。大约15%的过表达基因（769个）降低了生长速率。该基因集富含细胞周期调控基因、信号分子和转录因子。大多数毒性基因的过表达导致与已知缺失突变体表型不同的表型，这表明过表达表型通常反映了特定的调节失衡，而不是蛋白质复合物化学计量的破坏。还在细胞周期蛋白依赖性激酶突变体（pho85 Delta）的背景下测定了全局过表达效应。所得的基因集富集Pho85p目标，并确定酵母钙调神经磷酸酶响应转录因子Crz1p作为底物。这种方法的大规模应用应该提供一种识别特定信号通路调控的靶分子的策略。
Many disease states result from gene overexpression, often in a specific genetic context. To explore gene overexpression phenotypes systematically, we assembled an array of 5280 yeast strains, each containing an inducible copy of an S. cerevisiae gene, covering > 80% of the genome. Approximately 15% of the overexpressed genes (769) reduced growth rate. This gene set was enriched for cell cycle-regulated genes, signaling molecules, and transcription factors. Overexpression of most toxic genes resulted in phenotypes different from known deletion mutant phenotypes, suggesting that overexpression phenotypes usually reflect a specific regulatory imbalance rather than disruption of protein complex stoichiometry. Global overexpression effects were also assayed in the context of a cyclin-dependent kinase mutant (pho85 Delta). The resultant gene set was enriched for Pho85p targets and identified the yeast calcineurin-responsive transcription factor Crz1p as a substrate. Large-scale application of this approach should provide a strategy for identifying target molecules regulated by specific signaling pathways.