Regulating a master regulator: establishing tissue-specific gene expression in skeletal muscle.
MyoD is a master regulator of the skeletal muscle gene expression program. ChIP-Seq analysis has recently revealed that MyoD binds to a large number of genomic loci in differentiating myoblasts, yet only activates transcription at a subset of these genes. Here we discuss recent data suggesting that the ability of MyoD to mediate gene expression is regulated through the function of Polycomb and Trithorax Group proteins. Based on studies of the muscle-specific myog gene, we propose a model where the transcriptional activators Mef2d and Six4 mediate recruitment of Trithorax Group proteins Ash2L/MLL2 and UTX to MyoD-bound promoters to overcome the Polycomb-mediated repression of muscle genes. Modulation of the interaction between Ash2L/MLL2 and Mef2d by the p38α MAPK signaling pathway in turns provides fine-tuning of the muscle-specific gene expression program. Thus Mef2d, Six4, and p38α MAPK function coordinately as regulators of a master regulator to mediate expression of MyoD target genes.
Aziz
Arif
A
Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, CA.
Liu
Qi-Cai
QC
Dilworth
F Jeffrey
FJ
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D056426:Genetic Loci / Q000502:physiology; D056466:Histone Demethylases; D011495:Histone-Lysine N-Methyltransferase; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D026161:MADS Domain Proteins / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D064326:MEF2 Transcription Factors; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000378:metabolism*; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism; D017570:MyoD Protein / Q000096:biosynthesis* / Q000235:genetics; D032446:Myoblasts / Q000378:metabolism; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism; D018008:Myogenin / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009928:Organ Specificity / Q000502:physiology; D063146:Polycomb-Group Proteins; D011401:Promoter Regions, Genetic / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C497422:KMT2A protein, human; C120898:KMT2D protein, human; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578043:MEF2D protein, human; C503799:MYOG protein, human; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D018006:Myogenic Regulatory Factors; D018008:Myogenin; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; C490851:SIX4 protein, human; D015534:Trans-Activators; D051788:Myeloid-Lymphoid Leukemia Protein; D056466:Histone Demethylases; C523998:KDM6A protein, human; D011495:Histone-Lysine N-Methyltransferase; D048051:p38 Mitogen-Activated Protein Kinases