Ultraconserved elements are associated with homeostatic control of splicing regulators by alternative splicing and nonsense-mediated decay
Ultraconserved elements are associated with homeostatic control of splicing regulators by alternative splicing and nonsense-mediated decay
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DOI：
10.1101/gad.1525507
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发表时间：
2007-03-15
影响因子：
10.5
通讯作者：
Ares, Manuel, Jr.
中科院分区：
文献类型：
--
作者：
Ni, Julie Z.;Grate, Leslie;Ares, Manuel, Jr.
许多选择性剪接事件产生具有过早终止密码子的rna，表明选择性剪接加上无义介导的衰变（AS-NMD）可能在转录后调节基因表达。我们在小鼠中测试了这一想法，通过阻断NMD和使用剪接敏感微阵列测量异构体表征的变化。我们发现了一类高度保守的含有终止密码子的外显子，其包含使转录本对NMD敏感。对其他例子的基因组搜索发现，在具有多种功能的基因中有50个这样的外显子。这些外显子在编码剪接激活子的基因中异常频繁，并且意外地在哺乳动物谱系中所谓的“超保守”元素中富集。进一步的分析表明，剪接激活因子（如SR蛋白）的mrna的NMD是由剪接激活事件触发的，而负作用的hnRNP蛋白的mrna的NMD是由剪接抑制触发的，这种极性与剪接调节基因表达的广泛稳态控制一致。我们认为，在剪接因子基因中，围绕这些调节剪接事件的极端基因组保护表明了在脊椎动物细胞中保持rna结合蛋白水平的紧密调节稳态的进化重要性。
Many alternative splicing events create RNAs with premature stop codons, suggesting that alternative splicing coupled with nonsense-mediated decay (AS-NMD) may regulate gene expression post-transcriptionally. We tested this idea in mice by blocking NMD and measuring changes in isoform representation using splicing-sensitive microarrays. We found a striking class of highly conserved stop codon-containing exons whose inclusion renders the transcript sensitive to NMD. A genomic search for additional examples identified > 50 such exons in genes with a variety of functions. These exons are unusually frequent in genes that encode splicing activators and are unexpectedly enriched in the so-called "ultraconserved" elements in the mammalian lineage. Further analysis show that NMD of mRNAs for splicing activators such as SR proteins is triggered by splicing activation events, whereas NMD of the mRNAs for negatively acting hnRNP proteins is triggered by splicing repression, a polarity consistent with widespread homeostatic control of splicing regulator gene expression. We suggest that the extreme genomic conservation surrounding these regulatory splicing events within splicing factor genes demonstrates the evolutionary importance of maintaining tightly tuned homeostasis of RNA-binding protein levels in the vertebrate cell.