Skeletal muscle programming and re-programming

Abstract

The discovery of the transcription factor MyoD and its ability to induce muscle differentiation was the first demonstration of genetically programmed cell transdifferentiation. MyoD functions by activating a feed-forward circuit to regulate muscle gene expression. This requires binding to specific E-boxes throughout the genome, followed by recruitment of chromatin modifying complexes and transcription machinery. MyoD binding can be modified by both cooperative factors and inhibitors, including microRNAs that may serve as important developmental switches. Recent studies indicate that epigenetic regulation of MyoD binding sites is another important mechanism for controlling MyoD activity, which may ultimately limit its ability to induce transdifferentiation to cells with permissive epigenetic 'landscapes.'

Figure 1

Transcription factor binding specificity and chromatin context work together to control cell differentiation. (a) Schematic nucleus showing only a few chromatids and a representation of MYOD E-boxes associated with muscle genes (red) or not associated with muscle genes (blue). (b) Chromatin context appears to be pre-determined by the cell lineage (open, accessible compartments shown in white; closed, inaccessible compartments in gray). An outstanding question is how such chromatin contexts are determined in the first place, or modified, by the different cell lineages. (c) Exogenous expression of MYOD converts MEFs into muscle, but not P19 mouse embryonal carcinoma cells. The developmental outcome is a consequence of the interplay between MYOD binding patterns and the pre-set chromatin context. Photomicrographs at the bottom show muscle cells derived from differentiated MEFs appearing on the left and undifferentiated P19 cells on the right (nuclei in blue are DAPI stained; muscle cells in green due to staining with myosin heavy chain antibody; colors merged in both photomicrographs)