Alternately spliced WT1 antisense transcripts interact with WT1 sense RNA and show epigenetic and splicing defects in cancer
Alternately spliced WT1 antisense transcripts interact with WT1 sense RNA and show epigenetic and splicing defects in cancer
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DOI：
10.1261/rna.562907
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发表时间：
2007-12-01
期刊：
影响因子：
4.5
通讯作者：
Brown, Keith W.
中科院分区：
文献类型：
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作者：
Dallosso, Anthony R.;Hancock, Anne L.;Brown, Keith W.
许多哺乳动物基因含有重叠的反义RNA，但这些转录本的功能和作用机制大多尚不清楚。WT1是一个发育成熟的基因，在肾母细胞瘤和急性髓系白血病中发生突变，具有反义转录本(WT1-AS)，我们已经发现WT1调节WT1蛋白水平。在这项研究中，我们发现WT1-AS以多种剪接形式存在，这些剪接形式通常与WT1 RNA在人和小鼠组织中平行表达。我们证明WT1-AS的表达与WT1内含子1中反义调节区(ARR)的甲基化有关，在正常肾脏中表现为印迹单等位基因表达，在WT中表现为印迹丢失。然而，我们没有发现小鼠Wt1-AS印记的证据。WT1-AS转录产物输出到细胞质中，与WT1基因外显子1重叠区的WT1mRNA形成异源双链。在AML中，WT1-AS经常存在异常剪接，这可能在AML的发生发展中起一定作用。这些结果表明，WT1编码保守的反义RNA，这些RNA可能通过RNA：RNA相互作用对WT1的表达起重要调节作用，并且可以通过多种机制在癌症中解除调控。
Many mammalian genes contain overlapping antisense RNAs, but the functions and mechanisms of action of these transcripts are mostly unknown. WT1 is a well-characterized developmental gene that is mutated in Wilms' tumor (WT) and acute myeloid leukaemia (AML) and has an antisense transcript (WT1-AS), which we have previously found to regulate WT1 protein levels. In this study, we show that WT1-AS is present in multiple spliceoforms that are usually expressed in parallel with WT1 RNA in human and mouse tissues. We demonstrate that the expression of WT1-AS correlates with methylation of the antisense regulatory region (ARR) in WT1 intron 1, displaying imprinted monoallelic expression in normal kidney and loss of imprinting in WT. However, we find no evidence for imprinting of mouse Wt1-as. WT1-AS transcripts are exported into the cytoplasm and form heteroduplexes with WT1 mRNA in the overlapping region in WT1 exon 1. In AML, there is often abnormal splicing of WT1-AS, which may play a role in the development of this malignancy. These results show that WT1 encodes conserved antisense RNAs that may have an important regulatory role in WT1 expression via RNA: RNA interactions, and which can become deregulated by a variety of mechanisms in cancer.