Distinct protein arginine methyltransferases promote ATP-dependent chromatin remodeling function at different stages of skeletal muscle differentiation.

Temporal regulation of gene expression is a hallmark of cellular differentiation pathways, yet the mechanisms controlling the timing of expression for different classes of differentiation-specific genes are not well understood. We previously demonstrated that the class II arginine methyltransferase Prmt5 was required for skeletal muscle differentiation at the early stages of myogenesis (C. S. Dacwag, Y. Ohkawa, S. Pal, S. Sif, and A. N. Imbalzano, Mol. Cell. Biol. 27:384-394, 2007). Specifically, when Prmt5 levels were reduced, the ATP-dependent SWI/SNF chromatin-remodeling enzymes could not interact with or remodel the promoter of myogenin, an essential early gene. Here we investigated the requirement for Prmt5 and the class I arginine methyltransferase Carm1/Prmt4 in the temporal control of myogenesis. Both arginine methyltransferases could bind to and modify histones at late-gene regulatory sequences. However, the two enzymes showed sequential requirements for gene expression. Prmt5 was required for early-gene expression but dispensable for late-gene expression. Carm1/Prmt4 was required for late- but not for early-gene expression. The reason for the requirement for Carm1/Prmt4 at late genes was to facilitate SWI/SNF chromatin-remodeling enzyme interaction and remodeling at late-gene loci. Thus, distinct arginine methyltransferases are employed at different times of skeletal muscle differentiation for the purpose of facilitating ATP-dependent chromatin-remodeling enzyme interaction and function at myogenic genes.