Functional Pre-mRNA trans-Splicing of Coactivator CoAA and Corepressor RBM4 during Stem/Progenitor Cell Differentiation
Functional Pre-mRNA trans-Splicing of Coactivator CoAA and Corepressor RBM4 during Stem/Progenitor Cell Differentiation
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DOI：
10.1074/jbc.m109.006999
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发表时间：
2009-07-03
影响因子：
4.8
通讯作者：
Ko, Lan
中科院分区：
文献类型：
--
作者：
Brooks, Yang S.;Wang, Guanghu;Ko, Lan
选择性剪接产生功能不同的基因产物，它们的平衡在细胞分化和发育中起着关键作用。我们之前已经表明，肿瘤相关的增强子在共激活因子基因CoAA中的缺失导致其选择性剪接的改变。在这里，我们确定了两个基因间剪接变异，一个含锌指的共激活子CoAZ和一个非编码转录物ncCoAZ，在CoAA和它的下游共抑制基因RBM4之间。在干细胞/祖细胞神经分化过程中，我们发现CoAA和RBM4转录物之间的切换选择性剪接和反式剪接导致野生型CoAA、RBM4及其变体的谱系特异性表达。CoAA、RBM4或其变体的稳定表达阻止了这种开关并破坏了胚状体的形成。此外，CoAA和RBM4在第10外显子处对靶基因Tau进行反调控，其剪接活性受到各剪接变体的控制。进一步的系统发育分析表明，哺乳动物CoAA和RBM4基因与果蝇的基因Lark有着共同的祖先，后者被认为是调节早期发育和昼夜节律的基因。因此，CoAA和RBM4转录本之间的反式剪接可能代表了在进化过程中保存的一种必要的调节。我们的研究结果表明，转录辅激活因子和辅抑制因子的连锁剪接控制参与了干细胞/祖细胞分化。CoAA和RBM4的选择性剪接不平衡，由于它们在癌症中共同增强子的缺失，可能会解除对干细胞/祖细胞分化的调节。
Alternative splicing yields functionally distinctive gene products, and their balance plays critical roles in cell differentiation and development. We have previously shown that tumor-associated enhancer loss in coactivator gene CoAA leads to its altered alternative splicing. Here we identified two intergenic splicing variants, a zinc finger-containing coactivator CoAZ and a non-coding transcript ncCoAZ, between CoAA and its downstream corepressor gene RBM4. During stem/progenitor cell neural differentiation, we found that the switched alternative splicing and trans-splicing between CoAA and RBM4 transcripts result in lineage-specific expression of wild type CoAA, RBM4, and their variants. Stable expression of CoAA, RBM4, or their variants prevents the switch and disrupts the embryoid body formation. In addition, CoAA and RBM4 counter-regulate the target gene Tau at exon 10, and their splicing activities are subjected to the control by each splice variant. Further phylogenetic analysis showed that mammalian CoAA and RBM4 genes share common ancestry with the Drosophila melanogaster gene Lark, which is known to regulate early development and circadian rhythms. Thus, the trans-splicing between CoAA and RBM4 transcripts may represent a required regulation preserved during evolution. Our results demonstrate that a linked splicing control of transcriptional coactivator and corepressor is involved in stem/progenitor cell differentiation. The alternative splicing imbalance of CoAA and RBM4, because of loss of their common enhancer in cancer, may deregulate stem/progenitor cell differentiation.