We work in the field of systems and synthetic biology, studying the large-scale organization of proteins. Essentially, we try to reconstruct the 'wiring diagrams' of cells, learning how all proteins encoded by a genome are associated into pathways, systems, and networks. We're interested both in discovering the functions of the proteins and in learning their underlying organizational principles. The work is about half computation, half experiment, with the former focusing on reconstructing genome-scale gene networks and the latter tending to be high-throughput functional genomics and proteomics approaches for studying thousands of genes/proteins in parallel, such as quantitative shotgun proteomics mass spectrometry and high-throughput automated fluorescence microcopy. Such data help us construct quantitative models of cells, and put us on the road to developing predictive, rather than merely descriptive, theories of biology.
With these tools, we now have some (still limited) ability to rationally predict the consequences of disrupting a specific gene. This often lets us identify candidate genes for diseases or traits. We've now experimentally validated >100 candidates for diverse traits in a wide range of organisms, including yeast, C. elegans, Arabidopsis, frogs, mice, and humans. We obviously can't work on all of these ourselves! In our own lab, we primarily culture yeast, C. elegans, and mammalian cells. We also collaborate extensively with experts on other organisms; this lets us test the generality of our methods. For example, in yeast we've predicted and validated many new ribosome biogenesis genes. In C. elegans, we predicted suppressors of the loss of the Retinoblastoma tumor suppressor, 'curing' worms of model tumors. In Arabidopsis, we've rationally identified genes regulating root growth, drought resistance, and pigmentation. In vertebrates, we've used gene networks to assign functions to a birth defect gene and to identify entirely new birth defect genes, confirming their roles in vivo.
Examples of validated computational predictions - in Xenopus, a new regulator of angiogenesis (PNAS, 2010); Arabidopsis, a new regulator of lateral root formation (Nature Biotech, 2010); and C. elegans, a new regulator of the Retinoblastoma tumor suppressor (Nature Genetics, 2008).
Finding disease genes from lower organisms - New algorithms (the phenolog method, PNAS, 2010) have helped us identify non-obvious models of human diseases, including a yeast model for angiogenesis defects, a worm model for breast cancer, and a plant model for craniofacial alterations and deafness. Illustration by Katherine Weir. Vector female silhouette under Creative Commons Attribution 2.0 from 'Keep Fit' Vector Pack, Blog.SpoonGraphics.
|2013||Li Z, Park Y, Marcotte EM , A bacteriophage tailspike domain promotes self-cleavage of a human membrane-bound transcription factor, the myelin regulatory factor MYRF , PLoS Biology 11(8):e1001624.|
|2012||Havugimana PC, Hart GT, Nepusz T, Yang H, Turinsky AL, Li Z, Wang P, Boutz DR, Fong V, Babu M, Craig SA, Hu P, Phanse S, Wan C, Vlasblom J, Dar V, Bezginov A, Wu GC, Wodak SJ, Tillier ERM, Paccanaro A, Marcotte EM, Emili A, Census of Human Soluble Protein Complexes, Cell 150:1068-1081.|
|2011||Lee I, Seo Y-S, Coltrane D, Hwang S, Oha T, Marcotte EM, Ronald PC, Genetic dissection of the biotic stress response using a genome-scale gene network for rice, Proc Natl Acad Sci USA 108(45):18548-18553.|
|2010||Vogel C, Abreu Rde S, Ko D, Le SY, Shapiro BA, Burns SC, Sandhu D, Boutz DR, Marcotte EM, Penalva LO, Sequence signatures and mRNA concentration can explain two-thirds of protein abundance variation in a human cell line, Molecular Systems Biology 6:400.|
|2010||McGary KL, Park TJ, Woods JO, Cha HJ, Wallingford JB, Marcotte EM, Systematic discovery of nonobvious human disease models through orthologous phenotypes, Proc Natl Acad Sci U S A 107:6544-9 view.|
|2010||Lee I, Ambaru B, Thakkar P, Marcotte EM, Rhee SY, Rational association of genes with traits using a genome-scale gene network for Arabidopsis thaliana, Nature Biotechnology 28:149-156 view.|
|2009||Tabor JJ, Salis H, Simpson ZB, Chevalier AA, Levskaya A, Marcotte EM, Voigt CA, Ellington AD, A synthetic genetic edge detection program, Cell 137:1272-1281.|
|2009||Gray RS, Abitua PB, Wlodarczyk BJ, Blanchard O, Lee I, Weiss G, Marcotte EM, Wallingford JB, Finnell RH, The planar cell polarity effector protein Fuzzy is essential for targeted membrane trafficking, ciliogenesis, and mouse embryonic development, Nature Cell Biology 11:1225-32.|
|2009||Li Z, Lee I, Moradi E, Hung NJ, White J, Johnson AW, Marcotte EM, Rational extension of the ribosome biogenesis pathway using network-guided genetics, PLoS Biology 7:e1000213 view.|
|2009||Narayanaswamy R, Levy M, Tsechansky M, Stovall GM, O'Connell J, Mirrielees J, Ellington AD, Marcotte EM, Widespread reorganization of metabolic enzymes into reversible assemblies upon nutrient starvation, Proc Natl Acad Sci U S A 106:10147-52 view.|
|2008||Lee I, Lehner B, Crombie C, Wong W, Fraser AG, Marcotte EM, A single network comprising the majority of genes accurately predicts the phenotypic effects of gene perturbation in C. elegans, Nature Genetics 40:181-188 view.|