The Trithorax protein Ash1L promotes myoblast fusion by activating Cdon expression

Ilaria Castiglioni,Giulia Ferri,Roberta Caccia,Davide Gabellini,Giuseppina Caretti,Jose Manuel Garcia-Manteiga,Kenichi Nishioka,Ivan Molineris

doi:10.1038/s41467-018-07313-8

Abstract

Myoblast fusion (MF) is required for muscle growth and repair, and its alteration contributes to muscle diseases. The mechanisms governing this process are incompletely understood, and no epigenetic regulator has been previously described. Ash1L is an epigenetic activator belonging to the Trithorax group of proteins and is involved in FSHD muscular dystrophy, autism and cancer. Its physiological role in skeletal muscle is unknown. Here we report that Ash1L expression is positively correlated with MF and reduced in Duchenne muscular dystrophy. In vivo, ex vivo and in vitro experiments support a selective and evolutionary conserved requirement for Ash1L in MF. RNA- and ChIP-sequencing indicate that Ash1L is required to counteract Polycomb repressive activity to allow activation of selected myogenesis genes, in particular the key MF gene Cdon. Our results promote Ash1L as an important epigenetic regulator of MF and suggest that its activity could be targeted to improve cell therapy for muscle diseases.

Highlights

Myoblast fusion (MF) is required for muscle growth and repair, and its alteration contributes to muscle diseases
To begin investigating the physiological role of Ash1L in the skeletal muscle, we evaluated its expression in three crucial processes: muscle development, muscle regeneration, and in vitro muscle differentiation (Fig. 1)
During murine prenatal development and adulthood, Ash1L expression resulted maximal in fetal skeletal muscles, when myoblast fusion events are most frequent[11], and was progressively and significantly reduced reaching a minimum at P28, when myoblast fusion is normally off (Fig. 1a)

Summary

Introduction

Myoblast fusion (MF) is required for muscle growth and repair, and its alteration contributes to muscle diseases. The genetic reprogramming of somatic cells could occur following stem cell fusion[6] Besides these important examples, a specific and tightly regulated type of fusion is crucial for skeletal muscle tissue formation, growth, and repair[1,7,8]. During embryonic development, mononucleated muscle cells, termed myoblasts, undergo massive proliferation, providing the required number of precursor cells to build skeletal muscles. They exit the cell cycle, start to differentiate and fuse with one another to generate multinucleated and fully differentiated myofibers[7,8]. Despite its involvement in facioscapulohumeral (FSHD) muscular dystrophy[41], the physiological role of Ash1L in skeletal muscle is unknown

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Conclusion