TGF-β/Smad2/3 signaling directly regulates several miRNAs in mouse ES cells and early embryos.
TGF-β/Smad2/3 signaling directly regulates several miRNAs in mouse ES cells and early embryos.
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DOI：
10.1371/journal.pone.0055186
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Episkopou V
中科院分区：
文献类型：
--
作者：
Redshaw N;Camps C;Sharma V;Motallebipour M;Guzman-Ayala M;Oikonomopoulos S;Thymiakou E;Ragoussis J;Episkopou V
转化生长因子-β（TGF-β）信号通路是正常胚胎发育和组织稳态所必需的主要通路之一，具有抗肿瘤但也具有促肿瘤转移的性质。该途径直接调节介导其下游功能的几个靶基因，然而很少有microRNA（miRNAs）被鉴定为靶。miRNA是基因表达的调节剂，在发育中起重要作用，并与包括癌症在内的疾病有明显的关联。对于初级转录物（pri-miRNA、pri-miR）的转录调控知之甚少，而几种成熟的miRNA通常来源于初级转录物。本研究旨在鉴定小鼠胚胎干细胞和早期胚胎中受TGF-β信号调节的miRNAs。我们使用诱导型ES细胞系统来维持高水平的TGF-β活化/磷酸化Smad 2/3效应物，其是该途径的转录因子，以及阻断其活化的特异性抑制剂。通过在Smad 2/3激活12小时后和抑制16小时后进行短RNA深度测序，我们生成了响应性miRNA的数据库。对这些miRNAs亚组的启动子/增强子分析显示，发现pri-miR-181 c/d和pri-miR-341 c/3072簇的转录依赖于激活的Smad 2/3。这些miRNAs中的几种在早期小鼠胚胎中表达，此时已知该途径起着重要作用。用TGF-β抑制剂处理胚胎导致其水平降低，证实它们是体内该途径的靶标。此外，我们还发现pri-miR-341 - 3072的转录也依赖于FoxH 1，FoxH 1是一种已知的Smad 2/3在早期发育过程中的转录伴侣。总之，我们的数据表明，miRNAs在ES细胞和早期胚胎中直接受TGF-β/Smad 2/3通路调节。由于已知由TGF-β/Smad 2/3途径调节的功能的体细胞异常是肿瘤抑制和转移的基础，因此这项研究也为参与癌症的miRNA提供了资源。
The Transforming Growth Factor-β (TGF-β) signaling pathway is one of the major pathways essential for normal embryonic development and tissue homeostasis, with anti-tumor but also pro-metastatic properties in cancer. This pathway directly regulates several target genes that mediate its downstream functions, however very few microRNAs (miRNAs) have been identified as targets. miRNAs are modulators of gene expression with essential roles in development and a clear association with diseases including cancer. Little is known about the transcriptional regulation of the primary transcripts (pri-miRNA, pri-miR) from which several mature miRNAs are often derived. Here we present the identification of miRNAs regulated by TGF-β signaling in mouse embryonic stem (ES) cells and early embryos. We used an inducible ES cell system to maintain high levels of the TGF-β activated/phosphorylated Smad2/3 effectors, which are the transcription factors of the pathway, and a specific inhibitor that blocks their activation. By performing short RNA deep-sequencing after 12 hours Smad2/3 activation and after 16 hours inhibition, we generated a database of responsive miRNAs. Promoter/enhancer analysis of a subset of these miRNAs revealed that the transcription of pri-miR-181c/d and the pri-miR-341∼3072 cluster were found to depend on activated Smad2/3. Several of these miRNAs are expressed in early mouse embryos, when the pathway is known to play an essential role. Treatment of embryos with TGF-β inhibitor caused a reduction of their levels confirming that they are targets of this pathway in vivo. Furthermore, we showed that pri-miR-341∼3072 transcription also depends on FoxH1, a known Smad2/3 transcription partner during early development. Together, our data show that miRNAs are regulated directly by the TGF-β/Smad2/3 pathway in ES cells and early embryos. As somatic abnormalities in functions known to be regulated by the TGF-β/Smad2/3 pathway underlie tumor suppression and metastasis, this research also provides a resource for miRNAs involved in cancer.
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影响因子：
4.1
作者：
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通讯作者：
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影响因子：
4.6
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DOI：
10.1073/pnas.1017576108
发表时间：
2011-07-12
影响因子：
11.1
作者：
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通讯作者：
Fields, R. Douglas