横纹肌肉瘤中编码确定血统的成肌转录因子的基因中的外显子跳越。

IF 1.8 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Cold Spring Harbor Molecular Case Studies Pub Date : 2022-08-06 DOI:10.1101/mcs.a006190
Erin Butler, Lin Xu, Dinesh Rakheja, Blake Schwettmann, Shireen Toubbeh, Lei Guo, Jiwoon Kim, Stephen X Skapek, Yanbin Zheng
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引用次数: 0

摘要

横纹肌肉瘤(RMS)是一种由肌母细胞样细胞组成的儿童肉瘤,这表明骨骼肌末端分化存在缺陷。为了探索分化程序中的潜在缺陷,我们在编码驱动骨骼肌谱系承诺和分化的转录因子的基因中寻找 mRNA 剪接变体。我们研究了两例RMS病例,发现剪接变异导致 "跳过 "MYOD1三个外显子中的第二个。来自42个肿瘤和其他RMS细胞系的RNA-Seq数据显示,MYOD1和MYF5中的第2个外显子都发生了跳过,但MYF6或MYOG中没有。对 MYOD1 mRNA 的补充分子分析发现,在另外 5 个 RMS 病例中存在外显子跳越的证据。功能研究表明,所谓的 MYODΔEx2 蛋白不能强有力地诱导肌肉特异性基因,其异位表达在培养成纤维细胞和 RMS 异种移植中具有选择性优势。总之,我们发现了之前未曾在 RMS 中发现的 MYOD1 和 MYF5 的外显子跳过现象,并提出替代剪接可能是改变这两种转录因子在 RMS 中功能的一种机制。
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Exon skipping in genes encoding lineage-defining myogenic transcription factors in rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is a childhood sarcoma composed of myoblast-like cells, which suggests a defect in terminal skeletal muscle differentiation. To explore potential defects in the differentiation program, we searched for mRNA splicing variants in genes encoding transcription factors driving skeletal muscle lineage commitment and differentiation. We studied two RMS cases and identified altered splicing resulting in "skipping" the second of three exons in MYOD1. RNA-Seq data from 42 tumors and additional RMS cell lines revealed exon 2 skipping in both MYOD1 and MYF5 but not in MYF6 or MYOG. Complementary molecular analysis of MYOD1 mRNA found evidence for exon skipping in 5 additional RMS cases. Functional studies showed that so-called MYODΔEx2 protein failed to robustly induce muscle-specific genes, and its ectopic expression conferred a selective advantage in cultured fibroblasts and an RMS xenograft. In summary, we present previously unrecognized exon skipping within MYOD1 and MYF5 in RMS, and we propose that alternative splicing can represent a mechanism to alter the function of these two transcription factors in RMS.

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来源期刊
Cold Spring Harbor Molecular Case Studies
Cold Spring Harbor Molecular Case Studies MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
3.20
自引率
0.00%
发文量
54
期刊介绍: Cold Spring Harbor Molecular Case Studies is an open-access, peer-reviewed, international journal in the field of precision medicine. Articles in the journal present genomic and molecular analyses of individuals or cohorts alongside their clinical presentations and phenotypic information. The journal''s purpose is to rapidly share insights into disease development and treatment gained by application of genomics, proteomics, metabolomics, biomarker analysis, and other approaches. The journal covers the fields of cancer, complex diseases, monogenic disorders, neurological conditions, orphan diseases, infectious disease, gene therapy, and pharmacogenomics. It has a rapid peer-review process that is based on technical evaluation of the analyses performed, not the novelty of findings, and offers a swift, clear path to publication. The journal publishes: Research Reports presenting detailed case studies of individuals and small cohorts, Research Articles describing more extensive work using larger cohorts and/or functional analyses, Rapid Communications presenting the discovery of a novel variant and/or novel phenotype associated with a known disease gene, Rapid Cancer Communications presenting the discovery of a novel variant or combination of variants in a cancer type, Variant Discrepancy Resolution describing efforts to resolve differences or update variant interpretations in ClinVar through case-level data sharing, Follow-up Reports linked to previous observations, Plus Review Articles, Editorials, and Position Statements on best practices for research in precision medicine.
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