A MyoD-generated feed-forward circuit temporally patterns gene expression during skeletal muscle differentiation.
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.
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Bennett H
BH
Penn
Donald A
DA
Bergstrom
F Jeffrey
FJ
Dilworth
Eyal
E
Bengal
Stephen J
SJ
Tapscott
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology*; D064326:MEF2 Transcription Factors; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D017570:MyoD Protein / Q000502:physiology*; D018006:Myogenic Regulatory Factors; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
D017931:DNA Primers; D004268:DNA-Binding Proteins; D064326:MEF2 Transcription Factors; C578044:Mef2d protein, mouse; D017570:MyoD Protein; D018006:Myogenic Regulatory Factors; D014157:Transcription Factors; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases