Abstract
Neat1 is widely expressed in many tissues and cells and exerts pro-proliferation effects on many cancer cells. However, little is known about the function of Neat1 in myogenesis. Here we characterized the roles of Neat1 in muscle cell formation and muscle regeneration. Gain- or loss-of-function studies in C2C12 cells demonstrated that Neat1 accelerates myoblast proliferation but suppresses myoblast differentiation and fusion. Further, knockdown of Neat1 in vivo increased the cross-sectional area of muscle fibers but impaired muscle regeneration. Mechanically, Neat1 physically interacted with Ezh2 mainly through the core binding region (1001–1540 bp) and recruited Ezh2 to target gene promoters. Neat1 promoted myoblast proliferation mainly by decreasing the expression of the cyclin-dependent kinase inhibitor P21 gene but inhibited myoblast differentiation by suppressing the transcription of myogenic marker genes, such as Myog, Myh4, and Tnni2. Altogether, we uncover a previously unknown function of Neat1 in muscle development and the molecular mechanism by which Neat1 regulates myogenesis.
Highlights
Skeletal muscle is the most abundant tissue in the mammalian body and plays a pivotal role in regulating body metabolism and homeostasis[1]
We investigated the roles of Neat[1] in myogenesis and found that Neat[1] regulates myoblast proliferation and differentiation by interacting with Ezh[2], defining a novel function of Neat[1] in muscle development and regeneration
The expression levels of Neat[1] along with paired box (Pax)[7] and myogenic differentiation 1 (Myod) were highly increased during the early stage of regeneration and decreased when the newly formed fibers maturation and regeneration completed
Summary
Skeletal muscle is the most abundant tissue in the mammalian body and plays a pivotal role in regulating body metabolism and homeostasis[1]. Myog and Mrf[4] are expressed after Myod and Myf[5] and determine terminal muscle cell differentiation. Satellite cells (SCs) are activated and undergoing proliferation, and paired box (Pax) 7 and Myod genes are upregulated at this stage. SCs differentiate into myotubes, upon which Pax genes are downregulated and Myog upregulated[9]. Epigenetic regulation, such as DNA methylation[10], histone modifications[11,12], and noncoding RNA functions[13,14], play important roles in the transcriptional regulation of myogenesis and ensure the normal proliferation and differentiation of muscle progenitors[15,16]. Enhancer of zeste homolog 2 (Ezh2) is a subunit of the epigenetic regulator polycomb repressive complex 2 (PRC2) responsible for trimethylation of lysine
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