Caenorhabditis elegans period homolog lin-42 regulates the timing of heterochronic miRNA expression.
Caenorhabditis elegans period homolog lin-42 regulates the timing of heterochronic miRNA expression.
复制标题
秀丽隐杆线虫周期同源物 lin-42 调节异时 miRNA 表达的时间。
DOI：
10.1073/pnas.1414856111
复制
发表时间：
2014
影响因子：
11.1
通讯作者：
Rougvie,AnnE
中科院分区：
文献类型：
--
作者：
McCulloch,KatherineA;Rougvie,AnnE
MicroRNAs(MiRNAs)是通过靶mRNAs的3‘非编码区转录后调控基因表达的小RNA，在秀丽隐杆线虫慢性途径中首次被发现。自那以后，miRNAs在许多生物体中被发现，并具有广泛的功能，包括控制人类的分化和多能性。lin-4和let-7家族的miRNAs调节发育时间。它们适当的时间表达确保了细胞谱系模式的正确计时和顺序执行。虽然人们对miRNA的生物发生有很多了解，但对miRNA表达是如何定时和调控的了解较少。lin-42是果蝇和哺乳动物昼夜节律基因周期的蠕虫同源基因，是异时性基因途径的另一个核心组成部分。lin-42突变体具有早熟表型，其后期程序执行得太早，但flin-42在定时途径中的位置尚不清楚。在这里，我们证明了lin-42负向调节异时miRNA转录。Let-7和相关的miRNA miR-48在inlin-42突变体中早熟积累。这一缺陷反映了转录调控的错误，因为观察到初级miRNA转录本(pri-miRNAs)和Alet-7启动子：：GFP融合的表达增强。Pri-miRNA水平在幼虫发育过程中振荡，其模式使人想起flin-42的表达。重要的是，我们证明了这种循环不需要lin-42；相反，峰值幅度增加了。遗传分析进一步证实lin-42通过let-7家族miRNAs发挥作用。综上所述，这些数据表明flin-42在发育时序中的一个关键功能是抑制pri-miRNAs水平，防止它们作为成熟miRNAs过早表达。
MicroRNAs (miRNAs) are small RNAs that regulate gene expression posttranscriptionally via the 3′ UTR of target mRNAs and were first identified in theCaenorhabditis elegansheterochronic pathway. miRNAs have since been found in many organisms and have broad functions, including control of differentiation and pluripotency in humans.lin-4andlet-7–family miRNAs regulate developmental timing inC. elegans, and their proper temporal expression ensures cell lineage patterns are correctly timed and sequentially executed. Although much is known about miRNA biogenesis, less is understood about how miRNA expression is timed and regulated.lin-42, the worm homolog of the circadian rhythm geneperiodof flies and mammals, is another core component of the heterochronic gene pathway.lin-42mutants have a precocious phenotype, in which later-stage programs are executed too early, but the placement oflin-42in the timing pathway is unclear. Here, we demonstrate thatlin-42negatively regulates heterochronic miRNA transcription. let-7 and the related miRNA miR-48 accumulate precociously inlin-42mutants. This defect reflects transcriptional misregulation because enhanced expression of both primary miRNA transcripts (pri-miRNAs) and alet-7promoter::gfp fusion are observed. The pri-miRNA levels oscillate during larval development, in a pattern reminiscent oflin-42expression. Importantly, we show thatlin-42is not required for this cycling; instead, peak amplitude is increased. Genetic analyses further confirm thatlin-42acts throughlet-7family miRNAs. Taken together, these data show that a key function oflin-42in developmental timing is to dampen pri-miRNAs levels, preventing their premature expression as mature miRNAs.