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m6A-dependent biogenesis of circular RNAs in male germ cells.
Cell Research ( IF 28.1 ) Pub Date : 2020-02-11 , DOI: 10.1038/s41422-020-0279-8 Chong Tang 1, 2 , Yeming Xie 1 , Tian Yu 1 , Na Liu 2 , Zhuqing Wang 1 , Rebekah J Woolsey 3 , Yunge Tang 4, 5 , Xinzong Zhang 4, 5 , Weibing Qin 4, 5 , Ying Zhang 4, 5 , Ge Song 4, 5 , Weiwei Zheng 4, 5 , Juan Wang 2 , Weitian Chen 2 , Xiongyi Wei 2 , Zhe Xie 2, 6 , Rachel Klukovich 1 , Huili Zheng 1 , David R Quilici 3 , Wei Yan 1, 7, 8
Cell Research ( IF 28.1 ) Pub Date : 2020-02-11 , DOI: 10.1038/s41422-020-0279-8 Chong Tang 1, 2 , Yeming Xie 1 , Tian Yu 1 , Na Liu 2 , Zhuqing Wang 1 , Rebekah J Woolsey 3 , Yunge Tang 4, 5 , Xinzong Zhang 4, 5 , Weibing Qin 4, 5 , Ying Zhang 4, 5 , Ge Song 4, 5 , Weiwei Zheng 4, 5 , Juan Wang 2 , Weitian Chen 2 , Xiongyi Wei 2 , Zhe Xie 2, 6 , Rachel Klukovich 1 , Huili Zheng 1 , David R Quilici 3 , Wei Yan 1, 7, 8
Affiliation
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The majority of circular RNAs (circRNAs) spliced from coding genes contain open reading frames (ORFs) and thus, have protein coding potential. However, it remains unknown what regulates the biogenesis of these ORF-containing circRNAs, whether they are actually translated into proteins and what functions they play in specific physiological contexts. Here, we report that a large number of circRNAs are synthesized with increasing abundance when late pachytene spermatocytes develop into round and then elongating spermatids during murine spermatogenesis. For a subset of circRNAs, the back splicing appears to occur mostly at m6A-enriched sites, which are usually located around the start and stop codons in linear mRNAs. Consequently, approximately a half of these male germ cell circRNAs contain large ORFs with m6A-modified start codons in their junctions, features that have been recently shown to be associated with protein-coding potential. Hundreds of peptides encoded by the junction sequences of these circRNAs were detected using liquid chromatography coupled with mass spectrometry, suggesting that these circRNAs can indeed be translated into proteins in both developing (spermatocytes and spermatids) and mature (spermatozoa) male germ cells. The present study discovered not only a novel role of m6A in the biogenesis of coding circRNAs, but also a potential mechanism to ensure stable and long-lasting protein production in the absence of linear mRNAs, i.e., through production of circRNAs containing large ORFs and m6A-modified start codons in junction sequences.
中文翻译：
雄性生殖细胞中环状 RNA 的 m6A 依赖性生物发生。
大多数由编码基因剪接而成的环状 RNA (circRNA) 含有开放阅读框 (ORF)，因此具有蛋白质编码潜力。然而，目前尚不清楚是什么调节这些含有 ORF 的 circRNA 的生物发生，它们是否实际上被翻译成蛋白质以及它们在特定的生理环境中发挥什么功能。在这里，我们报道了在小鼠精子发生过程中，当粗线期晚期精母细胞发育成圆形然后伸长的精子细胞时，大量的circRNA被合成，并且丰度不断增加。对于 circRNA 的子集，反向剪接似乎主要发生在 m6A 富集位点，这些位点通常位于线性 mRNA 的起始密码子和终止密码子周围。因此，大约一半的雄性生殖细胞 circRNA 包含大的 ORF，其连接处具有 m6A 修饰的起始密码子，这些特征最近已被证明与蛋白质编码潜力相关。使用液相色谱结合质谱检测到了这些 circRNA 连接序列编码的数百种肽，表明这些 circRNA 确实可以在发育中（精母细胞和精子细胞）和成熟（精子）雄性生殖细胞中翻译成蛋白质。本研究不仅发现了 m6A 在编码 circRNA 的生物合成中的新作用，而且还发现了一种在线性 mRNA 缺失的情况下确保稳定且持久的蛋白质生产的潜在机制，即通过产生含有大 ORF 和 m6A 的 circRNA -连接序列中修饰的起始密码子。
更新日期：2020-02-11
中文翻译：
雄性生殖细胞中环状 RNA 的 m6A 依赖性生物发生。
大多数由编码基因剪接而成的环状 RNA (circRNA) 含有开放阅读框 (ORF)，因此具有蛋白质编码潜力。然而，目前尚不清楚是什么调节这些含有 ORF 的 circRNA 的生物发生，它们是否实际上被翻译成蛋白质以及它们在特定的生理环境中发挥什么功能。在这里，我们报道了在小鼠精子发生过程中，当粗线期晚期精母细胞发育成圆形然后伸长的精子细胞时，大量的circRNA被合成，并且丰度不断增加。对于 circRNA 的子集，反向剪接似乎主要发生在 m6A 富集位点，这些位点通常位于线性 mRNA 的起始密码子和终止密码子周围。因此，大约一半的雄性生殖细胞 circRNA 包含大的 ORF，其连接处具有 m6A 修饰的起始密码子，这些特征最近已被证明与蛋白质编码潜力相关。使用液相色谱结合质谱检测到了这些 circRNA 连接序列编码的数百种肽，表明这些 circRNA 确实可以在发育中（精母细胞和精子细胞）和成熟（精子）雄性生殖细胞中翻译成蛋白质。本研究不仅发现了 m6A 在编码 circRNA 的生物合成中的新作用，而且还发现了一种在线性 mRNA 缺失的情况下确保稳定且持久的蛋白质生产的潜在机制，即通过产生含有大 ORF 和 m6A 的 circRNA -连接序列中修饰的起始密码子。
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