Title: Genetic noise control via protein oligomerization

Abstract

Gene expression in a cell entails random reaction events occurring over disparate time scales. Thus, molecular noise that often results in phenotypic and population-dynamic consequences sets a fundamental limit to biochemical signaling. While there have been numerous studies correlating the architecture of cellular reaction networks with noise tolerance, only a limited effort has been made to understand the dynamical role of protein-protein associations. We have developed a fully stochastic model for the positive feedback control of a single gene, as well as a pair of genes (toggle switch), integrating quantitative results from previous in vivo and in vitro studies. In particular, we explicitly account for the fast protein binding-unbinding kinetics, RNA polymerases, and the promoter/operator sequences of DNA. We find that the overall noise-level is reduced and the frequency content of the noise is dramatically shifted to the physiologically irrelevant high-frequency regime in the presence of protein dimerization. This is independent of the choice of monomer or dimer as transcription factor and persists throughout the multiple model topologies considered. For the toggle switch, we additionally find that the presence of a protein dimer, either homodimer or heterodimer, may significantly reduce its intrinsic switching rate. Hence, the dimer promotes the robustmore » function of bistable switches by preventing the uninduced (induced) state from randomly being induced (uninduced). The specific binding between regulatory proteins provides a buffer that may prevent the propagation of fluctuations in genetic activity. The capacity of the buffer is a non-monotonic function of association-dissociation rates. Since the protein oligomerization per se does not require extra protein components to be expressed, it provides a basis for the rapid control of intrinsic or extrinsic noise. The stabilization of phenotypically important toggle switches, and nested positive feedback loops in general, is of direct implications to organism fitness. Finally, noise control through oligomerization suggests avenues for the design of robust synthetic gene circuits for engineering purposes.« less

Authors:

Ghim, C; Almaas, E

Publication Date:

Thu Jun 12 00:00:00 EDT 2008

Research Org.:

Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

Sponsoring Org.:

USDOE

OSTI Identifier:

945534

Report Number(s):

LLNL-JRNL-408313
TRN: US200903%%626

DOE Contract Number:  

W-7405-ENG-48

Resource Type:

Journal Article

Journal Name:

BMC Systems Biology, N/A, N/A, November 3, 2008, pp. 2:94

Additional Journal Information:

Journal Volume: 2

Country of Publication:

United States

Language:

English

Subject:

59 BASIC BIOLOGICAL SCIENCES; ARCHITECTURE; BUFFERS; DIMERIZATION; DIMERS; DNA; FEEDBACK; FLUCTUATIONS; GENES; GENETICS; IN VITRO; IN VIVO; KINETICS; MONOMERS; PROTEINS; RNA POLYMERASES; STABILIZATION; SWITCHES; TRANSCRIPTION FACTORS