Transient Responses And Adaptation To Steady State In A Eukaryotic Gene Regulation System

INSTITUTE OF PHYSICS PUBLISHING Phys. Biol. 1 (2004) 67–76

PHYSICAL BIOLOGY PII: S1478-3967(04)78989-5

Transient responses and adaptation to steady state in a eukaryotic gene regulation system
Erez Braun1 and Naama Brenner2
1 2

Department of Physics, Technion—Israel Institute of Technology, Haifa 32000, Israel Department of Chemical Engineering, Technion—Israel Institute of Technology,Haifa 32000, Israel

E-mail: erez@physics.technion.ac.il

Received 1 February 2004 Accepted for publication 13 April 2004 Published 29 April 2004 Online at stacks.iop.org/PhysBio/1/67
DOI: 10.1088/1478-3967/1/2/003

Abstract Understanding the structure and functionality of eukaryotic gene regulation systems is of fundamental importance in many areas of biology. While most recent studiesfocus on static or short-term properties, measuring the long-term dynamics of these networks under controlled conditions is necessary for their complete characterization. We demonstrate adaptive dynamics in a well-known system of metabolic regulation, the GAL system in the yeast S. cerevisiae. This is a classic model for a eukaryotic genetic switch, induced by galactose and repressed by glucose. Wefollowed the expression of a reporter gfp under a GAL promoter at single-cell resolution in large population of yeast cells. Experiments were conducted for long time scales, several generations, while controlling the environment in continuous culture. This combination enabled us, for the first time, to distinguish between transient responses and steady state. We find that both galactose inductionand glucose repression are only transient responses. Over several generations, the system converges to a single robust steady state, independent of external conditions. Thus, at steady state the GAL network loses its hallmark functionality as a sensitive carbon source rheostat. This result suggests that, while short-term dynamics are determined by specific modular responses, over long time scalesinter-modular interactions take over and shape a robust steady state response of the regulatory system.

1. Introduction
Genetic regulatory networks, their structure and functionality, are the focus of current research in several areas of biology. These networks control the level of gene expression in response to intracellular and external signals. Specific stimulus-response relationships, such asswitch-like behaviour and graded induction, are important for determining cell fate (Davidson 2001, Gerhart and Kirscner 1997, Wilkins 2002). The response of a genetic regulatory system is usually characterized by a well-defined function of a small number of inputs. However, recent large-scale analyses have revealed that genetic regulatory networks are highly complex and multifunctional (Brem et al2002, Ideker et al 2001, Lee et al 2002, Pilpel et al 2001). These properties suggest that
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adaptive dynamics, context and history dependence should play important roles in the response of genetic regulatory systems, as they do in many other physiological systems. Thus, uncovering the adaptive behaviour of genetic regulation systems over time must complement theefforts to map their network wiring. An important example for adaptation was recently provided in a study of the genome-wide stress response in yeast (Gasch et al 2000). This work showed that following a specific response to an environmental change, the cells adapt their gene expression programme to a new steady state not very different from the one before the environmental shift; the global changesin transcript abundance immediately following the environmental change were largely transient. Specific cell responses to non-stressful signals are also likely to be composed of a transient part, followed by adaptation to 67

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E Braun and N Brenner

Galactose Galactose (out) (in) Gal2 Gal1 Gal10 Gal7

Glucose-6-P Gal5

Gal4 Gal80 Gal3...