Chemogenomic profiling: identifying the functional interactions of small molecules in yeast - PubMed (original) (raw)

Comparative Study

. 2004 Jan 20;101(3):793-8.

doi: 10.1073/pnas.0307490100. Epub 2004 Jan 12.

Affiliations

Comparative Study

Chemogenomic profiling: identifying the functional interactions of small molecules in yeast

Guri Giaever et al. Proc Natl Acad Sci U S A. 2004.

Abstract

We demonstrate the efficacy of a genome-wide protocol in yeast that allows the identification of those gene products that functionally interact with small molecules and result in the inhibition of cellular proliferation. Here we present results from screening 10 diverse compounds in 80 genome-wide experiments against the complete collection of heterozygous yeast deletion strains. These compounds include anticancer and antifungal agents, statins, alverine citrate, and dyclonine. In several cases, we identified previously known interactions; furthermore, in each case, our analysis revealed novel cellular interactions, even when the relationship between a compound and its cellular target had been well established. In addition, we identified a chemical core structure shared among three therapeutically distinct compounds that inhibit the ERG24 heterozygous deletion strain, demonstrating that cells may respond similarly to compounds of related structure. The ability to identify on-and-off target effects in vivo is fundamental to understanding the cellular response to small-molecule perturbants.

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Figures

Fig. 1.

Fig. 1.

A genome-wide readout of heterozygous strain sensitivity profiled at 250 μM methotrexate. The FD score is plotted along the y axis as a function of the 5,918 heterozygous yeast deletion strains ordered by ORF name. The greater the FD score, the more sensitive the strain. Essential ORFs are red and nonessential ORFs are blue. Strains above the dashed line are considered significantly sensitive (see Materials and Methods). Only those genes that scored significantly sensitive in eight of nine replicate experiments are labeled.

Fig. 2.

Fig. 2.

Distribution of gene ontology (GO) biological process terms for a list of 22 genes that, when heterozygous, confer significant sensitivity in at least two independent experiments in 5-FU at 19.2, 38.5, or 76.9 μM. The percent of genes sensitive to 5-FU is plotted along the y axis in each category relative to that of the whole genome. Only the GO terms with a P value <2.5E-06 are shown.

Fig. 3.

Fig. 3.

A genome-wide profile of homozygous strain sensitivity to 125 μM cisplatin. Axes shown are equivalent to those in Fig. 1. Only the strains that were scored as significantly sensitive are labeled.

Fig. 4.

Fig. 4.

Individual growth analysis of the HMG1 and HMG2 heterozygous and homozygous deletion strains in the presence of atorvastatin. Atorvastatin was 0 μM(A), 62.5 μM(B), 125 μM(C), or 250 μM(D). At the concentrations used in the HIP screens (62.5 and 125 μM), only the HMG1 heterozygous strain is sensitive, not the HMG2 heterozygous strain. At the highest concentration of atorvastatin (250 μM) both heterozygous strains are sensitive, as would be expected if both genes contribute to the HMG-CoA reductase activity of the cell. Comparable analysis in the presence of lovastatin yielded similar results (data not shown).

Fig. 5.

Fig. 5.

A comparison of the HIP profiles of fenpropimorph (2.3 μM; A), alverine citrate (500 μM; B), and dyclonine (C; 500 μM). Axes shown are equivalent to those in Fig. 1. In each case, the five most significant strains are labeled. (Insets) Illustration of the compound structure. The chemical core structure shared between the three compounds is shown in red.

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