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Abstract：
Duchenne muscular dystrophy (DMD) is an X-linked disorder caused by loss of function mutations in the dystrophin gene (Dmd), resulting in progressive muscle weakening. Here we modelled the longitudinal expression of endogenous Dmd, and its paralogue Utrn, in mice and in myoblasts by generating bespoke bioluminescent gene reporters. As utrophin can partially compensate for Dmd-deficiency, these reporters were used as tools to ask whether chromatin-modifying drugs can enhance Utrn expression in developing muscle. Myoblasts treated with different PRC2 inhibitors showed significant increases in Utrn transcripts and bioluminescent signals, and these responses were independently verified by conditional Ezh2 deletion. Inhibition of ERK1/2 signalling provoked an additional increase in Utrn expression that was also seen in Dmd-mutant cells, and maintained as myoblasts differentiate. These data reveal PRC2 and ERK1/2 to be negative regulators of Utrn expression and provide specialised molecular imaging tools to monitor utrophin expression as a therapeutic strategy for DMD.
摘要：
Duchenne型肌营养不良症（DMD）是一种由肌营养不良蛋白基因（Dmd）功能缺失突变引起的X连锁疾病，导致肌肉逐渐减弱。在这里，我们模拟了内源性Dmd的纵向表达，和它的比喻Utrn，通过生成定制的生物发光基因报告基因，在小鼠和成肌细胞中。由于肌萎缩素可以部分补偿Dmd缺乏，这些报告基因被用作询问染色质修饰药物是否可以增强Utrn在发育中肌肉中的表达的工具.用不同的PRC2抑制剂处理的成肌细胞显示Utrn转录本和生物发光信号显著增加,这些反应通过条件Ezh2缺失独立验证。ERK1/2信号传导的抑制引起了Utrn表达的额外增加，这也在Dmd突变细胞中看到。并保持成肌细胞分化。这些数据揭示PRC2和ERK1/2是Utrn表达的负调节因子,并且提供了专门的分子成像工具来监测作为DMD的治疗策略的乌托素表达。
