Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK.
Mol Ther Nucleic Acids. 2012 May 15;1(5):e23. doi: 10.1038/mtna.2012.15.
Myostatin (Mstn) is a secreted growth factor that negatively regulates muscle mass and is therefore a potential pharmacological target for the treatment of muscle wasting disorders such as Duchenne muscular dystrophy. Here we describe a novel Mstn blockade approach in which small interfering RNAs (siRNAs) complementary to a promoter-associated transcript induce transcriptional gene silencing (TGS) in two differentiated mouse muscle cell lines. Silencing is sensitive to treatment with the histone deacetylase inhibitor trichostatin A, and the silent state chromatin mark H3K9me2 is enriched at the Mstn promoter following siRNA transfection, suggesting epigenetic remodeling underlies the silencing effect. These observations suggest that long-term epigenetic silencing may be feasible for Mstn and that TGS is a promising novel therapeutic strategy for the treatment of muscle wasting disorders.
肌肉生长抑制素 (Mstn) 是一种分泌性生长因子，可负向调节肌肉质量，因此是治疗肌肉萎缩症等疾病的潜在药物靶点，如杜氏肌营养不良症。在这里，我们描述了一种新的 Mstn 阻断方法，其中与启动子相关的转录物互补的小干扰 RNA (siRNA) 诱导两种分化的小鼠肌肉细胞系中的转录基因沉默 (TGS)。沉默对组蛋白去乙酰化酶抑制剂曲古抑菌素 A 的处理敏感，并且沉默状态染色质标记 H3K9me2 在 siRNA 转染后富集在 Mstn 启动子上，表明沉默效应下存在表观遗传重塑。这些观察结果表明，Mstn 的长期表观遗传沉默可能是可行的，并且 TGS 是治疗肌肉萎缩症的一种很有前途的新型治疗策略。
