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Saeed Tavazoie

Genomic and computational studies of biological networks

The overall objective of our research is to better understand the structural and dynamical properties of biological networks. We have focused primarily on the intracellular networks which regulate the expression of genes. These, so-called, transcriptional networks are at the top of the hierarchy of regulatory systems within cells, and as such, are central to establishing and maintaining specific patterns of gene expression. Intuitive behaviors of cells, such as adaptation and differentiation, are fundamentally orchestrated by these networks. Genetic and biochemical approaches are providing us with an increasingly detailed and mechanistic picture of transcriptional regulation at single loci. However, our knowledge about the global structure of transcriptional networks--such as their overall connectivity and organization--remains sparse. In addition, we lack the conceptual framework for integrating such knowledge into a predictive understanding of their dynamics. We are using genomic, computational, and analytic methods to address these challenges.

The stereotyped model of transcriptional regulation is mediated by sequence-specific DNA-binding proteins, called transcription factors which bind to their cognate sites on DNA, and through their interaction with the general transcriptional machinery, and/or modification of chromatin structure, activate or repress the expression of a nearby gene. A transcription factor and its DNA-binding site (cis-regulatory element) form the "connection", through which, the expression (or activity of the protein product) of one gene influences the expression of another gene. We have used whole-genome surveys of gene expression, and pattern recognition algorithms to identify such connections within the transcriptional networks of the yeast, S. cerevisiae. We found that this discovery-oriented approach efficiently recapitulates much of what decades of hypothesis-driven efforts have uncovered about transcriptional regulatory elements in yeast. We have also discovered hundreds of putative elements whose biological significance remains to be validated experimentally.

We are also using whole-genome, in vivo methods to directly identify DNA-protein interactions. Taking advantage of high-density oligonucleotide arrays (DNA chips), we are now able to simultaneously monitor the occupancy of ~500 DNA-protein interaction sites in E. coli. We are correlating these data to whole-genome mRNA expression measurements in order to discern the regulatory consequences for the occupancy of the bound sites.

Ongoing projects in the laboratory include:

1. Developing algorithms for inferring the structure of networks from genomic data.
2. Developing experimental methods for validating computational predictions of networks.
3. Elucidating the combinatorial logic of regulation mediated by multiple cis-regulatory elements.
4. Scaling these methods to the size and complexity of metazoan genomes.

Evolution provides us with a unifying perspective. Our long-term goal is to better understand how the structural and dynamical properties of networks reflect, and depend on, the physical, chemical, multicellular, and ecological contexts in which they have evolved.

Selected Publications

Goodarzi H, Hottes AK, Tavazoie S. (2009) Global discovery of adaptive mutations. Nat Methods 6: 581-583. PubMed

Vora T, Hottes AK, Tavazoie S. (2009) Protein occupancy landscape of a bacterial genome. Mol Cell. 35: 247-253. PubMed

Lu X, Li JM, Elemento O, Tavazoie S, Wieschaus EF. (2009) Coupling of zygotic transcription to mitotic control at the Drosophila mid-blastula transition. Development. 136: 2101-2110. PubMed

Girgis HS, Hottes AK, Tavazoie S. (2009) Genetic architecture of intrinsic antibiotic susceptibility. PLoS ONE. 4: e5629. PubMed

Amini S, Goodarzi H, Tavazoie S. (2009) Genetic dissection of an exogenously induced biofilm in laboratory and clinical isolates of E. coli. PLoS Pathog. 5: e1000432. PubMed

Freckleton G, Lippman SI, Broach JR, Tavazoie S. (2009) Microarray profiling of phage-display selections for rapid mapping of transcription factor-DNA interactions. PLoS Genet. 5: e1000449. PubMed

Legesse-Miller A, Elemento O, Pfau SJ, Forman JJ, Tavazoie S, Coller HA. (2009) let-7 overexpression leads to an increased fraction of cells in G2/M, direct down-regulation of Cdc34 and stabilization of Wee1 kinase in primary fibroblasts. J Biol Chem. 284: 6605-6609. PubMed

Tagkopoulos I, Liu YC, Tavazoie S. (2008) Predictive behavior within microbial genetic networks. Science 320: 1313-1317. PubMed

Elemento O, Tavazoie S. (2007) Fastcompare: a nonalignment approach for genome-scale discovery of DNA and mRNA regulatory elements using network-level conservation. Methods Mol Biol. 395: 349-366. PubMed

Elemento O, Slonim N, Tavazoie S. (2007) A universal framework for regulatory element discovery across all genomes and data types. Mol Cell 28: 337-350. PubMed

Girgis HS, Liu Y, Ryu WS, Tavazoie S. (2007) A comprehensive genetic characterization of bacterial motility. PLoS Genet 3: 1644-1660. PubMed

De Renzis S, Elemento O, Tavazoie S, Wieschaus EF. (2007) Unmasking activation of the zygotic genome using chromosomal deletions in the Drosophila embryo. PLoS Biol 5: e117. (Erratum in: PLoS Biol 5: e213, PLoS Biol 5: e195.) PubMed

Lahav R, Gammie A, Tavazoie S, Rose MD (2007) Role of transcription factor Kar4 in regulating downstream events in the Saccharomyces cerevisiae pheromone response pathway. Mol Cell Biol 27: 818-829. PubMed

Slonim N, Elemento O, Tavazoie S (2006). Ab initio genotype–phenotype association reveals intrinsic modularity in genetic networks. Mol Syst Biol  2:2006.0005. PubMed

Elemento O and Tavazoie S (2005). Fast and systematic genome-wide discovery of conserved regulatory elements using a non-alignment based approach. Genome Biol 6: R18.

Chan CS, Elemento O and Tavazoie S (2005). Revealing posttranscriptional regulatory elements through network-level conservation. PLoS Comput Biol 1: e69. PubMed

Wang Y, Pierce M, Schneper L, Guldal CG, Zhang X, Tavazoie S, Broach JR (2004). Ras and Gpa2 mediate one branch of a redundant glucose signaling pathway in yeast. PLoS Biol 2: E128. PubMed

Pritsker M, Liu YC, Beer MA and Tavazoie S (2004). Whole-genome discovery of transcription factor binding sites by network-level conservation. Genome Res 14: 99-108. PubMed

Kurdistani SK, Tavazoie S and Grunstein M (2004). Mapping global histone acetylation patterns to gene expression. Cell 117: 721-733. PubMed

Jim K, Parmar K, Singh M and Tavazoie S (2004). A cross-genomic approach for systematic mapping of phenotypic traits to genes. Genome Res 14: 109-115. PubMed

Beer MA and Tavazoie S (2004). Predicting gene expression from sequence. Cell 117: 185-198. PubMed

Kurdistani SK, Robyr D, Tavazoie S and Grunstein M (2002). Genome-wide binding map of the histone deacetylase Rpd3 in yeast. Nat Genet 31: 248-254. PubMed

Badarinarayana V, Estep PW 3rd, Shendure J, Edwards J, Tavazoie S, Lam F, Church GM (2001). Selection analyses of insertional mutants using subgenic-resolution arrays. Nat Biotechnol 19: 1060-1065. PubMed