National Institute of
General Medical Sciences

 

Regev and colleagues will develop computational techniques to infer and characterize biological modules from the massive datasets that contain information about the expression of genes or interactions between proteins. The proposed modules identified by these techniques, and their inferred behavior, can then be validated experimentally by deleting or manipulating the component genes or proteins, and will also be subject to theoretical analysis as described under project 2, below.

 

 

Fisher will collaborate with experimental colleagues to model the behavior of three types of biological module: those that perform Boolean (logical) functions, such as the set of genes controlling development of the fruit fly embryo; those that measure environmental parameters, such as the sets of proteins that detect concentration gradients in bacteria and yeast; and those that provide quantitative control of a biological process, such as the proteins that control the assembly of a mitotic spindle of a pre-determined length. The aim of this project is to establish a productive dialogue between experiment and theory, to create models that predict the behavior of biological systems, and then to understand how these models work.

 

 

Murray and colleagues will study the structure, function, and evolution of the collection of genes and proteins that control mating in the budding yeast, Saccharomyces cerevisiae. In addition to studying how this module evokes a switch-like response to a chemical mating signal, and how its response changes as the components that comprise the module are perturbed, Murray et al. will evolve the mating module in the lab to alter its logical behavior, its specificity, and its connectivity with other modules.

 

 

The addition of phosphate groups to proteins (‘phosphorylation’) is a key event in the transmission and processing of information in cells. Thorn and colleagues are developing a technique, based on fluorescence resonance energy transfer, to monitor the phosphorylation of hundreds of proteins simultaneously and in real time. Applying this technique to the yeast mating module (see project 3) will provide a new, quantitative way to monitor and dissect the function of this module.

 

 

Elowitz and colleagues will study the behavior of simple synthetic modules — genetic regulatory networks built from scratch from a small number of well characterized genetic elements. By mutating these elements systematically, Elowitz et al. will study the effects of varying module design on module function. By combining modeling and simulation with these experiments, Elowitz et al. aim to understand how the structure of a genetic regulatory module determines not only its function, but its ability to maintain or change that function during evolution.

 

 

Laub and colleagues will investigate the control of the modules that carry out the cell division cycle in the bacterium Caulobacter crescentus. Stable progression through the cell cycle requires the cell to receive and integrate a variety of signals, and translate these signals into the events that are necessary to produce viable daughter cells. Laub et al. will identify the genetic modules involved in cell-cycle progression in Caulobacter, characterize the connectivity of the network of proteins that control these modules, and dissect the design principles of regulatory modules by sensitively measuring the effects of removing one or more of several levels of redundant regulation.

 

 

Yeast cells exhibit an ‘environmental stress response’, in which the stimulation of distinct molecular pathways (by different environmental stresses, or ‘signals’) leads to both signal-specific outcomes and others that are common to many different signals. This raises the question of how signaling modules can be connected to a common response while otherwise remaining insulated from one another. Rando and colleagues will examine the role of chromatin (the complex of DNA and proteins that comprises the physical structure of chromosomes) in integrating signals that lead to the regulation of gene expression in response to stress, looking for general rules that govern the behavior of chromatin as a signal-processing element.

 

 

The study of modularity in biological systems is mostly concerned with molecular and cellular networks, but the ultimate challenge is the integration of complex processes across many levels, from molecules to whole organisms. The work of Hofmann and colleagues will span this range, as they undertake a study of how gene expression responds to changes in social status in the African cichlid fish Astatotilapia burtoni. Hofmann et al. aim to determine whether dedicated modules (such as gene networks, neural circuits, or hormonal pathways) underlie the ability of A. burtoni to maintain its integrity and function while it undergoes comprehensive changes in behavior in response to a changing social environment.

 

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