Linc-RAM is required for FGF2 function in regulating myogenic cell differentiation
Linc-RAM is required for FGF2 function in regulating myogenic cell differentiation
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Linc-RAM 是 FGF2 调节肌原细胞分化功能所必需的
DOI：
10.1080/15476286.2018.1431494
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发表时间：
2018-02
期刊：
影响因子：
4.1
通讯作者：
Zhu Dahai
中科院分区：
文献类型：
--
作者：
Zhao Yixia;Cao Fengqi;Yu Xiaohua;Chen Chuyan;Meng Jiao;Zhong Ran;Zhang Yong;Zhu Dahai
骨骼肌干细胞（又称卫星细胞）的肌源性分化受到内在和外在调控因子的密切调控。碱性成纤维细胞生长因子（FGF 2）是有据可查的卫星细胞的自我更新和分化，通过抑制MyoD。我们最近发现了一个MyoD调节和骨骼肌特异性表达的长非编码RNA Linc RAM，它通过促进MyoD/Baf 60 c/Brg 1复合物组装来增强肌原性分化。本文研究了Linc-RAM基因在肌细胞分化过程中的转录调控和细胞内信号通路。首先，我们证明Linc-RAM在肌细胞中受FGF 2通过Ras/Raf/Mek/Erk信号通路负调控。MyoD的过表达显著减弱了用FGF 2处理的C2 C12细胞中Linc-RAM启动子活性的抑制。MyoD的敲除消除了从MyoD−/−; Pax 7-nGFP小鼠的骨骼肌中分选的卫星细胞中FGF 2介导的Linc-RAM基因转录的抑制，表明抑制MyoD是FGF 2介导的Linc-RAM表达所必需的。对于功能意义，我们表明Linc-RAM的过表达挽救了FGF 2诱导的C2 C12细胞分化抑制，表明Linc-RAM的抑制是FGF 2介导的肌源性分化抑制所必需的。因此，我们能够通过使用离体培养的单纤维系统和从Linc-RAM-/-; Pax 7-nGFP敲除小鼠中分选的卫星细胞，进一步证实Linc-RAM抑制对FGF 2调节的肌源性分化抑制的需要。总之，本研究不仅揭示了FGF 2介导的Linc-RAM基因表达的细胞内信号转导，而且还证明了Linc-RAM在FGF 2介导的肌细胞分化中的功能意义。
ABSTRACT Myogenic differentiation of skeletal muscle stem cells, also known satellite cells, is tightly orchestrated by extrinsic and intrinsic regulators. Basic fibroblast growth factor (FGF2) is well documented to be implicated in satellite cell self-renewal and differentiation by repressing MyoD. We recently identified a MyoD-regulated and skeletal muscle-specifically expressed long non-coding RNA Linc-RAM which enhances myogenic differentiation by facilitating MyoD/Baf60c/Brg1 complex assembly. Herein, we investigated the transcriptional regulation and intracellular signaling pathway in mediating Linc-RAM gene expression during muscle cell differentiation. Firstly, we demonstrate Linc-RAM is negatively regulated by FGF2 via Ras/Raf/Mek/Erk signaling pathway in muscle cells. Overexpression of MyoD significantly attenuates repression of Linc-RAM promoter activities in C2C12 cells treated with FGF2. Knockout of MyoD abolishes FGF2-mediated repression of Linc-RAM gene transcription in satellite cells sorted from skeletal muscle of MyoD−/−;Pax7-nGFP mice, suggesting inhibition of MyoD is required for FGF2-mediated expression of Linc-RAM. For the functional significance, we show that overexpression of Linc-RAM rescues FGF2-induced inhibition of C2C12 cell differentiation, indicating inhibition of Linc-RAM is required for FGF2-mediated suppression of myogenic differentiation. Consistently, we are able to further corroborate the requirement of Linc-RAM inhibition for FGF2-modulated repression of myogenic differentiation by using an ex vivo cultured single fiber system and satellite cells sorted from Linc-RAM−/−;Pax7-nGFP knockout mice. Collectively, the present study not only reveals the intracellular signaling in FGF2-mediated Linc-RAM gene expression but also demonstrate the functional significance of Linc-RAM in FGF2-mediated muscle cell differentiation.
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影响因子：
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作者：
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