Trends in Parasitology
ReviewChemical genomics for studying parasite gene function and interaction
Section snippets
What is meant by chemical genomics?
Chemical genomics is a means to study biology by recapitulating the effect of changes in gene integrity (e.g., mutations) and chromatin structure (e.g., epigenetic gene regulation) through the pharmacologic effect of a small molecule (SM) 1, 2. Effects elicited by SMs can take place either through direct interaction with a target protein, or indirectly by modulating expression or post-transcriptional/translational modification [2]. Experimentally, a cell line(s) is treated with various SMs and
SMs as tools for phenotypic screens
Changes in a genome can have different effects on a cell. Phenotypic differences between individual parts of an organism are largely controlled by differences in their genomic DNA. Genetic variations such as nucleotide substitution, insertion/deletion (indel), copy-number variation (CNV), and epigenetic modifications likely affect cell growth or survival to some degree. At the molecular level, if a change occurs in the coding region of a gene, the change may alter protein structure or enzyme
High-throughput screening (HTS) and genome-wide approaches to study targets of SMs
Most bioactive SMs carry out their pharmacologic action through binding to protein targets. Therefore, identification of protein targets is important in our understanding of the mode of action and the mechanisms underlying SM efficacy. Various biochemical approaches such as photo-crosslinking, radioisotope labeling, and affinity chromatography have been used to identify SM targets [16]; however, these methods are labor-intensive, time-consuming, and often generate inconclusive experimental
Concluding remarks and future perspectives
The ultimate goal of chemical genomics is to link variations in the genome to differences in cell survival, growth, and differentiation. Although it will be difficult to detect mutations that are essential for cell survival, many nonessential but important genetic variations can be identified through chemical genomics approaches. If a sufficiently diverse array of pharmacologically active SMs are screened against a large number of cell lines or microbes, it is possible to build connections or
Acknowledgments
This work was supported by the National Natural Science Foundation of China (grants 81220108019, 81271858, and 81201324), by Project 111 of the State Bureau of Foreign Experts and Ministry of Education of China (B06016), and by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Center for Advancing Translational Sciences, National Institutes of Health. We thank Dr Ronald Johnson for comments, and intramural editor Brenda Rae Marshall
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