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小鼠中的肌肉生长抑制素缺乏会增加骨骼肌中Dlk1-Dio3基因座的整体基因表达。

Myostatin-deficiency in mice increases global gene expression at the Dlk1-Dio3 locus in the skeletal muscle.

作者信息

Hitachi Keisuke, Tsuchida Kunihiro

机构信息

Division for Therapies Against Intractable Diseases, Institute for Comprehensive Medical Science (ICMS), Fujita Health University, Toyoake, Aichi 470-1192, Japan.

出版信息

Oncotarget. 2017 Jan 24;8(4):5943-5953. doi: 10.18632/oncotarget.13966.

DOI:10.18632/oncotarget.13966
PMID:27992376
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5351603/
Abstract

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.

摘要

肌肉生长抑制素是转化生长因子-β超家族的成员之一，是骨骼肌生长和发育的负调节因子。抑制肌肉生长抑制素会导致哺乳动物骨骼肌质量增加；因此，肌肉生长抑制素被认为是治疗骨骼肌萎缩的潜在靶点。然而，骨骼肌中肌肉生长抑制素的下游分子尚未完全阐明。在这里，我们确定小鼠12号染色体qF1上的Dlk1-Dio3位点，在绵羊中也被称为臀肌肥大位点，是肌肉生长抑制素的一个新的下游靶点。在肌肉生长抑制素基因敲除小鼠的骨骼肌中，Dlk1-Dio3位点成熟miRNA的表达显著增加。miRNA水平的增加是由Dlk1-Dio3位点的转录激活引起的，因为在肌肉生长抑制素基因敲除小鼠中观察到初级miRNA转录本显著增加。此外，我们发现在肌肉生长抑制素缺陷的骨骼肌中，Dlk1-Dio3位点的编码和非编码基因（Dlk1、Gtl2、Rtl1/Rtl1as和Rian）表达增加。此外，在肌肉生长抑制素基因敲除小鼠中观察到与Dlk1-Dio3位点调控相关的表观遗传变化。综上所述，这是第一份证明肌肉生长抑制素在调节骨骼肌中Dlk1-Dio3（臀肌肥大）位点作用的报告。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6449/5351603/9f17ac588dd8/oncotarget-08-5943-g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6449/5351603/30dfc9386c61/oncotarget-08-5943-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6449/5351603/437021f61c2d/oncotarget-08-5943-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6449/5351603/9f17ac588dd8/oncotarget-08-5943-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6449/5351603/3402029da71b/oncotarget-08-5943-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6449/5351603/9372805365f3/oncotarget-08-5943-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6449/5351603/eac1a4e8c410/oncotarget-08-5943-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6449/5351603/e3d76e7fb28e/oncotarget-08-5943-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6449/5351603/30dfc9386c61/oncotarget-08-5943-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6449/5351603/437021f61c2d/oncotarget-08-5943-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6449/5351603/9f17ac588dd8/oncotarget-08-5943-g007.jpg

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