Multiple microRNAs regulate human FOXP2 gene expression by targeting sequences in its 3' untranslated region.
Multiple microRNAs regulate human FOXP2 gene expression by targeting sequences in its 3' untranslated region.
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DOI：
10.1186/s13041-014-0071-0
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发表时间：
2014-10-01
期刊：
影响因子：
3.6
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Fu L;Shi Z;Luo G;Tu W;Wang X;Fang Z;Li X
人类 FOXP2 基因突变会导致言语和语言障碍。 FOXP2蛋白是一种转录因子，调节许多下游基因的表达，这些基因可能在神经系统发育和功能中发挥重要作用。足量的功能性 FOXP2 蛋白被认为对于语音和语言神经回路的正常发育至关重要。然而，FOXP2基因表达是如何调控的尚不清楚。 FOXP2 mRNA 具有约 4 kb 长的 3' 非翻译区 (3' UTR)，是其蛋白质编码区的两倍，表明 FOXP2 可以受到 microRNA (miRNA) 的调节。我们通过序列分析和体外细胞系统鉴定了多种调节人类 FOXP2 基因表达的 miRNA。重点关注 let-7a、miR-9 和 miR-129-5p 这三种大脑富集的 miRNA，我们发现这些 miRNA 以剂量依赖性方式调节人 FOXP2 表达，并靶向 FOXP2 3' UTR 中的特定序列。我们进一步表明，这三种 miRNA 在人类胎儿大脑的小脑中表达，而 FOXP2 也在那里表达。我们的结果揭示了人类 FOXP2 3' UTR 序列的新调控功能以及多个 miRNA 和人类 FOXP2 基因之间的调控相互作用。 let-7a、miR-9 和 miR-129-5p 在人胎儿小脑中的表达与其在早期小脑发育过程中调节 FOXP2 表达的作用一致。这些结果表明，各种遗传和环境因素可能通过 miRNA-FOXP2 调控网络促进言语和语言发育以及相关的神经发育障碍。本文的在线版本 (doi:10.1186/s13041-014-0071-0) 包含补充材料，可供授权用户使用。
Mutations in the human FOXP2 gene cause speech and language impairments. The FOXP2 protein is a transcription factor that regulates the expression of many downstream genes, which may have important roles in nervous system development and function. An adequate amount of functional FOXP2 protein is thought to be critical for the proper development of the neural circuitry underlying speech and language. However, how FOXP2 gene expression is regulated is not clearly understood. The FOXP2 mRNA has an approximately 4-kb-long 3′ untranslated region (3′ UTR), twice as long as its protein coding region, indicating that FOXP2 can be regulated by microRNAs (miRNAs). We identified multiple miRNAs that regulate the expression of the human FOXP2 gene using sequence analysis and in vitro cell systems. Focusing on let-7a, miR-9, and miR-129-5p, three brain-enriched miRNAs, we show that these miRNAs regulate human FOXP2 expression in a dosage-dependent manner and target specific sequences in the FOXP2 3′ UTR. We further show that these three miRNAs are expressed in the cerebellum of the human fetal brain, where FOXP2 is known to be expressed. Our results reveal novel regulatory functions of the human FOXP2 3′ UTR sequence and regulatory interactions between multiple miRNAs and the human FOXP2 gene. The expression of let-7a, miR-9, and miR-129-5p in the human fetal cerebellum is consistent with their roles in regulating FOXP2 expression during early cerebellum development. These results suggest that various genetic and environmental factors may contribute to speech and language development and related neural developmental disorders via the miRNA-FOXP2 regulatory network. The online version of this article (doi:10.1186/s13041-014-0071-0) contains supplementary material, which is available to authorized users.
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