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Proc Natl Acad Sci U S A. 2013 Jan 29;110(5):1964-9. doi: 10.1073/pnas.1216108110. Epub 2013 Jan 10.

Incoherent feed-forward regulatory logic underpinning glucocorticoid receptor action.

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1
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143, USA.

Abstract

The complexity and specificity of metazoan transcription are determined by combinatorial control of the composition and activity of regulatory complexes. To investigate the basis of this specificity, we focused on the glucocorticoid receptor (GR), a single regulatory factor that integrates multiple signals to give rise to many distinct patterns of expression. We measured the expression of a set of genes, each directly GR-regulated, but by different mechanisms in two cell lines. We varied ligand (dose, chemistry, and duration of treatment), GR (expression level and functionality), and a non-GR regulatory factor that commonly interacts with GR. Our study revealed distinct expression patterns within this set of genes, but all could be modeled by an incoherent feed-forward regulatory logic. Cellular signals, operating on GR and other factors within regulatory complexes, may define and modulate the kinetics and strength of the activating or inhibitory paths of the regulatory logic. Thus, characterizing systems behavior by perturbing single or multiple signals can reveal general principles of regulation, providing an approach to the dissection and deconvolution of combinatorial control.

PMID:
23307810
PMCID:
PMC3562826
DOI:
10.1073/pnas.1216108110
[Indexed for MEDLINE]
Free PMC Article
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