MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China.
RNA Biomedical Institute, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
Genome Res. 2020 May;30(5):661-672. doi: 10.1101/gr.257121.119. Epub 2020 May 18.
Antisense transcription of protein-coding genes has been increasingly recognized as an important regulatory mechanism of gene expression. However, less is known about the extent and importance of antisense transcription of noncoding genes. Here, we investigate the breadth and dynamics of antisense transcription of miRNAs, a class of important noncoding RNAs. Because the antisense transcript of a miRNA is likely to form a hairpin suitable as the substrate of ADARs, which convert adenosine to inosine in double-stranded RNAs, we used A-to-I RNA editing as ultrasensitive readout for antisense transcription of the miRNAs. Through examining the unstranded targeted RNA-seq libraries covering all miRNA loci in 25 types of human tissues, we identified 7275 editing events located in 81% of the antisense strand of the miRNA loci, thus uncovering the previously unknown prevalent antisense transcription of the miRNAs. We found that antisense transcripts are tightly regulated, and a substantial fraction of miRNAs and their antisense transcripts are coexpressed. Sense miRNAs have been shown to down-regulate the coexpressed antisense transcripts, whereas the act of antisense transcription, rather than the transcripts themselves, regulates the expression of sense miRNAs. RNA editing tends to decrease the miRNA accessibility of the antisense transcripts, therefore protecting them from being degraded by the sense-mature miRNAs. Altogether, our study reveals the landscape of antisense transcription and editing of miRNAs, as well as a previously unknown reciprocal regulatory circuit of sense-antisense miRNA pairs.
反义转录的蛋白质编码基因已被越来越多地认为是一个重要的基因表达调控机制。然而，对非编码基因反义转录的程度和重要性知之甚少。在这里，我们研究了 miRNA 的反义转录的广度和动态，miRNA 是一类重要的非编码 RNA。由于 miRNA 的反义转录本很可能形成一个发夹，适合作为 ADARs 的底物，ADARs 将双链 RNA 中的腺苷转换为肌苷，因此我们使用 A 到 I 的 RNA 编辑作为 miRNA 反义转录的超灵敏读出。通过检查覆盖 25 个人类组织中所有 miRNA 基因座的无链靶向 RNA-seq 文库，我们鉴定了 7275 个位于 miRNA 基因座反义链 81%的编辑事件，从而揭示了 miRNA 反义转录的先前未知的普遍存在。我们发现反义转录物受到严密调控，并且相当一部分 miRNA 和它们的反义转录物是共表达的。已经表明 sense miRNAs 下调共表达的反义转录物，而反义转录本身，而不是转录本本身，调节 sense miRNAs 的表达。RNA 编辑倾向于降低反义转录物的 miRNA 可及性，从而保护它们免受来自 sense-成熟 miRNA 的降解。总之，我们的研究揭示了 miRNA 的反义转录和编辑的全景，以及以前未知的 sense-antisense miRNA 对的相互调节回路。
