Functional genomic analysis of the let-7 regulatory network in Caenorhabditis elegans.
Functional genomic analysis of the let-7 regulatory network in Caenorhabditis elegans.
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DOI：
10.1371/journal.pgen.1003353
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Pasquinelli AE
中科院分区：
文献类型：
--
作者：
Hunter SE;Finnegan EF;Zisoulis DG;Lovci MT;Melnik-Martinez KV;Yeo GW;Pasquinelli AE
let-7 microRNA（miRNA）调节许多动物物种的细胞分化。let-7活性的丧失导致秀丽隐杆线虫的异常发育和人类细胞中不受抑制的细胞增殖，这有助于肿瘤发生。这些缺陷是由于通常在let-7调节下的蛋白质编码基因的不适当表达。虽然let-7的一些直接靶标已经被鉴定，但let-7不足在发育中的动物中的全基因组效应尚未得到充分研究。在这里，我们报告的结果，分子和遗传分析，旨在确定全球网络的基因调控的let-7在C。优美的通过筛选也有助于let-7突变表型的误调节基因，我们推导出let-7调节的生理相关潜在靶点列表。出现了20个新的let-7突变体特征性外阴破裂或额外缝细胞分裂表型的抑制因子。发现其中三个基因（opt-2、prmt-1和T27D12.1）以let-7依赖性方式与Argonaute相关，并且可能是该miRNA的新型直接靶点。总体而言，具有各种活动的基因的复杂网络受到let-7调节，以在蠕虫发育期间协调各组织的发育时间。在过去的十年中，microRNAs（miRNAs）已被公认为许多生物学途径中基因表达的关键调节因子。这些小的非编码RNA靶向特定的蛋白质编码基因进行抑制。这种特异性由22个核苷酸的miRNA与靶信使RNA（mRNA）中的序列之间的部分碱基配对相互作用介导。不完全碱基配对的使用意味着单个miRNA可以调节许多不同的mRNA，但这也意味着识别这些靶标并不简单。最早发现的miRNAs之一let-7通常通过一系列尚未完全描述的靶标促进细胞分化途径。在这里，我们利用分子和遗传学的方法来确定在秀丽隐杆线虫let-7 miRNA的生物学相关的目标。我们的分析表明，let-7直接和间接地调节了大量的基因。C中let-7活性的丧失。elegans导致多种发育异常并最终导致死亡。我们发现了let-7的新靶点，当它们未能得到适当调控时，这些靶点会导致这些表型。鉴于let-7从蠕虫到人类的高度保守性，我们的研究强调了可能在let-7跨物种调控下的新基因和途径。
The let-7 microRNA (miRNA) regulates cellular differentiation across many animal species. Loss of let-7 activity causes abnormal development in Caenorhabditis elegans and unchecked cellular proliferation in human cells, which contributes to tumorigenesis. These defects are due to improper expression of protein-coding genes normally under let-7 regulation. While some direct targets of let-7 have been identified, the genome-wide effect of let-7 insufficiency in a developing animal has not been fully investigated. Here we report the results of molecular and genetic assays aimed at determining the global network of genes regulated by let-7 in C. elegans. By screening for mis-regulated genes that also contribute to let-7 mutant phenotypes, we derived a list of physiologically relevant potential targets of let-7 regulation. Twenty new suppressors of the rupturing vulva or extra seam cell division phenotypes characteristic of let-7 mutants emerged. Three of these genes, opt-2, prmt-1, and T27D12.1, were found to associate with Argonaute in a let-7–dependent manner and are likely novel direct targets of this miRNA. Overall, a complex network of genes with various activities is subject to let-7 regulation to coordinate developmental timing across tissues during worm development. In the past decade, microRNAs (miRNAs) have become recognized as key regulators of gene expression in many biological pathways. These small, non-coding RNAs target specific protein-coding genes for repression. The specificity is mediated by partial base-pairing interactions between the 22 nucleotide miRNA and sequences in the target messenger RNA (mRNA). The use of imperfect base-pairing means that a single miRNA can regulate many different mRNAs, but it also means that identifying these targets is not straightforward. One of the first discovered miRNAs, let-7, generally promotes cellular differentiation pathways through a repertoire of targets that is yet to be fully described. Here we utilized molecular and genetic approaches to identify biologically relevant targets of the let-7 miRNA in Caenorhabditis elegans. Our analyses indicate that let-7 regulates a large cast of genes, both directly and indirectly. Loss of let-7 activity in C. elegans results in multiple developmental abnormalities and, ultimately, death. We uncovered new targets of let-7 that contribute to these phenotypes when they fail to be properly regulated. Given the highly conserved nature of let-7 from worms to humans, our studies highlight new genes and pathways potentially under let-7 regulation across species.
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影响因子：
64.5
作者：
Hafner M;Landthaler M;Burger L;Khorshid M;Hausser J;Berninger P;Rothballer A;Ascano M Jr;Jungkamp AC;Munschauer M;Ulrich A;Wardle GS;Dewell S;Zavolan M;Tuschl T
通讯作者：
Tuschl T
影响因子：
64.8
作者：
Baek, Daehyun;Villen, Judit;Shin, Chanseok;Camargo, Fernando D.;Gygi, Steven P.;Bartel, David P.
通讯作者：
Bartel, David P.
DOI：
10.4161/cc.7.19.6778
发表时间：
2008-10
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Ding XC;Slack FJ;Grosshans H
通讯作者：
Grosshans H
影响因子：
11.4
作者：
Ding, Xavier C.;Grosshans, Helge
通讯作者：
Grosshans, Helge
影响因子：
4.1
作者：
Beitzinger, Michaela;Peters, Lasse;Meister, Gunter
通讯作者：
Meister, Gunter