Malat1 interacts with Suv39h1 to regulate MyoD transcriptional activity and is down-regulated by miR-181 binding during myogenic differentiation and muscle regeneration

As one of the most abundant lncRNAs in various cell types the exact cellular function of Malat1 is a matter of intense investigation. In this study we characterized the function of Malat1 in skeletal muscle cells and muscle regeneration. Utilizing both cell culture and knock-out mouse, our findings demonstrate that Malat1 plays a role in regulating gene expression during myogenic differentiation of myoblast cells. Specifically, we found that knock-down of Malat1 accelerated the myogenic differentiation in cultured cells. Consistently in vivo Malat1 knock-out mouse displayed enhanced muscle regeneration after injury and deletion of Malat1 in dystrophic Mdx mouse also improved the muscle regeneration. Mechanistically, we showed that 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, miR-181a expression increases and targets the nuclear Malat1 transcripts for degradation through Ago2 dependent nRISC 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.

作为多种细胞中含量最为丰富的长链非编码RNA（lncRNA）之一，Malat1的确切细胞功能一直是学界深入研究的热点课题。本研究针对Malat1在骨骼肌细胞及肌肉再生过程中的功能展开了系统性表征分析。本研究结合细胞培养与基因敲除小鼠模型开展实验，结果表明Malat1在成肌细胞的肌源性分化过程中参与调控基因表达。具体而言，实验发现敲低Malat1可加速体外培养中成肌细胞的肌源性分化进程。在体内实验中，Malat1基因敲除小鼠在肌肉损伤后的再生能力显著增强；而在肌营养不良型Mdx小鼠中敲除Malat1，同样可改善其肌肉再生状况。从分子机制层面来看，本研究证实：在增殖期成肌细胞中，Malat1会将Suv39h1招募至肌分化因子1（MyoD）结合位点，介导组蛋白3赖氨酸9三甲基化（H3K9me3），进而抑制靶基因的表达。当细胞进入分化阶段后，微小RNA-181a（miR-181a）的表达水平上调，并通过依赖于Argonaute2（Ago2）的核RNA诱导沉默复合物（nRISC）机制，靶向降解细胞核内的Malat1转录本；Malat1水平的降低随后会破坏Suv39h1/异染色质蛋白1β（HP1β）/组蛋白去乙酰化酶1（HDAC1）的抑制复合物稳定性，并被包含Set7的激活复合物所取代，从而使MyoD能够完成反式激活过程。综上，本研究明确了肌发生过程中miR-181a-Malat1-MyoD/Suv39h1调控轴，并揭示了Malat1在基因调控中此前未被发现的全新分子机制。

搜集汇总

背景与挑战

背景概述

该数据集聚焦于研究lncRNA Malat1在肌源性分化和肌肉再生中的调控机制，通过RNA-Seq技术分析了小鼠成肌细胞样本。关键发现包括Malat1通过与Suv39h1相互作用抑制MyoD转录活性，并在分化过程中被miR-181a下调以促进基因表达激活。数据集包含2个对照样本，总数据量为20.65 GB，旨在揭示miR-181a-Malat1-MyoD/Suv39h1轴在肌生成中的分子作用。