Regulation of alternative splicing by the core spliceosomal machinery
Regulation of alternative splicing by the core spliceosomal machinery
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DOI：
10.1101/gad.2004811
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发表时间：
2011-02-15
影响因子：
10.5
通讯作者：
Blencowe, Benjamin J.
中科院分区：
文献类型：
--
作者：
Saltzman, Arneet L.;Pan, Qun;Blencowe, Benjamin J.
选择性剪接(AS)在蛋白质组多样性的产生和基因调控中发挥着重要作用。然而，基本剪接机制在调节AS中的作用仍然知之甚少。在这里，我们证明了核心SnRNP(小核核糖核蛋白)蛋白SMB/B9通过促进在其自身的前mRNA中包括一个高度保守的替代外显子来自我调节其表达，该外显子针对剪接的转录产物进行无义介导的mRNA衰退(NMD)。人类细胞中SMB/B9的耗尽导致SnRNPs水平的降低和数百个额外的可选外显子的包涵体水平的显著降低，而对结构性外显子剪接水平的影响相对较小。受影响的替代外显子富含编码RNA加工和其他RNA结合因子的基因，这些外显子的一部分还通过激活NMD来调节基因表达。因此，我们的结果证明了核心剪接体机制在控制外显子网络中的作用，该外显子网络似乎调节了许多RNA加工因子的水平。
Alternative splicing (AS) plays a major role in the generation of proteomic diversity and in gene regulation. However, the role of the basal splicing machinery in regulating AS remains poorly understood. Here we show that the core snRNP (small nuclear ribonucleoprotein) protein SmB/B9 self-regulates its expression by promoting the inclusion of a highly conserved alternative exon in its own pre-mRNA that targets the spliced transcript for nonsense-mediated mRNA decay (NMD). Depletion of SmB/B9 in human cells results in reduced levels of snRNPs and a striking reduction in the inclusion levels of hundreds of additional alternative exons, with comparatively few effects on constitutive exon splicing levels. The affected alternative exons are enriched in genes encoding RNA processing and other RNA-binding factors, and a subset of these exons also regulate gene expression by activating NMD. Our results thus demonstrate a role for the core spliceosomal machinery in controlling an exon network that appears to modulate the levels of many RNA processing factors.