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Curr Biol. 2013 Dec 2;23(23):2336-45. doi: 10.1016/j.cub.2013.09.043. Epub 2013 Nov 7.

Msn2 coordinates a stoichiometric gene expression program.

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Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143,USA; Howard Hughes Medical Institute, St. Louis, MO 63110, USA; The California Institute for Quantitative Biosciences, Berkeley, CA 94720, USA. Electronic address:



Many cellular processes operate in an "analog" regime in which the magnitude of the response is precisely tailored to the intensity of the stimulus. In order to maintain the coherence of such responses, the cell must provide for proportional expression of multiple target genes across a wide dynamic range of induction states. Our understanding of the strategies used to achieve graded gene regulation is limited.


In this work, we document a relationship between stress-responsive gene expression and the transcription factor Msn2 that is graded over a large range of Msn2 concentrations. We use computational modeling and in vivo and in vitro analyses to dissect the roots of this relationship. Our studies reveal a simple and general strategy based on noncooperative low-affinity interactions between Msn2 and its cognate binding sites as well as competition over a large number of Msn2 binding sites in the genome relative to the number of Msn2 molecules.


In addition to enabling precise tuning of gene expression to the state of the environment, this strategy ensures colinear activation of target genes, allowing for stoichiometric expression of large groups of genes without extensive promoter tuning. Furthermore, such a strategy enables precise modulation of the activity of any given promoter by addition of binding sites without altering the qualitative relationship between different genes in a regulon. This feature renders a given regulon highly "evolvable."

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