Projects and Scientists
The center brings together eight projects that investigate the structure, function and evolution of functional modules in a variety of organisms.
Kobi Benenson uses RNAi-based control modules to build general-purpose logic circuits that report on gene expression profiles in mammalian cells (Rinaudo et al. 2007). George Church develops approaches to rapidly generate a large number of transcription circuits using directed splicing and ligation (DSL) and ways to facilitate directed evolution of these circuits in vivo.
Naama Barkai applies theoretical and computational tools to study the influence of promoter properties on the evolution of gene expression. In collaboration with Andrew Murray she also studies how mating yeast cells signal their presence and recognize their position.
Andrew Murray, the center’s principal investigator, is dissecting and evolving the mating module of budding yeast. Recent accomplishments include the evolution of a five-fold mating preference in a laboratory model of sympatric speciation (Leu & Murray 2006), the development of general methods to map and identify mutations (Segre et al. 2006), and the engineering of the graded pheromone response into a hysteretic switch by putting modified signaling proteins under the control of a pheromone-inducible promoter (Ingolia & Murray, 2007). Andrew Murray also devises methods to measure fundamental parameters of evolution such as mutation rates. In collaboration with M. Desai and D. Fisher, he developed and tested a model that predicted the rate of evolution (Desai et al. 2007), and his groupinvestigated the conditions under which mutators accelerated evolution (Thompson et al. 2006).
Michael Elowitz, in collaboration with Michael Surette, is studying how the function of natural and man-made bacterial transcriptional networks depends on quantitative variation in intracellular and environmental parameters. They identified the independent tuning of differentiation frequency and duration as a design principle, and showed that noise is actually required for cellular differentiation (Suel et al, 2007).
Sharad Ramanathan uses single-cell experiments, modeling and theory to investigate the costs and benefits of the starvation response in budding yeast.
Kevin Verstrepen investigates whether tandem repeats serve as hyper-variable modules in genes and promoters. His group has developed an algorithm to find and annotate repeats and predict whether they vary in number.
Kevin Foster's goal is to characterize evolutionary cooperation and conflict in microbial social traits at both the genetic and phenotypic level, using a combination of empirical and theoretical approaches. In a simulation of biofilm development his group found that slime production in biofilms can benefit the slime-producers by pushing their descendents up into the nutrient- and oxygen-rich regions of the biofilm (Xavier and Foster, 2007).
Katharina Ribbeck studies the permeability properties of mucus, an important filter that lines epithelial surfaces.
Former Projects and Scientists
Aviv Regev, in collaboration with Nir Friedman and George Church, used computational approaches to find modules, analyze their structure and function, and reconstruct their evolution. Recent accomplishments include:
- Module Map, a computational approach for associating the regulation of modules with biological conditions; for cancer, this approach identified collections of molecules that shed new light on metastasis (Segal et al. 2004; Segal et al. 2005);
- showing that, although the genes in transcriptional modules are evolutionarily conserved, the transcription factors and DNA motifs that control their expression are not (Tanay et al. 2005);
- GeneXPress, a framework for analyzing modules that allows users to find modules, see their components, and compare the effects of different definitions of modules (Segal et al. 2004).
- SYNERGY, and algorithm that reliably distinguishes orthologs from paralogs on a genomic scale; its use led to the identification of seven principles that govern copy number variation across 300 million years of fungal evolution, and clarified the contribution of copy number variation to genome and module evolution (Wapinski et al. 2007).
Daniel Fisher built theoretical models, and using them to predict and analyze the behavior of modules in vivo. This work has led to improved understanding of the generation of segment polarity in Drosophila (Ingolia 2004) and, in collaboration with the Mitchison lab at Harvard Medical School, to a model for meiotic spindle organization in Xenopus egg extracts (Burbank et al. 2006, 2007).
Kurt Thorn has developed methods to monitor protein modification and interactions in yeast, using fluorescence resonance energy transfer (FRET) microscopy (Sheff & Thorn 2004). He has also used these techniques in a collaboration with Michael Laub, to find interactions between two-component signaling proteins in the bacterium Caulobacter crescentus.
Michael Laub used genomics, genetics, biochemistry, cell biology, and computational biology to study the structure and function of the circuits that control the cell cycle of the bacterium Caulobacter crescentus. Recent accomplishments include a systematic investigation of deletion phenotypes and substrate specificity of two-component signaling proteins in Caulobacter, leading to the discovery of a highly conserved, essential signaling pathway controlling cell envelope biogenesis and structure (Skerker et al. 2005), the delineation of a complete signaling pathway controlling stalk biogenesis during cell cycle progression (Biondi et al. 2006), and an integrated genetic circuit that ensures oscillations in activity of the master cell cycle regulator CtrA (Biondi et al., 2007).
Oliver Rando studied chromatin structure and function, using a novel microarray to determine nucleosome positions and modification states over 0.5 Mb of the yeast genome, at 20-base-pair resolution. This work has led to the following discoveries:
- Most of the yeast genome is found in well positioned, rather than delocalized, nucleosomes; and most promoters have a long nucleosome-free region where transcription starts, which is enriched for poly-dA-dT stretches and conserved transcription factor binding sites (Yuan et al. 2005).
- Putting conserved A-rich sequences at a heterologous location can make a nucleosome-free region (Raisner et al. 2005).
- The pattern of histone modification in yeast nucleosomes is much less complex, and much less instructive, than advocates of a “histone code” have proposed (Liu et al. 2005).
- nucleosomes exchange rapidly at promoters and at known chromatin boundary elements; histone replacement rates over coding regions correlate with polymerase density (Dion et al. 2007)
Christine Queitsch asked how genetic variation, maternal effects and chaperone levels determine developmental trajectories and fitness of Arabidopsis thaliana (Sangster et al. 2007). Her lab also developed an Arabidopsis genotyping array using insertions and deletion polymorphisms.
Hans Hofmann explored the molecular basis of neural and behavioral plasticity in the African cichlid fish Astatotilapia burtoni. His group used a combination of behavioral observation and microarray analysis (Renn et al. 2004) to map the genetic modules responsible for the dramatic behavioral and physiological transitions between territorial (“macho”) and non-territorial (“wimp”) males.
