Overview of High Throughput Screening
Genetic or environmental interventions can alter cellular phenotypes. Many cell-based screens simply seek to identify specific interventions such as a siRNA or small molecule that result in a desired cellular phenotype. More powerful screens seek to identify suppressors or enhancers of a primary genetic or environmental intervention. Suppressor interactions indicate that the two elements are in the same pathway. Enhancer interactions (e.g. synthetic lethality) indicate that the two elements are in separate but compensating pathways. Such screens can identify pathway elements and organisation, identify gene-gene and gene-environment interactions which underlie in complex genetic diseases, and also through gene-chemical interactions identify pathway specific drugs. For illustrative examples see the reference list below.
Principles of Genetic Interaction
Mani R, St Onge RP, Hartman JLt, Giaever G, & Roth FP (2008) Defining genetic interaction. Proc Natl Acad Sci U S A 105(9):3461-3466.
St Onge RP, et al. (2007) Systematic pathway analysis using high-resolution fitness profiling of combinatorial gene deletions. Nat Genet 39(2):199-206.
Whitehurst AW, et al. (2007) Synthetic lethal screen identification of chemosensitizer loci in cancer cells. Nature 446(7137):815-819.
Castoreno AB, et al. (2010) Small molecules discovered in a pathway screen target the Rho pathway in cytokinesis. Nat Chem Biol 6(6):457-463
Signaling Molecule - Gene Interactions
Tang, W., Dodge, M., Gundapaneni, D., Michnoff, C., Roth, M. & Lum, L. A genome-wide RNAi screen for Wnt/beta-catenin pathway components identifies unexpected roles for TCF transcription factors in cancer. Proc Natl Acad Sci U S A 105, 9697-702 (2008).
Zhang EE, et al. (2009) A genome-wide RNAi screen for modifiers of the circadian clock in human cells. Cell 139(1):199-210.
Collinet C, et al. (2010) Systems survey of endocytosis by multiparametric image analysis. Nature 464(7286):243-249.
Huh JR, et al. (2011) Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORgammat activity. Nature 472(7344):486-490.
Huang SM, et al. (2009) Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 461(7264):614-620.
Chong CR, Chen X, Shi L, Liu JO, & Sullivan DJ, Jr. (2006) A clinical drug library screen identifies astemizole as an antimalarial agent. Nat Chem Biol 2(8):415-416.
Professor Shoumo Bhattacharya MD MSc (Biochem) FRCP FESC FMedSci
BHF Chair of Cardiovascular Medicine
Department of Cardiovascular Medicine & Wellcome Trust Centre for Human Genetics