Bridging high-throughput genetic and transcriptional data reveals cellular responses to alpha-synuclein toxicity

被引:223
作者
Yeger-Lotem, Esti [1 ,2 ]
Riva, Laura [2 ]
Su, Linhui Julie [1 ]
Gitler, Aaron D. [1 ]
Cashikar, Anil G. [1 ]
King, Oliver D. [1 ]
Auluck, Pavan K. [1 ,3 ,4 ,5 ]
Geddie, Melissa L. [1 ]
Valastyan, Julie S. [1 ,6 ]
Karger, David R. [7 ]
Lindquist, Susan [1 ,8 ]
Fraenkel, Ernest [2 ,7 ]
机构
[1] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA
[2] MIT, Dept Biol Engn, Cambridge, MA 02139 USA
[3] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA
[4] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA
[5] Harvard Univ, Sch Med, Boston, MA 02115 USA
[6] MIT, Dept Biol, Cambridge, MA 02139 USA
[7] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA
[8] MIT, Howard Hughes Med Inst, Dept Biol, Cambridge, MA 02139 USA
关键词
DNA-DAMAGING AGENTS; PARKINSONS-DISEASE; SACCHAROMYCES-CEREVISIAE; YEAST-CELLS; NETWORK; PATHWAY; GENOME; CHOLESTEROL; MECHANISMS; APOPTOSIS;
D O I
10.1038/ng.337
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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. By comparing the results of these two assays across various stimuli, we found that genetic screens tend to identify response regulators, whereas 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 used this approach to reveal cellular pathways responding to the toxicity of alpha-synuclein, a protein implicated in several neurodegenerative disorders including Parkinson's disease. For this we screened an established yeast model to identify genes that when overexpressed alter alpha-synuclein toxicity. Bridging these data and data from mRNA profiling provided functional explanations for many of these genes and identified previously unknown relations between alpha-synuclein toxicity and basic cellular pathways.
引用
收藏
页码:316 / 323
页数:8
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