The protein arginine methyltransferase Prmt5 is required for myogenesis because it facilitates ATP-dependent chromatin remodeling.
Skeletal muscle differentiation requires the coordinated activity of transcription factors, histone modifying enzymes, and ATP-dependent chromatin remodeling enzymes. The type II protein arginine methyltransferase Prmt5 symmetrically dimethylates histones H3 and H4 and numerous nonchromatin proteins, and prior work has implicated Prmt5 in transcriptional repression. Here we demonstrate that MyoD-induced muscle differentiation requires Prmt5. One of the first genes activated during differentiation encodes the myogenic regulator myogenin. Prmt5 and dimethylated H3R8 (histone 3 arginine 8) are localized at the myogenin promoter in differentiating cells. Modification of H3R8 required Prmt5, and reduction of Prmt5 resulted in the abrogation of promoter binding by the Brg1 ATPase-associated with the SWI/SNF chromatin remodeling enzymes and all subsequent events associated with gene activation, including increases in chromatin accessibility and stable binding by MyoD. Prmt5 and dimethylated H3R8 were also associated with the myogenin promoter in activated satellite cells isolated from muscle tissue, further demonstrating the physiological relevance of these observations. The data indicate that Prmt5 facilitates myogenesis because it is required for Brg1-dependent chromatin remodeling and gene activation at a locus essential for differentiation. We therefore conclude that a histone modifying enzyme is necessary to permit an ATP-dependent chromatin remodeling enzyme to function.
Dacwag
Caroline S
CS
Department of Cell Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA.
Ohkawa
Yasuyuki
Y
Pal
Sharmistha
S
Sif
Saïd
S
Imbalzano
Anthony N
AN
D000255:Adenosine Triphosphate / Q000737:chemistry*; D000818:Animals; D002454:Cell Differentiation; D002469:Cell Separation; D002843:Chromatin / Q000737:chemistry* / Q000378:metabolism; D004265:DNA Helicases / Q000378:metabolism; D019175:DNA Methylation; D004262:DNA Restriction Enzymes / Q000378:metabolism; D005434:Flow Cytometry; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism; D009132:Muscles / Q000378:metabolism*; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding; D011496:Protein Methyltransferases / Q000378:metabolism / Q000502:physiology*; D011484:Protein-Arginine N-Methyltransferases; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D002843:Chromatin; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D000255:Adenosine Triphosphate; D011496:Protein Methyltransferases; C498518:Prmt5 protein, mouse; D011484:Protein-Arginine N-Methyltransferases; D004262:DNA Restriction Enzymes; C513194:Smarca4 protein, mouse; D004265:DNA Helicases