TGF-β/Smad2/3 signaling directly regulates several miRNAs in mouse ES cells and early embryos.

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 fu...

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Autores principales:	Nicholas Redshaw, Carme Camps, Vikas Sharma, Mehdi Motallebipour, Marcela Guzman-Ayala, Spyros Oikonomopoulos, Efstathia Thymiakou, Jiannis Ragoussis, Vasso Episkopou
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0a2eba45ff01472ab54a4c533d4d69f3
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spelling	oai:doaj.org-article:0a2eba45ff01472ab54a4c533d4d69f32021-11-18T07:59:18ZTGF-β/Smad2/3 signaling directly regulates several miRNAs in mouse ES cells and early embryos.1932-620310.1371/journal.pone.0055186https://doaj.org/article/0a2eba45ff01472ab54a4c533d4d69f32013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23390484/?tool=EBIhttps://doaj.org/toc/1932-6203The 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.Nicholas RedshawCarme CampsVikas SharmaMehdi MotallebipourMarcela Guzman-AyalaSpyros OikonomopoulosEfstathia ThymiakouJiannis RagoussisVasso EpiskopouPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 1, p e55186 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Nicholas Redshaw Carme Camps Vikas Sharma Mehdi Motallebipour Marcela Guzman-Ayala Spyros Oikonomopoulos Efstathia Thymiakou Jiannis Ragoussis Vasso Episkopou TGF-β/Smad2/3 signaling directly regulates several miRNAs in mouse ES cells and early embryos.
description	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.
format	article
author	Nicholas Redshaw Carme Camps Vikas Sharma Mehdi Motallebipour Marcela Guzman-Ayala Spyros Oikonomopoulos Efstathia Thymiakou Jiannis Ragoussis Vasso Episkopou
author_facet	Nicholas Redshaw Carme Camps Vikas Sharma Mehdi Motallebipour Marcela Guzman-Ayala Spyros Oikonomopoulos Efstathia Thymiakou Jiannis Ragoussis Vasso Episkopou
author_sort	Nicholas Redshaw
title	TGF-β/Smad2/3 signaling directly regulates several miRNAs in mouse ES cells and early embryos.
title_short	TGF-β/Smad2/3 signaling directly regulates several miRNAs in mouse ES cells and early embryos.
title_full	TGF-β/Smad2/3 signaling directly regulates several miRNAs in mouse ES cells and early embryos.
title_fullStr	TGF-β/Smad2/3 signaling directly regulates several miRNAs in mouse ES cells and early embryos.
title_full_unstemmed	TGF-β/Smad2/3 signaling directly regulates several miRNAs in mouse ES cells and early embryos.
title_sort	tgf-β/smad2/3 signaling directly regulates several mirnas in mouse es cells and early embryos.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/0a2eba45ff01472ab54a4c533d4d69f3
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TGF-β/Smad2/3 signaling directly regulates several miRNAs in mouse ES cells and early embryos.

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