Bridging the gap between high-throughput genetic and transcriptional data reveals cellular pathways responding to alpha-synuclein toxicity
Author(s)Yeger-Lotem, Esti; Riva, Laura; Su, Linhui Julie; Gitler, Aaron D.; Cashikar, Anil G.; King, Oliver D.; Auluck, Pavan K.; Geddie, Melissa L.; Valastyan, Julie Suzanne; Karger, David R.; Lindquist, Susan; Fraenkel, Ernest; ... Show more Show less
Bridging high-throughput genetic and transcriptional data reveals cellular responses to alpha-synuclein toxicity
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Cells respond to stimuli by changes in various processes, including signaling pathways and gene expression. Efforts to identify components of these responses increasingly depend on mRNA profiling and genetic library screens, yet the functional roles of the genes identified by these assays often remain enigmatic. By comparing the results of these two assays across various cellular responses, we found that they are consistently distinct. Moreover, genetic screens tend to identify response regulators, while mRNA profiling frequently detects metabolic responses. We developed an integrative approach that bridges the gap between these data using known molecular interactions, thus highlighting major response pathways. We harnessed this approach to reveal cellular pathways related to alpha-synuclein, a small lipid-binding protein implicated in several neurodegenerative disorders including Parkinson disease. For this we screened an established yeast model for alphasynuclein toxicity to identify genes that when overexpressed alter cellular survival. Application of our algorithm to these data and data from mRNA profiling provided functional explanations for many of these genes and revealed novel relations between alpha-synuclein toxicity and basic cellular pathways.
DepartmentMassachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory; Massachusetts Institute of Technology. Department of Biological Engineering; Massachusetts Institute of Technology. Department of Biology; Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science; Whitehead Institute for Biomedical Research
Nature Publishing Group
Yeger-Lotem, Esti et al. “Bridging high-throughput genetic and transcriptional data reveals cellular responses to alpha-synuclein toxicity.” Nat Genet 41.3 (2009): 316-323.
Author's final manuscript