The research in the Cai group is focused on the systems biology and single molecule approach to signal transduction in living cells. We are interested in developing new microscopy techniques to measure the dynamics of post-translational modification in single cells as well as addressing biological questions in signaling and gene expression from simple eukaryotes to multi-cellular organisms.

We have recently discovered that, in single cells, signaling and gene expression events occur in a surprisingly dynamical and stochastic fashion. With quantitative single cell time-lapse fluorescence microscopy, we uncovered a previously unknown frequency-modulated (FM) mode of control in signaling, where signaling protein are coherently phosphorylated and de-phosphorylated in pulses within a single cell and the frequency and duration of pulses are modulated by external signal. We have shown that FM signaling (click here to watch movie clip) can allow coordinated control of gene expression and may have roles in diverse biological processes. These observations of a new mode of regulation provide the impetus to ask a broad range of scientific questions and develop new spectroscopic tools to visualize chemical dynamics in single cell.

The Scientific Questions
First, we are working on elucidating the mechanisms of FM pulses. We will use genetic perturbations and controlled protein-protein interactions to affect burst kinetics and quantitatively measure and model their effects on network dynamics. Second, given that many signaling pathways pulse and propagate to downstream genes, we will investigate in depth how bursting in diverse signaling pathways overlaps temporally to crosstalk and integrate at the promoter levels. Lastly, we will explore signaling dynamics in multi-cellular organisms and the roles they play in developmental cell fate decisions.

The Techniques
How do we visualize phosphorylation and other post-translational modifications in individual cells? We will develop optical tools to mark and track interactions between kinases (or phosphatases) and their target proteins. We will extend these techniques to the single molecule level and apply them to quantify signaling and gene expression events in living cells.

The research interest of our group lies at the interface of chemistry, physics and biology. To this end, we integrate quantitative physical techniques such as time-lapse fluorescence microscopy and single molecule detection with genetics and chemical biology to explore interdisciplinary problems.

Frequency-modulated nuclear localization bursts coordinate gene regulation.
Nature 445, 485 (2008) L. Cai*, C. Dalal*, M.E. Elowitz

A stochastic single-molecule event triggers phenotype switching of a bacterial cell.
Science 322, 422 (2008) P. Choi*, L. Cai* K. Frieda, X.S. Xie

Studying stochastic protein expression in individual cells with single molecule sensitivity.
Nature 440, 358 (2006) L.Cai*, N. Friedman*, X.S. Xie

Linking stochastic dynamics to population distribution: an analytical framework of gene expression.
Phys. Rev. Lett, 97, 168302 (2006) N. Friedman, L.Cai, X.S. Xie

* denotes equal contribution