Defective Regulation of MicroRNA Target Genes in Myoblasts from Facioscapulohumeral Dystrophy Patients
Defective Regulation of MicroRNA Target Genes in Myoblasts from Facioscapulohumeral Dystrophy Patients
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DOI：
10.1074/jbc.m113.504522
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发表时间：
2013-12-06
影响因子：
4.8
通讯作者：
Vassetzky, Yegor S.
中科院分区：
文献类型：
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作者：
Dmitriev, Petr;Stankevicins, Luiza;Vassetzky, Yegor S.
背景：FSHD以双同源盒型基因DUX4和DUX4c过表达为特征。结果：29种mirna在FSHD和正常成肌细胞中表达差异。其中12个mirna在异位表达DUX4c的成肌细胞中上调。结论：DUX4c与FSHD中观察到的异常miRNA表达谱有关。意义：我们在FSHD中观察到mirna基因调控的缺陷。面肩肱骨肌营养不良症（FSHD）是一种常染色体显性遗传性神经肌肉疾病，与染色体4q亚端粒区域3.3 kb长的大卫星重复序列（D4Z4）缺失有关。在该区域发现的大多数基因在FSHD成肌细胞中过表达，包括双同源盒基因DUX4和DUX4c。我们同时对FSHD和对照原代成肌细胞进行了miRNome/转录组分析。在本研究分析的365个microrna （miRNAs）中，发现29个在FSHD和正常成肌细胞中表达差异。21个microrna （miR-1、miR-7、miR-15a、miR-22、miR-30e、miR-32、miR-107、miR-133a、miR-133b、miR-139、miR-152、miR-206、miR-223、miR-302b、miR-331、miR-362、miR-365、miR-382、miR-496、miR-532、miR-654和miR-660）上调，8个microrna下调（miR-15b、miR-20b、miR-21、miR-25、miR-100、miR-155、miR-345和miR-594）。在FHSD中上调的miRNA中，有12个在异位表达DUX4c的细胞中也上调，表明该基因可以调节miRNA基因的转录。肌源性mirna miR-1、miR-133a、miR-133b和miR-206在FSHD成肌细胞中高表达，尽管如此，这些细胞并没有过早进入肌源性分化。这可能是由于在FSHD成肌细胞中，功能重要的靶基因，包括细胞周期、DNA损伤和泛素化相关基因，逃脱了肌源性microrna诱导的抑制。
Background: FSHD is characterized by the overexpression of double homeobox genes DUX4 and DUX4c. Results: We found 29 miRNAs differentially expressed between FSHD and normal myoblasts. Twelve of these miRNAs were up-regulated in myoblasts ectopically expressing DUX4c. Conclusion:DUX4c is linked to the abnormal miRNA expression profile observed in FSHD. Significance: We observe a defective gene regulation by miRNAs in FSHD.Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant hereditary neuromuscular disorder linked to the deletion of an integral number of 3.3-kb-long macrosatellite repeats (D4Z4) within the subtelomeric region of chromosome 4q. Most genes identified in this region are overexpressed in FSHD myoblasts, including the double homeobox genes DUX4 and DUX4c. We have carried out a simultaneous miRNome/transcriptome analysis of FSHD and control primary myoblasts. Of 365 microRNAs (miRNAs) analyzed in this study, 29 were found to be differentially expressed between FSHD and normal myoblasts. Twenty-one microRNAs (miR-1, miR-7, miR-15a, miR-22, miR-30e, miR-32, miR-107, miR-133a, miR-133b, miR-139, miR-152, miR-206, miR-223, miR-302b, miR-331, miR-362, miR-365, miR-382, miR-496, miR-532, miR-654, and miR-660) were up-regulated, and eight were down-regulated (miR-15b, miR-20b, miR-21, miR-25, miR-100, miR-155, miR-345, and miR-594). Twelve of the miRNAs up-regulated in FHSD were also up-regulated in the cells ectopically expressing DUX4c, suggesting that this gene could regulate miRNA gene transcription. The myogenic miRNAs miR-1, miR-133a, miR-133b, and miR-206 were highly expressed in FSHD myoblasts, which nonetheless did not prematurely enter myogenic differentiation. This could be accounted for by the fact that in FSHD myoblasts, functionally important target genes, including cell cycle, DNA damage, and ubiquitination-related genes, escape myogenic microRNA-induced repression.