对mRNA剪接的综合分析表明,GC含量表明Ewing肉瘤中盒式外显子包含改变。

NAR Cancer Pub Date : 2022-01-14 eCollection Date: 2022-03-01 DOI:10.1093/narcan/zcab052
Garrett T Graham, Saravana P Selvanathan, Stefan K Zöllner, Emily Stahl, Adam Shlien, Natasha J Caplen, Aykut Üren, Jeffrey A Toretsky
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引用次数: 4

摘要

尤文氏肉瘤(EwS)是一种小的圆形蓝细胞肿瘤,是第二常见的儿童骨癌。85%的EwS肿瘤表达融合癌蛋白EwS - fli1,这是t(11;22)互惠易位的产物。先前的研究表明,仅靠转录调控并不能完全描述EWS-FLI1的致癌能力,也不能提供对患者肿瘤分层的有效手段。对EwS细胞系和患者样本的研究表明,EwS - fli1也会破坏mRNA的生物发生。在这项工作中,我们都描述了在EwS肿瘤样本中异常剪接的mRNA的潜在特征,并对其他儿科肿瘤类型的mRNA剪接事件进行了分类。在这里,我们也使用短读段和长读段测序来鉴定有助于我们在尤文氏肉瘤中观察到的剪接谱的顺式因子。我们的分析表明,盒式外显子上游的GC含量是EwS中mRNA剪接的决定性因素。我们还描述了区分EwS肿瘤样本与假定的起源细胞,来自骨髓的人间充质干细胞(hMSC-BM)的特定剪接事件。最后,我们通过基序富集鉴定了特异性剪接因子PCBP2、RBMX和SRSF9,并证实了来自EwS细胞系肿瘤样本的发现。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Comprehensive profiling of mRNA splicing indicates that GC content signals altered cassette exon inclusion in Ewing sarcoma.

Comprehensive profiling of mRNA splicing indicates that GC content signals altered cassette exon inclusion in Ewing sarcoma.

Comprehensive profiling of mRNA splicing indicates that GC content signals altered cassette exon inclusion in Ewing sarcoma.

Comprehensive profiling of mRNA splicing indicates that GC content signals altered cassette exon inclusion in Ewing sarcoma.

Ewing sarcoma (EwS) is a small round blue cell tumor and is the second most frequent pediatric bone cancer. 85% of EwS tumors express the fusion oncoprotein EWS-FLI1, the product of a t(11;22) reciprocal translocation. Prior work has indicated that transcription regulation alone does not fully describe the oncogenic capacity of EWS-FLI1, nor does it provide an effective means to stratify patient tumors. Research using EwS cell lines and patient samples has suggested that EWS-FLI1 also disrupts mRNA biogenesis. In this work we both describe the underlying characteristics of mRNA that are aberrantly spliced in EwS tumor samples as well as catalogue mRNA splicing events across other pediatric tumor types. Here, we also use short- and long-read sequencing to identify cis-factors that contribute to splicing profiles we observe in Ewing sarcoma. Our analysis suggests that GC content upstream of cassette exons is a defining factor of mRNA splicing in EwS. We also describe specific splicing events that discriminate EwS tumor samples from the assumed cell of origin, human mesenchymal stem cells derived from bone marrow (hMSC-BM). Finally, we identify specific splicing factors PCBP2, RBMX, and SRSF9 by motif enrichment and confirm findings from tumor samples in EwS cell lines.

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