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| Chemogenomic profiling on a genomewide scale using reverse-engineered gene networks |
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| Author(s): di Bernardo D, Thompson MJ, Gardner TS, Chobot SE, Eastwood EL, Wojtovich AP, Elliott SJ, Schaus SE, Collins JJ |
| Source: NATURE BIOTECHNOLOGY Volume: 23 Issue: 3 Pages: 377-383 Published: MAR 2005 |
| Times Cited: 92 References: 45 |
| Abstract: A major challenge in drug discovery is to distinguish the molecular targets of a bioactive compound from the hundreds to thousands of additional gene products that respond indirectly to changes in the activity of the targets(1-8). Here, we present an integrated computational-experimental approach for computing the likelihood that gene products and associated pathways are targets of a compound. This is achieved by filtering the mRNA expression profile of compound-exposed cells using a reverse-engineered model of the cell's gene regulatory network. We apply the method to a set of 515 whole-genome yeast expression profiles resulting from a variety of treatments (compounds, knockouts and induced expression), and correctly enrich for the known targets and associated pathways in the majority of compounds examined. We demonstrate our approach with PTSB, a growth inhibitory compound with a previously unknown mode of action, by predicting and validating thioredoxin and thioredoxin reductase as its target. |
| Document Type: Article |
| Language: English |
| Reprint Address: Collins, JJ (reprint author), Boston Univ, Ctr BioDynam, Boston, MA 02215 USA |
Addresses:
1. Boston Univ, Ctr BioDynam, Boston, MA 02215 USA
2. Telethon Inst Genet Med, Naples, Italy
3. Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA
4. Boston Univ, Dept Chem, Boston, MA 02215 USA
5. Boston Univ, Ctr Chem Methodol & Lib Dev, Boston, MA 02215 USA |
| Publisher: NATURE PUBLISHING GROUP, 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA |
| Subject Category: Biotechnology & Applied Microbiology |
| IDS Number: 906IW |
| ISSN: 1087-0156 |
| DOI: 10.1038/nbt1075 |
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| | | | | | | | | Record from Web of Science® | | | | | | | | | |