Pax7 remodels the chromatin landscape in skeletal muscle stem cells

Karin C. Lilja, Nan Zhang, Alessandro Magli, Volkan Gunduz, Christopher J. Bowman, Robert W. Arpke, Radbod Darabi, Michael Kyba, Rita Perlingeiro, Brian D. Dynlacht

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11 Scopus citations


Pluripotent stem cells (PSC) hold great promise for the treatment of human skeletal muscle diseases. However, it remains challenging to convert PSC to skeletal muscle cells, and the mechanisms by which the master regulatory transcription factor, Pax7, promotes muscle stem (satellite) cell identity are not yet understood. We have taken advantage of PSC-derived skeletal muscle precursor cells (iPax7), wherein the induced expression of Pax7 robustly initiates the muscle program and enables the in vitro generation of precursors that seed the satellite cell compartment upon transplantation. Remarkably, we found that chromatin accessibility in myogenic precursors pre-figures subsequent activation of myogenic differentiation genes. We also found that Pax7 binding is generally restricted to euchromatic regions and excluded from H3K27 tri-methylated regions in muscle cells, suggesting that recruitment of this factor is circumscribed by chromatin state. Further, we show that Pax7 binding induces dramatic, localized remodeling of chromatin characterized by the acquisition of histone marks associated with enhancer activity and induction of chromatin accessibility in both muscle precursors and lineage-committed myoblasts. Conversely, removal of Pax7 leads to rapid reversal of these features on a subset of enhancers. Interestingly, another cluster of Pax7 binding sites is associated with a durably accessible and remodeled chromatin state after removal of Pax7, and persistent enhancer accessibility is associated with subsequent, proximal binding by the muscle regulatory factors, MyoD1 and myogenin. Our studies provide new insights into the epigenetic landscape of skeletal muscle stem cells and precursors and the role of Pax7 in satellite cell specification.

Original languageEnglish (US)
Article numbere0176190
JournalPloS one
Issue number4
StatePublished - Apr 2017

Bibliographical note

Funding Information:
This work was supported by the NIH (Grants: 5R01GM067132 and 1R21AR068786-01A1 to BDD, R01AR055299 to RP, and P30CA016087 [] to New York University School of Medicine's Genome Technology Center). AM was supported by a Regenerative Medicine Minnesota grant (MRM 2015 PDSCH 003; []).

Publisher Copyright:
© 2017 This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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