通过抑制 TNNT1 的产生,FUS 介导的肌生成抑制作用。

IF 3.2 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Molecular and Cellular Biology Pub Date : 2024-01-01 Epub Date: 2024-08-12 DOI:10.1080/10985549.2024.2383296
Eunbyul Ji, Poonam R Pandey, Jennifer L Martindale, Xiaoling Yang, Jen-Hao Yang, Dimitrios Tsitsipatis, Chang Hoon Shin, Yulan Piao, Jinshui Fan, Krystyna Mazan-Mamczarz, Nirad Banskota, Supriyo De, Myriam Gorospe
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引用次数: 0

摘要

肌肉发生是一个高度协调的过程,肌肉前体细胞(肌母细胞)在胚胎发生过程中发育成肌纤维,形成骨骼肌,并再生成肌。在这里,我们研究了 RNA 结合蛋白 FUS(融合于肉瘤中),它与肌肉和神经肌肉病变有关,但在肌生成过程中的特性却不甚明了。鉴于FUS水平在人类和小鼠骨骼肌生成模型中下降,且沉默FUS可促进肌生成,我们推测FUS可能是肌生成分化的抑制因子。有趣的是,过表达 FUS 会延迟肌生成,同时肌肉分化标志物的产生也会减慢。为了确定FUS抑制肌生成的机制,我们通过核糖核蛋白免疫沉淀(RIP)和RNA测序(RNA-seq)分析发现了FUS的RNA靶标。对结合的转录本进行严格筛选后发现,编码肌钙蛋白 T1(TNNT1)的 Tnnt1 mRNA 是 FUS 影响肌生成的主要效应物。我们发现,在肌母细胞中,FUS 将 Tnnt1 mRNA 保留在细胞核中,阻止了 TNNT1 的表达;然而,在肌生成过程中减少 FUS 或沉默 FUS 会释放 Tnnt1 mRNA,使其输出到细胞质中,从而使 TNNT1 翻译成功,促进肌生成。我们认为,FUS通过Tnnt1 mRNA的核保留机制抑制了TNNT1的表达,从而抑制了肌生成。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
FUS-Mediated Inhibition of Myogenesis Elicited by Suppressing TNNT1 Production.

Myogenesis is a highly orchestrated process whereby muscle precursor cells, myoblasts, develop into muscle fibers to form skeletal muscle during embryogenesis and regenerate adult muscle. Here, we studied the RNA-binding protein FUS (fused in sarcoma), which has been implicated in muscular and neuromuscular pathologies but is poorly characterized in myogenesis. Given that FUS levels declined in human and mouse models of skeletal myogenesis, and that silencing FUS enhanced myogenesis, we hypothesized that FUS might be a repressor of myogenic differentiation. Interestingly, overexpression of FUS delayed myogenesis, accompanied by slower production of muscle differentiation markers. To identify the mechanisms through which FUS inhibits myogenesis, we uncovered RNA targets of FUS by ribonucleoprotein immunoprecipitation (RIP) followed by RNA-sequencing (RNA-seq) analysis. Stringent selection of the bound transcripts uncovered Tnnt1 mRNA, encoding troponin T1 (TNNT1), as a major effector of FUS influence on myogenesis. We found that in myoblasts, FUS retained Tnnt1 mRNA in the nucleus, preventing TNNT1 expression; however, reduction of FUS during myogenesis or by silencing FUS released Tnnt1 mRNA for export to the cytoplasm, enabling TNNT1 translation and promoting myogenesis. We propose that FUS inhibits myogenesis by suppressing TNNT1 expression through a mechanism of nuclear Tnnt1 mRNA retention.

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来源期刊
Molecular and Cellular Biology
Molecular and Cellular Biology 生物-生化与分子生物学
CiteScore
9.80
自引率
1.90%
发文量
120
审稿时长
1 months
期刊介绍: Molecular and Cellular Biology (MCB) showcases significant discoveries in cellular morphology and function, genome organization, regulation of genetic expression, morphogenesis, and somatic cell genetics. The journal also examines viral systems, publishing papers that emphasize their impact on the cell.
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