Critical contribution of 3' non-seed base pairing to the in vivo function of the evolutionarily conserved let-7a microRNA.
Critical contribution of 3' non-seed base pairing to the in vivo function of the evolutionarily conserved let-7a microRNA.
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DOI：
10.1016/j.celrep.2022.110745
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发表时间：
2022-04-26
期刊：
影响因子：
8.8
通讯作者：
Ambros, Victor
中科院分区：
文献类型：
--
作者：
Duan, Ye;Veksler-Lublinsky, Isana;Ambros, Victor
种子区（g2-g8）的碱基配对对于microRNA靶向至关重要;然而，3′非种子区（g9-g22）的体内功能尚不清楚。在这里，我们报告了一个系统的研究microRNA let-7a的3′非种子核苷酸在体内的作用，其整个g9-g22区域是保守的bilaterians。我们发现3′端非种子序列在功能上将let-7a与其家族旁系同源物区分开来。g11-g16的完全配对对于let-7a完全抑制多个关键靶点，包括进化上保守的lin-41、daf-12和hbl-1是必不可少的。在g17-g22的核苷酸不太重要，但可以补偿g11-g16区域的错配。有趣的是，即使对于具有完美种子配对的位点，也可能需要与let-7a 3′非种子序列的某种最小互补性。这些结果提供了证据表明，种子和3′非种子碱基配对的特定构型可以严重影响microRNA介导的体内基因调控。Duan等人发现，g11-g16处的microRNA-靶标配对对于进化上保守的microRNA let-7a的功能至关重要; 3′配对对于调节多个靶标的完美和不完美种子都是必需的。这些发现提供了证据，表明特定microRNA非种子核苷酸的碱基配对可以对靶向调控做出重要贡献。
Base pairing of the seed region (g2–g8) is essential for microRNA targeting; however, the in vivo function of the 3′ non-seed region (g9–g22) is less well understood. Here, we report a systematic investigation of the in vivo roles of 3′ non-seed nucleotides in microRNA let-7a, whose entire g9–g22 region is conserved among bilaterians. We find that the 3′ non-seed sequence functionally distinguishes let-7a from its family paralogs. The complete pairing of g11–g16 is essential for let-7a to fully repress multiple key targets, including evolutionarily conserved lin-41, daf-12, and hbl-1. Nucleotides at g17–g22 are less critical but may compensate for mismatches in the g11–g16 region. Interestingly, a certain minimal complementarity to let-7a 3′ non-seed sequence can be required even for sites with perfect seed pairing. These results provide evidence that the specific configurations of both seed and 3′ non-seed base pairing can critically influence microRNA-mediated gene regulation in vivo. Duan et al. find that microRNA-target pairing at g11–g16 is critical for the function of evolutionarily conserved microRNA let-7a; 3′ pairing is required for both perfect and imperfect seed in regulating multiple targets. These findings provide evidence that base pairing of specific microRNA non-seed nucleotides can critically contribute to target regulation.
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