Genome-wide analyses of XRN1-sensitive targets in osteosarcoma cells identify disease-relevant transcripts containing G-rich motifs.
Genome-wide analyses of XRN1-sensitive targets in osteosarcoma cells identify disease-relevant transcripts containing G-rich motifs.
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DOI：
10.1261/rna.078872.121
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发表时间：
2021-10
期刊：
影响因子：
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通讯作者：
Newbury SF
中科院分区：
文献类型：
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作者：
Pashler AL;Towler BP;Jones CI;Haime HJ;Burgess T;Newbury SF
XRN1 是一种高度保守的核糖核酸外切酶，可沿 5'–3' 方向降解未加帽的 RNA。 XRN1 对 RNA 的降解在许多细胞和发育过程中很重要，并且与人类疾病相关。对黑腹果蝇的研究表明，XRN1 可以靶向特定的 RNA，这对发育途径具有重要影响。骨肉瘤是一种骨骼恶性肿瘤，占全球所有儿科癌症的 2%。自 20 世纪 70 年代以来，患者的五年生存率一直保持不变，因此进一步加深我们对这种疾病的分子了解至关重要。先前的研究表明，XRN1 在骨肉瘤细胞中下调；然而，XRN1 调控的可能促进骨肉瘤的转录本仍然难以捉摸。在这里，我们确认了骨肉瘤细胞系和患者样本中 XRN1 水平降低，并鉴定了人骨肉瘤细胞中 XRN1 敏感的转录本。在 XRN1 敲低的 SAOS-2 细胞中使用 RNA-seq，我们发现 1178 个基因受到差异调节。使用一种新颖的生物信息学方法，我们证明 134 个转录本显示出 XRN1 直接转录后调节的特征。长非编码 RNA (lncRNA) 在该组中富集，表明 XRN1 通常在控制这些细胞中 lncRNA 表达方面发挥重要作用。 HOTAIR 是 XRN1 靶向的潜在 lncRNA 之一，已知它在骨肉瘤中表达上调，并导致疾病进展。我们还在转录后调节的转录本中发现了富含 G 和 GU 基序，这些基序似乎使它们对 XRN1 降解敏感。因此，我们的结果为了解 XRN1 在人类细胞中与疾病相关的特异性提供了重要的见解。
XRN1 is a highly conserved exoribonuclease which degrades uncapped RNAs in a 5′–3′ direction. Degradation of RNAs by XRN1 is important in many cellular and developmental processes and is relevant to human disease. Studies in D. melanogaster demonstrate that XRN1 can target specific RNAs, which have important consequences for developmental pathways. Osteosarcoma is a malignancy of the bone and accounts for 2% of all pediatric cancers worldwide. Five-year survival of patients has remained static since the 1970s and therefore furthering our molecular understanding of this disease is crucial. Previous work has shown a down-regulation of XRN1 in osteosarcoma cells; however, the transcripts regulated by XRN1 which might promote osteosarcoma remain elusive. Here, we confirm reduced levels of XRN1 in osteosarcoma cell lines and patient samples and identify XRN1-sensitive transcripts in human osteosarcoma cells. Using RNA-seq in XRN1-knockdown SAOS-2 cells, we show that 1178 genes are differentially regulated. Using a novel bioinformatic approach, we demonstrate that 134 transcripts show characteristics of direct post-transcriptional regulation by XRN1. Long noncoding RNAs (lncRNAs) are enriched in this group, suggesting that XRN1 normally plays an important role in controlling lncRNA expression in these cells. Among potential lncRNAs targeted by XRN1 is HOTAIR, which is known to be up-regulated in osteosarcoma and contributes to disease progression. We have also identified G-rich and GU motifs in post-transcriptionally regulated transcripts which appear to sensitize them to XRN1 degradation. Our results therefore provide significant insights into the specificity of XRN1 in human cells which are relevant to disease.