A negative regulatory loop between microRNA and Hox gene controls posterior identities in Caenorhabditis elegans.
A negative regulatory loop between microRNA and Hox gene controls posterior identities in Caenorhabditis elegans.
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DOI：
10.1371/journal.pgen.1001089
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发表时间：
2010-09-02
期刊：
影响因子：
4.5
通讯作者：
Waterston RH
中科院分区：
文献类型：
--
作者：
Zhao Z;Boyle TJ;Liu Z;Murray JI;Wood WB;Waterston RH
人们发现 MicroRNA (miRNA) 可以调节真核物种的基因表达，但大多数 miRNA 基因的功能仍然未知。在这里，我们描述了如何在秀丽隐杆线虫早期发育过程中以细胞分辨率每分钟分析一个高度保守的 miRNA 基因 mir-57 的表达模式，为理解其功能提供了关键见解。值得注意的是，mir-57 表达显示出强烈的位置偏差，但几乎没有组织特异性，这种模式让人想起 Hox 基因的功能。尽管功能缺失突变产生了微小缺陷，但 mir-57 的过度表达会导致严重的后部缺陷，这也模仿了后部 Hox 基因 nob-1（Abd 同源物）的突变等位基因的表型。更重要的是，在与表达 mir-57 的亚系相同的两个后 AB 亚系中发现了 nob-1 表达，但发病时间更早。有趣的是，nob-1 充当 mir-57 表达的激活剂；它也是mir-57的直接目标。与此一致的是，mir-57 功能的丧失部分挽救了 nob-1 等位基因缺陷，表明 miRNA 和 Hox 基因之间存在负反馈调节环，以提供位置线索。鉴于 miRNA 和 Hox 基因的保守性，该调控机制可能在跨物种中广泛使用。这里用于探索 mir-57 功能的策略提供了一条剖析基因之间调控关系的途径。 miRNA 是在许多多细胞物种中发现的抑制基因表达的小RNA。其中许多在癌症和细胞命运决定中发挥着重要作用，但大多数 miRNA 的功能尚不确定。使用活细胞成像和自动表达分析，我们发现 miRNA 基因 mir-57 以一定位置而不是组织依赖性方式表达。 Hox 基因还调节不同组织中沿前后 (a-p) 轴的细胞命运模式。通过研究表达 mir-57 的细胞中表达的这些类别基因之间的相互作用，我们通过遗传分析和基因表达测定证明，后部 Hox 基因、nob-1 和 mir-57 之间的负反馈环调节线虫中后部细胞的命运决定。一方面，Hox 基因是 mir-57 表达正常激活所必需的，另一方面，Hox 基因作为 miRNA 的直接靶标发挥作用，并受到 miRNA 的抑制。鉴于这两个基因的保守性，Hox 和 miRNA 基因之间的负反馈回路可能会在物种之间广泛使用，以沿 a-p 轴调节细胞命运。详细的表达分析可能提供剖析 miRNA 调节作用的通用方法。
MicroRNAs (miRNAs) have been found to regulate gene expression across eukaryotic species, but the function of most miRNA genes remains unknown. Here we describe how the analysis of the expression patterns of a well-conserved miRNA gene, mir-57, at cellular resolution for every minute during early development of Caenorhabditis elegans provided key insights in understanding its function. Remarkably, mir-57 expression shows strong positional bias but little tissue specificity, a pattern reminiscent of Hox gene function. Despite the minor defects produced by a loss of function mutation, overexpression of mir-57 causes dramatic posterior defects, which also mimic the phenotypes of mutant alleles of a posterior Hox gene, nob-1, an Abd homolog. More importantly, nob-1 expression is found in the same two posterior AB sublineages as those expressing mir-57 but with an earlier onset. Intriguingly, nob-1 functions as an activator for mir-57 expression; it is also a direct target of mir-57. In agreement with this, loss of mir-57 function partially rescues the nob-1 allele defects, indicating a negative feedback regulatory loop between the miRNA and Hox gene to provide positional cues. Given the conservation of the miRNA and Hox gene, the regulatory mechanism might be broadly used across species. The strategy used here to explore mir-57 function provides a path to dissect the regulatory relationship between genes. miRNAs are small RNAs found in many multi-cellular species that inhibit gene expression. Many of them play important roles in cancer and cell fate determination, but the function of most miRNAs is uncertain. Using live cell imaging and automated expression analysis, we found a miRNA gene, mir-57, is expressed in a position rather than tissue dependent way. Hox genes also regulate cell fate patterning along anterior-posterior (a-p) axis across different tissues. By investigating interactions between genes of these classes expressed in mir-57 expressing cells, we demonstrated by both genetic analysis and gene expression assays that a negative feedback loop between a posterior Hox gene, nob-1, and mir-57 regulates posterior cell fate determination in C. elegans. On the one hand, the Hox gene is required for normal activation of mir-57 expression, and on the other, the Hox gene functions as a direct target of and is repressed by the miRNA. Given the conservation of the two genes, a negative feedback loop between Hox and miRNA genes might be broadly used across species to regulate cell fate along the a-p axis. Detailed expression analysis may provide a general way to dissect the regulatory role of miRNAs.
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