RNA components of the spliceosome regulate tissue-and cancer-specific alternative splicing
RNA components of the spliceosome regulate tissue-and cancer-specific alternative splicing
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DOI：
10.1101/gr.246678.118
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发表时间：
2019-10-01
期刊：
影响因子：
7
通讯作者：
Bradley, Robert K.
中科院分区：
文献类型：
--
作者：
Dvinge, Heidi;Guenthoer, Jamie;Bradley, Robert K.
前体信使RNA的可变剪接在人类细胞类型的建立和维持过程中起着关键作用。因此，对控制可变剪接的反式作用调节蛋白进行表征一直是许多研究的重点。近期的研究表明，即使是剪接体的核心蛋白成分（剪接进行所必需的），也能通过调节剪接位点的选择来促进剪接调控。我们在此表明，剪接体的RNA成分同样会影响可变剪接的决策。尽管这些被称为U1、U2、U4、U5和U6的小核RNA（snRNA）在剪接体中以等化学计量存在，但我们发现它们的相对水平在发育过程中、不同组织间以及癌症样本中存在一个数量级的差异。对单个snRNA进行生理相关的扰动会导致可变剪接中广泛的基因特异性差异，但不会导致整个转录组的剪接失败。在乳腺癌细胞系模型中对snRNA丰度变化特别敏感的基因，在具有临床多样性的浸润性乳腺导管癌队列中同样优先发生错剪接。由于异常的信使RNA剪接在许多癌症中普遍存在，我们提出，要全面理解这种失调的前体信使RNA加工过程，需要对snRNA以及蛋白质剪接因子进行研究。总之，我们的数据表明，剪接体的RNA成分并非如长期以来所认为的那样仅仅是基础因子。相反，这些非编码RNA构成了一个先前未被表征的可变剪接调控层，并有助于在健康细胞和恶性细胞中建立全局剪接程序。
Alternative splicing of pre-mRNAs plays a pivotal role during the establishment and maintenance of human cell types. Characterizing the trans-acting regulatory proteins that control alternative splicing has therefore been the focus of much research. Recent work has established that even core protein components of the spliceosome, which are required for splicing to proceed, can nonetheless contribute to splicing regulation by modulating splice site choice. We here show that the RNA components of the spliceosome likewise influence alternative splicing decisions. Although these small nuclear RNAs (snRNAs), termed U1, U2, U4, U5, and U6 snRNA, are present in equal stoichiometry within the spliceosome, we found that their relative levels vary by an order of magnitude during development, across tissues, and across cancer samples. Physiologically relevant perturbation of individual snRNAs drove widespread gene-specific differences in alternative splicing but not transcriptome-wide splicing failure. Genes that were particularly sensitive to variations in snRNA abundance in a breast cancer cell line model were likewise preferentially misspliced within a clinically diverse cohort of invasive breast ductal carcinomas. As aberrant mRNA splicing is prevalent in many cancers, we propose that a full understanding of such dysregulated pre-mRNA processing requires study of snRNAs, as well as protein splicing factors. Together, our data show that the RNA components of the spliceosome are not merely basal factors, as has long been assumed. Instead, these noncoding RNAs constitute a previously uncharacterized layer of regulation of alternative splicing, and contribute to the establishment of global splicing programs in both healthy and malignant cells.