Data from: High-resolution chemical dissection of a model eukaryote reveals targets, pathways and gene functions

Due to evolutionary conservation of biology, experimental knowledge captured from genetic studies in eukaryotic model organisms provides insight into human cellular pathways and ultimately physiology. Yeast chemogenomic profiling is a powerful approach for annotating cellular responses to small molecules. Using an optimized platform, we provide the relative sensitivities of the heterozygous and homozygous deletion collections for nearly 1800 biologically active compounds. The data quality enables unique insights into pathways that are sensitive and resistant to a given perturbation, as demonstrated with both known and novel compounds. We present examples of novel compounds that inhibit the therapeutically relevant fatty acid synthase and desaturase (Ole1p and Fas1p), and demonstrate how the individual profiles facilitate hypothesis-driven experiments to delineate compound mechanism of action. Importantly, the scale and diversity of tested compounds yields a dataset where the number of modulated pathways approaches saturation. This resource can be used to map novel biological connections, and also identify functions for unannotated genes. We validated hypotheses generated by global 2-way hierarchical clustering of profiles for (i) novel compounds with a similar mechanism of action acting upon microtubules or vacuolar ATPases, and (ii) an un-annotated ORF, YIL060w, that plays a role in respiration in the mitochondria. Finally, we identify and characterize background mutations in the widely used yeast deletion collection which should improve the interpretation of past and future screens throughout the community. This comprehensive resource of cellular responses enables the expansion of our understanding of eukaryotic pathway biology.由于生物学的进化保守性，从真核模式生物的遗传学研究中获取的实验知识，可为人类细胞通路乃至生理机能研究提供重要见解。酵母化学基因组谱分析是注释细胞对小分子应答反应的有效手段。本研究借助优化后的实验平台，为近1800种生物活性化合物提供了杂合缺失与纯合缺失突变体库的相对敏感性数据。优质的数据质量可让我们针对特定扰动下的敏感与耐受通路获得独特见解，这一点可通过已知与新型化合物得到验证。我们展示了可抑制治疗相关脂肪酸合酶与去饱和酶（Ole1p与Fas1p）的新型化合物案例，并阐明了单一样本谱如何助力基于假说的实验，以阐明化合物的作用机制。值得注意的是，受试化合物的规模与多样性使得本数据集所覆盖的调控通路数量接近饱和。该数据集可用于绘制新型生物学关联图谱，同时也可为未注释基因赋予功能注释。我们验证了通过全局双向层次聚类分析样本谱所生成的两类假说：一是作用于微管或液泡ATP酶的同类作用机制新型化合物，二是在线粒体呼吸过程中发挥功能的未注释开放阅读框（Open Reading Frame，ORF）YIL060w。最后，我们对当前广泛使用的酵母缺失突变体库中的背景突变进行了鉴定与特征分析，这将有助于全球学术共同体优化对既往及未来筛选实验结果的解读。本综合性细胞应答数据集，可推动我们对真核细胞通路生物学的认知拓展。