Maheshri:Research

We are interested in understanding and exploiting the phenotypic plasticity of microbial organisms; ie. their capability to generate new phenotypes (behavior, physiological state) by small, easily accessible changes. A classic biotechnological example of exploiting phenotypic plasticity is the current state of protein engineering. Small changes in (certain parts of) protein sequence can lead to large changes in function (or phenotype). The directed evolution of proteins has become an enormously successful technology that enables the exploration of the protein sequence space for different phenotypes. We aim to extend the idea of directed evolution to whole cell physiology in order to engineer organisms with many different cellular phenotypes.

Changes in phenotype are often preceded by wholesale changes in the gene expression state of many genes that can be due to molecular processes that occur over various time scales. Such processes are listed below:



However, the large-scale expression changes may originate from small changes in the expression of a small subset of genes that are then amplified by a regulatory network. Therefore, to create different cellular phenotypes, our current focus is on the rational and/or combinatorial modification of transcriptional regulatory networks in budding yeast. The central questions are: what component(s) of the network to change? how to change those components? can we predict the resulting phenotypes? We take an integrated theoretical and experimental approach to answer these questions. We are developing experimental systems in budding yeast to rapidly measure the consequences of genetic, epigenetic, and stochastic variation in different network components. Concurrently, we are developing models that predict the consequences of such variation in the network on the expression phenotype.

Projects
A synthetic promoter system to rapidly generate phenotypic diversity in a microbial population - Bradley Niesner

Frequency response and kinetic proofreading in the nucleocytoplasmic shuttling of transcription factors - C.J. Zopf

In vivo targeted mutagenesis - Shawn Finney-Manchester

Noise induced bimodality in positive feedback without bistability - T.L. To

The regulatory role of tandem repeats containing transcription factor binding sites - Tek Hyung Lee