Exploring regulatory networks of miR-96 in the developing inner ear.
Exploring regulatory networks of miR-96 in the developing inner ear.
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DOI：
10.1038/srep23363
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发表时间：
2016-03-18
影响因子：
4.6
通讯作者：
Steel KP
中科院分区：
文献类型：
--
作者：
Lewis MA;Buniello A;Hilton JM;Zhu F;Zhang WI;Evans S;van Dongen S;Enright AJ;Steel KP
microRNA Mir96的突变导致小鼠和人类耳聋。在体型较小的小鼠中，miR-96的种子区携带单个碱基对变化，对听力至关重要的感觉毛细胞不能完全发育并保留未成熟特征，这表明miR-96对协调毛细胞成熟很重要。我们之前的转录分析表明，许多基因在内耳缩小中被错误调控，我们在这里报告了进一步的错误调控基因。我们选择了三种互补的方法来利用这些转录数据探索miR-96控制的潜在网络。首先，我们使用从文献中手动整理的调控相互作用来构建一个包含转录数据的调控网络。其次，利用InnateDB数据库构建蛋白质-蛋白质相互作用网络。第三，利用基因集富集分析，鉴定富集错调控基因的基因集。我们已经确定了几种候选基因，包括Fos、Myc、Trp53和Nr3c1，它们介导了由diminuendo突变引起的一些表达变化，并证实了我们的预测，即Fos在diminuendo纯合子中下调。了解miR-96调控的通路可以为治疗因网络任何组成部分的扰动而导致的听力损失提供潜在的治疗靶点。
Mutations in the microRNA Mir96 cause deafness in mice and humans. In the diminuendo mouse, which carries a single base pair change in the seed region of miR-96, the sensory hair cells crucial for hearing fail to develop fully and retain immature characteristics, suggesting that miR-96 is important for coordinating hair cell maturation. Our previous transcriptional analyses show that many genes are misregulated in the diminuendo inner ear and we report here further misregulated genes. We have chosen three complementary approaches to explore potential networks controlled by miR-96 using these transcriptional data. Firstly, we used regulatory interactions manually curated from the literature to construct a regulatory network incorporating our transcriptional data. Secondly, we built a protein-protein interaction network using the InnateDB database. Thirdly, gene set enrichment analysis was used to identify gene sets in which the misregulated genes are enriched. We have identified several candidates for mediating some of the expression changes caused by the diminuendo mutation, including Fos, Myc, Trp53 and Nr3c1, and confirmed our prediction that Fos is downregulated in diminuendo homozygotes. Understanding the pathways regulated by miR-96 could lead to potential therapeutic targets for treating hearing loss due to perturbation of any component of the network.