Myostatin-deficiency in mice increases global gene expression at the Dlk1-Dio3 locus in the skeletal muscle.
Myostatin-deficiency in mice increases global gene expression at the Dlk1-Dio3 locus in the skeletal muscle.
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DOI：
10.18632/oncotarget.13966
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发表时间：
2017-01-24
期刊：
影响因子：
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通讯作者：
Tsuchida K
中科院分区：
文献类型：
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作者：
Hitachi K;Tsuchida K
肌生成抑制素是转化生长因子β超家族的成员，是骨骼肌生长和发育的负调节因子。肌生长抑制素抑制导致哺乳动物骨骼肌质量增加;因此，肌生长抑制素被认为是骨骼肌萎缩的潜在治疗靶点。然而，骨骼肌中肌生长抑制素的下游分子尚未完全阐明。在这里，我们确定了小鼠染色体12 qF 1上的Dlk 1-Dio 3基因座，也称为绵羊的callipyge基因座，作为肌肉生长抑制素的新下游靶点。在肌肉生长抑制素基因敲除小鼠的骨骼肌中，Dlk 1-Dio 3位点的成熟miRNA表达显著增加。增加的miRNA水平是由Dlk 1-Dio 3基因座的转录激活引起的，因为在肌生长抑制素敲除小鼠中观察到初级miRNA转录物的显著增加。此外，我们发现在肌生长抑制素缺乏的骨骼肌中，Dlk 1-Dio 3位点的编码和非编码基因（Dlk 1，Gtl 2，Rtl 1/Rtl 1as和Rian）的表达增加。此外，在肌肉生长抑制素敲除小鼠中观察到与Dlk 1-Dio 3基因座调节相关的表观遗传变化。两者合计，这是第一份报告证明肌肉生长抑制素在调节骨骼肌中的Dlk 1-Dio 3（callipyge）位点中的作用。
Myostatin, a member of the transforming growth factor-beta superfamily, is a negative regulator of skeletal muscle growth and development. Myostatin inhibition leads to increased skeletal muscle mass in mammals; hence, myostatin is considered a potential therapeutic target for skeletal muscle wasting. However, downstream molecules of myostatin in the skeletal muscle have not been fully elucidated. Here, we identified the Dlk1-Dio3 locus at the mouse chromosome 12qF1, also called as the callipyge locus in sheep, as a novel downstream target of myostatin. In skeletal muscle of myostatin knockout mice, the expression of mature miRNAs at the Dlk1-Dio3 locus was significantly increased. The increased miRNA levels are caused by the transcriptional activation of the Dlk1-Dio3 locus, because a significant increase in the primary miRNA transcript was observed in myostatin knockout mice. In addition, we found increased expression of coding and non-coding genes (Dlk1, Gtl2, Rtl1/Rtl1as, and Rian) at the Dlk1-Dio3 locus in myostatin-deficient skeletal muscle. Moreover, epigenetic changes, associated with the regulation of the Dlk1-Dio3 locus, were observed in myostatin knockout mice. Taken together, this is the first report demonstrating the role of myostatin in regulating the Dlk1-Dio3 (the callipyge) locus in the skeletal muscle.