An attractive approach to reduce gene expression is via the use of antisense oligonucleotides (ASOs) that harness the RNase H1 mechanism. Here we show that RNase H ASOs targeted to introns or exons robustly reduce the level of spliced RNA associated with chromatin. Surprisingly, intron-targeted ASOs reduce the level of pre-mRNA associated with chromatin to a greater extent than exon-targeted ASOs. This indicates that exon-targeted ASOs achieve full activity after the pre-mRNA has undergone splicing, but before the mRNA is released from chromatin. Even though RNase H ASOs can reduce the level of RNA associated with chromatin, the effect of ASO-directed RNA degradation on transcription has never been documented. Here we show that intron-targeted ASOs and, to a lesser extent, exon-targeted ASOs cause RNA polymerase II (Pol II) transcription termination in cultured cells and mice. Furthermore, ASO-directed transcription termination is mediated by the nuclear exonuclease XRN2.

中文翻译：

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指导RNA酶H切割新生转录物导致转录终止。

减少基因表达的一种有吸引力的方法是通过利用利用RNase H1机制的反义寡核苷酸（ASO）。在这里，我们显示针对内含子或外显子的RNase H ASO能够有效降低与染色质相关的剪接RNA的水平。出乎意料的是，与外显子靶向的ASO相比，内含子靶向的ASO降低了与染色质相关的pre-mRNA的水平。这表明在pre-mRNA经历剪接之后，但在从染色质释放mRNA之前，以外显子为靶点的ASO达到了全部活性。即使RNase H ASO可以降低与染色质相关的RNA水平，但是ASO指导的RNA降解对转录的影响从未得到证实。在这里，我们显示了针对内含子的ASO，在较小程度上，外显子靶向的ASO在培养的细胞和小鼠中导致RNA聚合酶II（Pol II）转录终止。此外，ASO定向转录终止是由核外切核酸酶XRN2介导的。