Mercuri Rafael L V, Conceição Helena B, Guardia Gabriela D A, Goldstein Gabriel, Vibranovski Maria D, Hinske Ludwig C, Galante Pedro A F
Hospital Sirio-Libanes, São Paulo, 01308-060, Brazil.
Interunidades Em Bioinformática, Universidade de São Paulo, São Paulo, 05508-000, Brazil.
Mob DNA. 2023 Sep 8;14(1):12. doi: 10.1186/s13100-023-00301-w.
Reverse-transcribed gene copies (retrocopies) have emerged as major sources of evolutionary novelty. MicroRNAs (miRNAs) are small and highly conserved RNA molecules that serve as key post-transcriptional regulators of gene expression. The origin and subsequent evolution of miRNAs have been addressed but not fully elucidated.
In this study, we performed a comprehensive investigation of miRNA origination through retroduplicated mRNA sequences (retro-miRs). We identified 17 retro-miRs that emerged from the mRNA retrocopies. Four of these retro-miRs had de novo origins within retrocopied sequences, while 13 retro-miRNAs were located within exon regions and duplicated along with their host mRNAs. We found that retro-miRs were primate-specific, including five retro-miRs conserved among all primates and two human-specific retro-miRs. All retro-miRs were expressed, with predicted and experimentally validated target genes except miR-10527. Notably, the target genes of retro-miRs are involved in key biological processes such as metabolic processes, cell signaling, and regulation of neurotransmitters in the central nervous system. Additionally, we found that these retro-miRs play a potential oncogenic role in cancer by targeting key cancer genes and are overexpressed in several cancer types, including liver hepatocellular carcinoma and stomach adenocarcinoma.
Our findings demonstrated that mRNA retrotransposition is a key mechanism for the generation of novel miRNAs (retro-miRs) in primates. These retro-miRs are expressed, conserved, have target genes with important cellular functions, and play important roles in cancer.
逆转录基因拷贝（反转录拷贝）已成为进化新奇性的主要来源。微小RNA（miRNA）是小的且高度保守的RNA分子，作为基因表达的关键转录后调节因子。miRNA的起源及后续进化已得到研究，但尚未完全阐明。
在本研究中，我们通过逆转录的mRNA序列（逆转录miRNA）对miRNA的起源进行了全面研究。我们鉴定出17个源自mRNA反转录拷贝的逆转录miRNA。其中4个逆转录miRNA在反转录拷贝序列中具有全新起源，而13个逆转录miRNA位于外显子区域并与其宿主mRNA一起复制。我们发现逆转录miRNA是灵长类特异性的，包括在所有灵长类中保守的5个逆转录miRNA和2个人类特异性的逆转录miRNA。除miR - 10527外，所有逆转录miRNA均有表达，且具有预测和实验验证的靶基因。值得注意的是，逆转录miRNA的靶基因参与关键生物学过程，如代谢过程、细胞信号传导以及中枢神经系统中神经递质的调节。此外，我们发现这些逆转录miRNA通过靶向关键癌症基因在癌症中发挥潜在致癌作用，并且在包括肝细胞肝癌和胃腺癌在内的几种癌症类型中过表达。
我们的研究结果表明，mRNA逆转座是灵长类中产生新型miRNA（逆转录miRNA）的关键机制。这些逆转录miRNA有表达、保守，具有具有重要细胞功能的靶基因，并在癌症中发挥重要作用。
