Malat1 regulates myogenic differentiation and muscle regeneration through modulating MyoD transcriptional activity.
Malat1 regulates myogenic differentiation and muscle regeneration through modulating MyoD transcriptional activity.
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DOI：
10.1038/celldisc.2017.2
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发表时间：
2017
期刊：
影响因子：
33.5
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Chen X;He L;Zhao Y;Li Y;Zhang S;Sun K;So K;Chen F;Zhou L;Lu L;Wang L;Zhu X;Bao X;Esteban MA;Nakagawa S;Prasanth KV;Wu Z;Sun H;Wang H
Malat1是各种细胞类型中最丰富的长非编码RNA之一；其确切的细胞功能仍然是一个深入研究的问题。在这项研究中，我们表征了 Malat1 在骨骼肌细胞和肌肉再生中的功能。利用体外和体内测定，我们证明 Malat1 在成肌细胞的生肌分化过程中具有调节基因表达的作用。具体来说，我们发现 Malat1 的敲除加速了培养细胞的肌原性分化。一致的是，Malat1 敲除小鼠在受伤后表现出增强的肌肉再生，而营养不良的 mdx 小鼠中 Malat1 的缺失也改善了肌肉再生。从机制上讲，在增殖的成肌细胞中，Malat1 将 Suv39h1 招募到 MyoD 结合位点，导致组蛋白 3 赖氨酸 9 (H3K9me3) 三甲基化，从而抑制靶基因表达。分化后，促肌源性 miR-181a 增加，并靶向核 Malat1 转录本，通过 Ago2 依赖性核 RNA 诱导的沉默复合体机制进行降解； Malat1 的减少随后导致 Suv39h1/HP1β/HDAC1 抑制复合物不稳定，并被含有 Set7 的激活复合物取代，从而发生 MyoD 反式激活。总之，我们的研究结果确定了 miR-181a-Malat1-MyoD/Suv39h1 在肌生成中的调控轴，并揭示了 Malat1 在基因调控中作用的先前未知的分子机制。
Malat1 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 Malat1 in skeletal muscle cells and muscle regeneration. Utilizing both in vitro and in vivo assays, we demonstrate that Malat1 has a role in regulating gene expression during myogenic differentiation of myoblast cells. Specifically, we found that knockdown of Malat1 accelerates the myogenic differentiation in cultured cells. Consistently, Malat1 knockout mice display enhanced muscle regeneration after injury and deletion of Malat1 in dystrophic mdx mice also improves the muscle regeneration. Mechanistically, in the proliferating myoblasts, Malat1 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 Malat1 transcripts for degradation through Ago2-dependent nuclear RNA-induced silencing complex machinery; the Malat1 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-Malat1-MyoD/Suv39h1 in myogenesis and uncover a previously unknown molecular mechanism of Malat1 action in gene regulation.