Drug-Induced Regulation of Target Expression
Open Access
- 9 September 2010
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Computational Biology
- Vol. 6 (9), e1000925
- https://doi.org/10.1371/journal.pcbi.1000925
Abstract
Drug perturbations of human cells lead to complex responses upon target binding. One of the known mechanisms is a (positive or negative) feedback loop that adjusts the expression level of the respective target protein. To quantify this mechanism systems-wide in an unbiased way, drug-induced differential expression of drug target mRNA was examined in three cell lines using the Connectivity Map. To overcome various biases in this valuable resource, we have developed a computational normalization and scoring procedure that is applicable to gene expression recording upon heterogeneous drug treatments. In 1290 drug-target relations, corresponding to 466 drugs acting on 167 drug targets studied, 8% of the targets are subject to regulation at the mRNA level. We confirmed systematically that in particular G-protein coupled receptors, when serving as known targets, are regulated upon drug treatment. We further newly identified drug-induced differential regulation of Lanosterol 14-alpha demethylase, Endoplasmin, DNA topoisomerase 2-alpha and Calmodulin 1. The feedback regulation in these and other targets is likely to be relevant for the success or failure of the molecular intervention. Many drug targets thought to be suitable for therapeutic purposes are subjected to positive or negative feedback loops upon chemical perturbations which might even account for the development of drug tolerance. In this study, we carried out the first systematic analysis of drug-induced differential expression of drug targets using the Connectivity Map, a resource that contains the genome-wide expression profiles of 1309 bioactive small molecules performed on four cultured human cells. The main obstacle in analyzing such a large set of profiles is the non-biological experimental variation across batches. We overcame this by developing a pipeline for strict filtering and state-of-the-art normalization and were able to utilize the Connectivity Map for assessing the drug-induced differential regulation of drug targets. Using the normalized data, we found that at least 8% of the drug-induced drug targets studied are differentially regulated in three cell lines; some of these confirm previous observations in other cell lines. Our work not only quantifies the amount of target expression feedback loops in three human cell lines, but also identifies so far unknown drug-induced target expression changes; some of them can be linked to the development of drug tolerance in patients.Keywords
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