Epigenetic regulation of satellite cell activation during muscle regeneration

Abstract

Satellite cells are a population of adult muscle stem cells that play a key role in mediating muscle regeneration. Activation of these quiescent stem cells in response to muscle injury involves modulating expression of multiple developmentally regulated genes, including mediators of the muscle-specific transcription program: Pax7, Myf5, MyoD and myogenin. Here we present evidence suggesting an essential role for the antagonistic Polycomb group and Trithorax group proteins in the epigenetic marking of muscle-specific genes to ensure proper temporal and spatial expression during muscle regeneration. The importance of Polycomb group and Trithorax group proteins in establishing chromatin structure at muscle-specific genes suggests that therapeutic modulation of their activity in satellite cells could represent a viable approach for repairing damaged muscle in muscular dystrophy.

Figure 1

Epigenetic regulation of developmentally regulated genes in satellite-cell-mediated muscle regeneration. Regulation of gene expression by Polycomb group (PcG) and Trithorax group (TrxG) methyltransferase complexes at developmentally regulated loci is depicted. Histone modifications or the presence of PcG/TrxG complexes on the gene highlighted in grey are predicted and have not been formally shown (please see text for rationale on the predictions). (a) Cells undergoing symmetrical cell division will express Pax7 and the genes involved in cell-cycle progression. These genes are predicted to be marked by TrxG-mediated H3K4me3, while the repressed MyoD/Myf5 and Myog genes would be marked by the repressive H3K27me3 mark. In the case of Myf5/MyoD, it will be interesting to determine whether these are bivalently marked genes poised for transcription. (b) During asymmetrical cell division, one of the two cells will go on to become a proliferating myoblast. The proliferating myoblast will express genes involved in cell-cycle progression, as well as Pax7, and Myf5/MyoD. These genes are known to be marked by H3K4me3 in proliferating myoblasts, and in the case of Myf5 it has been shown that this mark is established through the recruitment of TrxG proteins by Pax7. (c) In terminally differentiating cells that will fuse to the damaged fiber, Pax7 is silenced along with genes involved in cell-cycle progression. This repression involves PcG-mediated incorporation of H3K27me3 into the chromatin at these genes. At this time, the Myog gene becomes expressed as MyoD collaborates with Mef2d and Six4 to establish the transcriptionally permissive state of H3K4me3. MRF, muscle regulatory factor.