A highly expressed miR-101 isomiR is a functional silencing small RNA.
A highly expressed miR-101 isomiR is a functional silencing small RNA.
复制标题
DOI：
10.1186/1471-2164-14-104
复制
发表时间：
2013-02-15
期刊：
影响因子：
4.4
通讯作者：
Martí E
中科院分区：
文献类型：
--
作者：
Llorens F;Bañez-Coronel M;Pantano L;del Río JA;Ferrer I;Estivill X;Martí E
MicroRNAs(MiRNAs)是一种控制基因表达的非编码短小调控RNA，通常产生翻译抑制和基因沉默。高通量测序技术已经显示了大多数成熟miRNAs(IsomiRs)在长度和序列水平上的异质性。大多数异构体可以用miRNA生物发生过程中Dicer1或DROSHA裂解的变异性来解释，在miRNA的5‘或3’端(修剪变异体)。尽管异构体在不同的组织和生物体中已被描述，但它们作为基因表达调节器的功能验证仍然难以捉摸。在这里，我们表征了一个高度丰富的miR-101 5‘-修剪变异体(5’-isomiR-101)的表达和功能。对几种人体组织和细胞系的小RNA测序数据的分析表明，5‘-异构体R-101普遍存在，并且含量很高，特别是在大脑中。5‘-isomiR-101存在于AGO-2免疫复合物中，互补实验表明5’-isomiR-101与沉默复合体(RISC)的不同成员相互作用。此外，5‘-isomiR-101降低了5个有效的miR-101靶标的表达，表明它是一个功能变体。与miR-101相比，5‘-isomiR-101与RISC成员的结合效率和沉默程度都较低。对于某些靶点，miR-101和5‘-isomiR-101都显著降低了蛋白表达，而各自的mRNA水平没有变化。尽管大量重叠的预测靶点提示了相似的靶向生物学途径，但对不同年龄人脑中miR-101变体和预测的mRNA靶标的表达谱进行的相关性分析表明，miR-101和5‘-isomiR-101具有特定的功能。这些结果表明，异构体是功能变异体，并进一步表明，对于给定的miRNA，不同的异构体可能作为基因表达的定量和定性微调因子而对整体效应做出贡献。
MicroRNAs (miRNAs) are short non-coding regulatory RNAs that control gene expression usually producing translational repression and gene silencing. High-throughput sequencing technologies have revealed heterogeneity at length and sequence level for the majority of mature miRNAs (IsomiRs). Most isomiRs can be explained by variability in either Dicer1 or Drosha cleavage during miRNA biogenesis at 5’ or 3’ of the miRNA (trimming variants). Although isomiRs have been described in different tissues and organisms, their functional validation as modulators of gene expression remains elusive. Here we have characterized the expression and function of a highly abundant miR-101 5’-trimming variant (5’-isomiR-101). The analysis of small RNA sequencing data in several human tissues and cell lines indicates that 5’-isomiR-101 is ubiquitously detected and a highly abundant, especially in the brain. 5’-isomiR-101 was found in Ago-2 immunocomplexes and complementary approaches showed that 5’-isomiR-101 interacted with different members of the silencing (RISC) complex. In addition, 5’-isomiR-101 decreased the expression of five validated miR-101 targets, suggesting that it is a functional variant. Both the binding to RISC members and the degree of silencing were less efficient for 5’-isomiR-101 compared with miR-101. For some targets, both miR-101 and 5’-isomiR-101 significantly decreased protein expression with no changes in the respective mRNA levels. Although a high number of overlapping predicted targets suggest similar targeted biological pathways, a correlation analysis of the expression profiles of miR-101 variants and predicted mRNA targets in human brains at different ages, suggest specific functions for miR-101- and 5’-isomiR-101. These results suggest that isomiRs are functional variants and further indicate that for a given miRNA, the different isomiRs may contribute to the overall effect as quantitative and qualitative fine-tuners of gene expression.
登录
查看更多内容
DOI：
10.1073/pnas.0710263105
发表时间：
2008-04-29
影响因子：
11.1
作者：
Hebert, Sebastien S.;Horre, Katrien;De Strooper, Bart
通讯作者：
De Strooper, Bart
影响因子：
4.5
作者：
Bañez-Coronel M;Porta S;Kagerbauer B;Mateu-Huertas E;Pantano L;Ferrer I;Guzmán M;Estivill X;Martí E
通讯作者：
Martí E
影响因子：
16.8
作者：
Chi, Sung Wook;Hannon, Gregory J.;Darnell, Robert B.
通讯作者：
Darnell, Robert B.
影响因子：
37.3
作者：
Cao, Paul;Deng, Zhiyong;Sui, Guangchao
通讯作者：
Sui, Guangchao
影响因子：
12.3
作者：
Blow MJ;Grocock RJ;van Dongen S;Enright AJ;Dicks E;Futreal PA;Wooster R;Stratton MR
通讯作者：
Stratton MR