A MyoD-generated feed-forward circuit temporally patterns gene expression during skeletal muscle differentiation
- Bennett H. Penn1,2,
- Donald A. Bergstrom1,3,
- F. Jeffrey Dilworth1,
- Eyal Bengal4,6, and
- Stephen J. Tapscott1,2,5
- 1Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA; 2Molecular and Cellular Biology Program, Fred Hutchinson Cancer Research Center and the University of Washington, Seattle, Washington 98109, USA; 3Department of Laboratory Medicine, University of Washington School of Medicine, Seattle, Washington 98195, USA; 4Department of Biochemistry, Rappaport Institute for Research in the Medical Sciences, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel
Abstract
The development and differentiation of distinct cell types is achieved through the sequential expression of subsets of genes; yet, the molecular mechanisms that temporally pattern gene expression remain largely unknown. In skeletal myogenesis, gene expression is initiated by MyoD and includes the expression of specific Mef2 isoforms and activation of the p38 mitogen-activated protein kinase (MAPK) pathway. Here, we show that p38 activity facilitates MyoD and Mef2 binding at a subset of late-activated promoters, and the binding of Mef2D recruits Pol II. Most importantly, expression of late-activated genes can be shifted to the early stages of differentiation by precocious activation of p38 and expression of Mef2D, demonstrating that a MyoD-mediated feed-forward circuit temporally patterns gene expression.
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Footnotes
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Supplemental material is available at http://www.genesdev.org.
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Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1234304.
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Corresponding authors.
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↵5 E-MAIL stapscot{at}fhcrc.org; FAX (206) 667-6524.
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↵6 E-MAIL Bengal{at}tx.technion.ac.il; FAX 972-4-8535-773.
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- Accepted August 4, 2004.
- Received June 28, 2004.
- Cold Spring Harbor Laboratory Press
