Msx1 Cooperates with Histone H1b for Inhibition of Transcription and Myogenesis

Abstract

During embryogenesis, differentiation of skeletal muscle is regulated by transcription factors that include members of the Msx homeoprotein family. By investigating Msx1 function in repression of myogenic gene expression, we identified a physical interaction between Msx1 and H1b, a specific isoform of mouse histone H1. We found that Msx1 and H1b bind to a key regulatory element of MyoD, a central regulator of skeletal muscle differentiation, where they induce repressed chromatin. Moreover, Msx1 and H1b cooperate to inhibit muscle differentiation in cell culture and in Xenopus animal caps. Our findings define a previously unknown function for "linker" histones in gene-specific transcriptional regulation.

The epigenetic network regulating muscle development and regeneration

“…Msx-1 is implicated in inhibiting the differentiation of several mesenchymal lineages, including skeletal muscle, during embryogenesis (Bendall et al, 1999;Bendall and Abate-Shen, 2000). When looking for interacting partners for Msx-1 in C2C12 myoblasts Lee et al, found that it preferentially binds to the linker histone H1b (Lee et al, 2004). Linker histones are so called because of their role in keeping the nucleosomes juxtaposed, to form a highly compacted chromatin structure.…”

“…Other events, such as Msx1-dependent positioning of H1b histone (Lee et al, 2004) and Rho-mediated signalling (Carnac et al, 1998) must provide additional elements contributing to induce MyoD expression in muscle cells, although the relationship between these events remains unknown.…”

“…However, the mechanisms leading to MyoD (or Myf 5) induction in muscle precursors are still largely unknown. It has been recently described that the homeobox protein Msx1 plays a pivotal role in the temporal control of myogenesis (Lee et al, 2004). Msx-1 is implicated in inhibiting the differentiation of several mesenchymal lineages, including skeletal muscle, during embryogenesis (Bendall et al, 1999;Bendall and Abate-Shen, 2000).…”

“…Apart from their structural role, they participate in other regulatory functions, such as DNA repair (Downs et al, 2003), apoptosis (Konishi et al, 2003) and gene expression (Bouvet et al, 1994;Steinbach et al, 1997). Msx-1 targets H1b to the regulatory region of MyoD, and this recruitment is necessary for Msx-1 dependent repression of MyoD and inhibition of myogenesis (Lee et al, 2004). Of the several isoforms present in mice, the H1b subtype is expressed in undifferentiated cells, including muscle precursors, and its expression decreases as differentiation proceeds (Wang et al, 1997), consistent with a role in temporally restricting gene expression during development.…”

Slow-Adhering Stem Cells Derived from Injured Skeletal Muscle Have Improved Regenerative Capacity

“…In addition to functioning as an important regulator of limb and muscle development, 59,71 Msx1 has also been suggested as being able to promote dedifferentiation of muscle cells and to maintain the multipotency of stem cells. 48,72,73 In a previous study, we observed that Msx1 overexpression in muscle cells resulted in a greatly improved ratio of cells positive for Sca-1 to cells positive for CD34 (unpublished data). We also reported that traumatic injury is able to stimulate skeletal muscle cell dedifferentiation in vivo.…”