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| Content Provider | PubMed Central |
|---|---|
| Author | Brettman, Ari D. Tan, Pauline H. Tran, Khoa Shaw, Stanley Y. |
| Abstract | Despite rapid advances in the genetics of complex human diseases, understanding the significance of human disease alleles remains a critical roadblock to clinical translation. Here, we present a chemical biology approach that uses perturbation with small molecules of known mechanism to reveal mechanistic and therapeutic consequences of human disease alleles. To maximize human applicability, we perform chemical screening on multiple cell lines isolated from individual patients, allowing the effects of disease alleles to be studied in their native genetic context. Chemical screen analysis combines the logic of traditional genetic interaction screens with analytic methods from high-dimensionality gene expression analyses. We rank compounds according to their ability to discriminate between cell lines that are mutant vs. wild-type at a disease gene (i.e., the compounds induce phenotypes that differ the most across the two classes). A technique called Compound Set Enrichment Analysis (CSEA), modeled after a widely used method to identify pathways from gene expression data, identifies sets of functionally or structurally related compounds that are statistically enriched among the most discriminating compounds. This chemical:genetic interaction approach was applied to patient-derived cells in a monogenic form of diabetes and identified several classes of compounds (including FDA-approved drugs) that show functional interactions with the causative disease gene, and also modulate insulin secretion, a critical disease phenotype. In summary, perturbation of patient-derived cells with small molecules of known mechanism, together with compound-set based pathway analysis, can identify small molecules and pathways that functionally interact with disease alleles, and that can modulate disease networks for therapeutic effect. |
| Related Links | http://dx.doi.org/10.1007/978-1-4939-2269-7_2 |
| Ending Page | 27 |
| Page Count | 13 |
| Starting Page | 15 |
| File Format | |
| ISSN | 10643745 |
| e-ISSN | 19406029 |
| Journal | Methods in molecular biology (Clifton, N.J.) |
| Volume Number | 1263 |
| Language | English |
| Publisher Date | 2015-01-01 |
| Access Restriction | Open |
| Subject Keyword | Research in Higher Education |
| Content Type | Text |
| Resource Type | Article |
| Subject | Genetics Molecular Biology |
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