Histone methltransferase MLL4 controls myofiber identity and muscle performance through MEF2 interaction
Histone methltransferase MLL4 controls myofiber identity and muscle performance through MEF2 interaction
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组蛋白甲基转移酶 MLL4 通过 MEF2 相互作用控制肌纤维特性和肌肉性能
DOI：
10.1172/jci136155
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发表时间：
2020-09-01
影响因子：
15.9
通讯作者：
Gan, Zhenji
中科院分区：
文献类型：
--
作者：
Liu, Lin;Ding, Chenyun;Gan, Zhenji
骨骼肌依赖于收缩和代谢基因表达程序的精确编排，以指导纤维类型规范并确保肌肉性能。然而，这种纤维类型特异性的基因表达模式究竟是如何建立和维持的仍然不清楚。在这里，我们证明了组蛋白单甲基转移酶MLL 4（KMT 2D），一个增强子调节器丰富的慢肌纤维，在控制肌纤维的身份以及肌肉性能中起着至关重要的作用。小鼠中MLL 4的骨骼肌特异性消融导致缓慢氧化肌纤维基因程序下调，I型肌纤维数量减少，线粒体呼吸减少，这导致运动期间肌肉脂肪酸利用率和耐力降低。全基因组ChIP-Seq和mRNA-Seq分析显示，MLL 4直接与增强子结合，并作为肌细胞增强因子2（MEF 2）的共激活因子，激活慢氧化肌纤维基因的转录。重要的是，我们还发现MLL 4调节回路与人类的肌纤维型重塑有关。因此，我们的研究结果揭示了MLL 4在指定支配肌肉性能的肌纤维的结构和代谢特性方面的关键作用。这些发现为增强肌肉健康以对抗各种代谢和肌肉疾病提供了治疗机会。
Skeletal muscle depends on the precise orchestration of contractile and metabolic gene expression programs to direct fiber-type specification and to ensure muscle performance. Exactly how such fiber type-specific patterns of gene expression are established and maintained remains unclear, however. Here, we demonstrate that histone monomethyl transferase MLL4 (KMT2D), an enhancer regulator enriched in slow myofibers, plays a critical role in controlling muscle fiber identity as well as muscle performance. Skeletal muscle-specific ablation of MLL4 in mice resulted in downregulation of the slow oxidative myofiber gene program, decreased numbers of type I myofibers, and diminished mitochondrial respiration, which caused reductions in muscle fatty acid utilization and endurance capacity during exercise. Genome-wide ChIP-Seq and mRNA-Seq analyses revealed that MLL4 directly binds to enhancers and functions as a coactivator of the myocyte enhancer factor 2 (MEF2) to activate transcription of slow oxidative myofiber genes. Importantly, we also found that the MLL4 regulatory circuit is associated with muscle fiber-type remodeling in humans. Thus, our results uncover a pivotal role for MLL4 in specifying structural and metabolic identities of myofibers that govern muscle performance. These findings provide therapeutic opportunities for enhancing muscle fitness to combat a variety of metabolic and muscular diseases.