Evolutionary conserved circular MEF2A RNAs regulate myogenic differentiation and skeletal muscle development.

IF 4.5 2区 生物学 Q1 Agricultural and Biological Sciences PLoS Genetics Pub Date : 2023-09-07 eCollection Date: 2023-09-01 DOI:10.1371/journal.pgen.1010923
Xiaoxu Shen, Xiyu Zhao, Haorong He, Jing Zhao, Yuanhang Wei, Yuqi Chen, Shunshun Han, Yifeng Zhu, Yao Zhang, Qing Zhu, Huadong Yin
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Abstract

Circular RNAs (circRNAs) have been recognized as critical regulators of skeletal muscle development. Myocyte enhancer factor 2A (MEF2A) is an evolutionarily conserved transcriptional factor that regulates myogenesis. However, it remains unclear whether MEF2A produces functional circRNAs. In this study, we identified two evolutionarily conserved circular MEF2A RNAs (circMEF2As), namely circMEF2A1 and circMEF2A2, in chicken and mouse muscle stem cells. Our findings revealed that circMEF2A1 promotes myogenesis by regulating the miR-30a-3p/PPP3CA/NFATC1 axis, whereas circMEF2A2 facilitates myogenic differentiation by targeting the miR-148a-5p/SLIT3/ROBO2/β-catenin signaling pathway. Furthermore, in vivo experiments demonstrated that circMEF2As both promote skeletal muscle growth. We also discovered that the linear MEF2A mRNA-derived MEF2A protein binds to its own promoter region, accelerating the transcription of MEF2A and upregulating the expression of both linear MEF2A and circMEF2As, forming a MEF2A autoregulated positive feedback loop. Moreover, circMEF2As positively regulate the expression of linear MEF2A by adsorbing miR-30a-3p and miR-148a-5p, which directly contribute to the MEF2A autoregulated feedback loop. Importantly, we found that mouse circMEF2As are essential for the myogenic differentiation of C2C12 cells. Collectively, our results demonstrated the evolution, function, and underlying mechanisms of circMEF2As in animal myogenesis, which may provide novel insight for both the farm animal meat industry and human medicine.

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进化保守的环状MEF2A RNA调节肌源分化和骨骼肌发育。
环状核糖核酸(circRNAs)已被公认为骨骼肌发育的关键调节因子。肌细胞增强子因子2A(MEF2A)是一种进化上保守的调节肌发生的转录因子。然而,目前尚不清楚MEF2A是否产生功能性circRNA。在本研究中,我们在鸡和小鼠肌肉干细胞中鉴定了两种进化上保守的环状MEF2A RNA(circMEF2As),即circMEF2A1和circMEF2 A2。我们的研究结果表明,circMEF2A1通过调节miR-30a-3p/PPP3CA/NFATC1轴来促进肌发生,而circMEF2A2通过靶向miR-148a-5p/SLIT3/ROBO2/β-catenin信号通路来促进肌分化。此外,体内实验表明circMEF2As都能促进骨骼肌生长。我们还发现,线性MEF2A mRNA衍生的MEF2A蛋白与其自身的启动子区结合,加速了MEF2A的转录,并上调了线性MEF2A和circMEF2a的表达,形成了一个MEF2A自动调节的正反馈环。此外,circMEF2As通过吸附miR-30a-3p和miR-148a-5p正向调节线性MEF2A的表达,这直接有助于MEF2A自动调节的反馈回路。重要的是,我们发现小鼠circMEF2As对C2C12细胞的肌源性分化至关重要。总之,我们的研究结果证明了circMEF2As在动物肌肉发生中的进化、功能和潜在机制,这可能为农场动物肉工业和人类医学提供新的见解。
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来源期刊
PLoS Genetics
PLoS Genetics 生物-遗传学
CiteScore
8.10
自引率
2.20%
发文量
438
审稿时长
1 months
期刊介绍: PLOS Genetics is run by an international Editorial Board, headed by the Editors-in-Chief, Greg Barsh (HudsonAlpha Institute of Biotechnology, and Stanford University School of Medicine) and Greg Copenhaver (The University of North Carolina at Chapel Hill). Articles published in PLOS Genetics are archived in PubMed Central and cited in PubMed.
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