Malat1 regulates myogenic differentiation and muscle regeneration through modulating MyoD transcriptional activity

<jats:title>Abstract</jats:title><jats:p><jats:italic>Malat1</jats:italic> is one of the most abundant long non-coding RNAs in various cell types; its exact cellular function is still a matter of intense investigation. In this study we characterized the function of <jats:italic>Malat1</jats:italic> in skeletal muscle cells and muscle regeneration. Utilizing both <jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic> assays, we demonstrate that <jats:italic>Malat1</jats:italic> has a role in regulating gene expression during myogenic differentiation of myoblast cells. Specifically, we found that knockdown of <jats:italic>Malat1</jats:italic> accelerates the myogenic differentiation in cultured cells. Consistently, <jats:italic>Malat1</jats:italic> knockout mice display enhanced muscle regeneration after injury and deletion of <jats:italic>Malat1</jats:italic> in dystrophic mdx mice also improves the muscle regeneration. Mechanistically, in the proliferating myoblasts, <jats:italic>Malat1</jats:italic> recruits Suv39h1 to MyoD-binding loci, causing trimethylation of histone 3 lysine 9 (H3K9me3), which suppresses the target gene expression. Upon differentiation, the pro-myogenic miR-181a is increased and targets the nuclear <jats:italic>Malat1</jats:italic> transcripts for degradation through Ago2-dependent nuclear RNA-induced silencing complex machinery; the <jats:italic>Malat1</jats:italic> decrease subsequently leads to the destabilization of Suv39h1/HP1β/HDAC1-repressive complex and displacement by a Set7-containing activating complex, which allows MyoD trans-activation to occur. Together, our findings identify a regulatory axis of miR-181a-<jats:italic>Malat1</jats:italic>-MyoD/Suv39h1 in myogenesis and uncover a previously unknown molecular mechanism of <jats:italic>Malat1</jats:italic> action in gene regulation.</jats:p>