Direct generation of a homogeneous population of skeletal myoblasts from human embryonic stem cells (hESCs) and formation of tri-dimensional contractile structures for in dish disease modeling is a current challenge in regenerative medicine. Previous studies reported on the generation of myoblasts from ESC-derived embryoid bodies (EB), but not from undifferentiated ESCs, indicating the requirement for mesodermal transition to promote skeletal myogenesis. Here we show that selective absence of the SWI/SNF component BAF60C (encoded by SMARCD3) confers on hESCs resistance to MyoD-mediated activation of skeletal myogenesis. Forced expression of BAF60C enables MyoD to directly activate skeletal myogenesis in hESCs, by instructing MyoD nuclear positioning and allowing chromatin remodelling at target genes. BAF60C/MyoD-expressing hESCs are epigenetically committed myogenic progenitors, which bypass the mesodermal requirement and, when cultured as floating clusters, give rise to contractile tri-dimensional myospheres composed of skeletal myotubes. These results identify BAF60C as key epigenetic determinant of hESC commitment to the myogenic lineage, and establish the molecular basis for the unprecedented generation of hESC-derived myospheres exploitable for “in dish models” of muscular diseases.
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