The RNA degradation pathway regulates the function of GAS5 a non-coding RNA in mammalian cells.
The RNA degradation pathway regulates the function of GAS5 a non-coding RNA in mammalian cells.
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DOI：
10.1371/journal.pone.0055684
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Akimitsu N
中科院分区：
文献类型：
--
作者：
Tani H;Torimura M;Akimitsu N
对各种mRNA的研究表明，通过mRNA降解，转录本丰度的变化是控制各种生物途径的关键步骤。类似地，非编码RNA（ncRNA）水平的调节也被认为对它们的生物学功能很重要;然而，关于ncRNA周转对ncRNA功能调节的机制和生物学重要性知之甚少。生长停滞特异性5（GAS 5）ncRNA在血清饥饿诱导的生长停滞期间积累，并且其转录物通过充分表征的无义介导的RNA衰变（NMD）途径降解。历史上，NMD被发现作为RNA质量控制系统，以消除异常转录本;然而，越来越多的证据表明，NMD也调节生理转录本的丰度。有趣的是，GAS 5转录物具有结合糖皮质激素受体（GR）的能力，从而抑制其与DNA的配体依赖性缔合。GR结合各种糖皮质激素应答基因的启动子，包括糖尿病相关基因。在这项研究中，我们研究了RNA降解途径是否可以调节GAS 5的这种功能。我们使用5′-溴尿苷免疫沉淀追踪（BRIC）方法（一种直接测量RNA稳定性的无底物方法）测量了UPF 1缺失的人细胞中GAS 5的稳态丰度和衰减速率。我们发现，由于UPF 1耗竭导致的衰变率延长，GAS 5转录物水平升高，因此，与癌症相关的基因cIAP 2和SGK 1下调。此外，血清饥饿也增加了GAS 5的转录水平，因为延长衰减率，并反过来降低cIAP 2和SGK 1 mRNA的水平。综上所述，我们发现RNA降解途径可以调节哺乳动物细胞中GAS 5 ncRNA的功能。
Studies of various mRNAs have revealed that changes in the abundance of transcripts, through mRNA degradation, act as a critical step in the control of various biological pathways. Similarly, the regulation of non-coding RNA (ncRNA) levels is also considered to be important for their biological functions; however, far less is known about the mechanisms and biological importance of ncRNA turnover for the regulation of ncRNA functions. The growth arrest-specific 5 (GAS5) ncRNA accumulates during growth arrest induced by serum starvation and its transcript is degraded by the well characterized nonsense-mediated RNA decay (NMD) pathway. Historically, NMD was discovered as a RNA quality control system to eliminate aberrant transcripts; however, accumulating evidence shows that NMD also regulates the abundance of physiological transcripts. Interestingly, the GAS5 transcript has the ability to bind the glucocorticoid receptor (GR), resulting in the inhibition of its ligand-dependent association with DNA. The GR binds the promoters of various glucocorticoid-responsive genes, including apoptosis-related genes. In this study, we examined whether the RNA degradation pathway can regulate this function of GAS5. We measured the steady-state abundance and the decay rate of GAS5 in UPF1-depleted human cells using the 5′-bromo-uridine immunoprecipitation chase (BRIC) method, an inhibitor-free method for directly measuring RNA stability. We found that levels of the GAS5 transcript were elevated owing to prolonged decay rates in response to UPF1 depletion, and consequently the apoptosis-related genes, cIAP2 and SGK1, were down-regulated. In addition, serum starvation also increased the transcript levels of GAS5 because of prolonged decay rates, and conversely decreased levels of cIAP2 and SGK1 mRNA. Taken together, we found that the RNA degradation pathway can regulate the function of the GAS5 ncRNA in mammalian cells.
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