Rev-Erb co-regulates muscle regeneration via tethered interaction with the NF-Y cistrome.
Rev-Erb co-regulates muscle regeneration via tethered interaction with the NF-Y cistrome.
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DOI：
10.1016/j.molmet.2017.05.001
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发表时间：
2017-07
影响因子：
8.1
通讯作者：
Flaveny CA
中科院分区：
文献类型：
--
作者：
Welch RD;Guo C;Sengupta M;Carpenter KJ;Stephens NA;Arnett SA;Meyers MJ;Sparks LM;Smith SR;Zhang J;Burris TP;Flaveny CA
骨骼肌质量和力量的丧失是创伤性损伤和退行性肌病的主要特征。不幸的是，药物干预通常无法阻止生活质量的长期下降。在培养的C2C12成肌细胞中，减少REV-Erb介导的基因抑制已被证明刺激成肌细胞分化。然而，REV-ERB多向性抑制肌肉分化的机制还不是很清楚。在本研究中，我们试图阐明REV-ERB在体内肌肉分化和再生调节中的作用。利用REV-ERBα/βshRNA、药理配体和REV-ERBα缺失和杂合子小鼠，我们探讨了REV-ERBα/β调控肌肉分化和肌肉再生的机制。对REV-ERB在成肌细胞分化过程中的芯片序列分析表明，REV-ERBα不是通过同源的REV-ERB/ROR反应元件在转录上调节肌肉的分化，而是可能通过与细胞命运调节因子-Y在CCAAT基序上的相互作用来调节肌肉的分化。肌肉分化是由REV-Erb从一些肌肉发生蛋白的启动子和增强子元件的CCAAT基序中释放出来的。在REV-ERBα杂合子小鼠中，REV-ERB表达的部分缺失加速了体内肌肉修复，而REV-ERB基因敲除小鼠与野生型小鼠相比，在再生修复方面表现出缺陷。杂合子小鼠和基因敲除小鼠之间的这些表型差异并不明显依赖于对损伤的MRF诱导。同样，对受损肌肉中REV-ERB抑制活性的药理学干扰也加速了对急性损伤的再生修复。破坏受损肌肉中的Rev-Erb活性，通过转录抑制生肌程序，加速再生肌肉的修复/分化。因此，REV-ERB可能是治疗多种肌肉疾病的有效靶点。在成肌细胞分化过程中，核受体Rev-Erb从生肌基因启动子和增强子区域释放出来。REV-Erb通过与CCAAT基序上的细胞命运调节因子NF-Y相互作用来调节成肌细胞的分化。REV-ERB拮抗剂通过刺激成肌细胞分化来加速急性肌肉损伤后的肌肉再生。人类肌肉分化可以通过以REV-ERB为靶点的药理配体来调节。
The loss of skeletal muscle mass and strength are a central feature of traumatic injury and degenerative myopathies. Unfortunately, pharmacological interventions typically fail to stem the long-term decline in quality of life. Reduced Rev-Erb-mediated gene suppression in cultured C2C12 myoblasts has been shown to stimulate myoblast differentiation. Yet the mechanisms that allow Rev-Erb to pleiotropically inhibit muscle differentiation are not well understood. In this study, we sought to elucidate the role of Rev-Erb in the regulation of muscle differentiation and regeneration in vivo. Using Rev-Erbα/β shRNAs, pharmacological ligands, and Rev-Erbα null and heterozygous mice, we probed the mechanism of Rev-Erbα/β regulation of muscle differentiation and muscle regeneration. ChIP seq analysis of Rev-Erb in differentiating myoblasts showed that Rev-Erbα did not transcriptionally regulate muscle differentiation through cognate Rev-Erb/ROR-response elements but through possible interaction with the cell fate regulator NF-Y at CCAAT-motifs. Muscle differentiation is stimulated by Rev-Erb release from CCAAT-motifs at promoter and enhancer elements of a number of myogenesis proteins. Partial loss of Rev-Erb expression in mice heterozygous for Rev-Erbα accelerated muscle repair in vivo whereas Rev-Erb knockout mice showed deficiencies in regenerative repair compared to wild type mice. These phenotypic differences between heterozygous and knockout mice were not apparently dependent on MRF induction in response to injury. Similarly, pharmacological disruption of Rev-Erb suppressive activity in injured muscle accelerated regenerative repair in response to acute injury. Disrupting Rev-Erb activity in injured muscle accelerates regenerative muscle repair/differentiation through transcriptional de-repression of myogenic programs. Rev-Erb, therefore, may be a potent therapeutic target for a myriad of muscular disorders. The nuclear receptor Rev-Erb is released from myogenic gene promoter and enhancer regions during myoblast differentiation. Rev-Erb regulates myoblast differentiation through interaction with the cell-fate regulator NF-Y at CCAAT-motifs. Rev-Erb antagonists accelerate muscle regeneration following acute muscle injury by stimulating myoblast differentiation. Human muscle differentiation can be regulated using pharmacological ligands that target Rev-Erb.