ZBED6 regulates Igf2 expression partially through its regulation of miR483 expression

Abstract The expression of Igf2 in mammals shows a complex regulation involving multiple promoters and epigenetic mechanisms. We previously identified a novel regulatory mechanism based on the interaction between the transcriptional factor ZBED6 and Igf2 intron. Disruption of the ZBED6-Igf2 interact...

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Autores principales:	Rakan Naboulsi, Mårten Larsson, Leif Andersson, Shady Younis
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b3207640c18a4a53ac68ecdbbeda91e0
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spelling	oai:doaj.org-article:b3207640c18a4a53ac68ecdbbeda91e02021-12-02T17:17:40ZZBED6 regulates Igf2 expression partially through its regulation of miR483 expression10.1038/s41598-021-98777-02045-2322https://doaj.org/article/b3207640c18a4a53ac68ecdbbeda91e02021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-98777-0https://doaj.org/toc/2045-2322Abstract The expression of Igf2 in mammals shows a complex regulation involving multiple promoters and epigenetic mechanisms. We previously identified a novel regulatory mechanism based on the interaction between the transcriptional factor ZBED6 and Igf2 intron. Disruption of the ZBED6-Igf2 interaction leads to a dramatic up-regulation of IGF2 expression postnatally. In the current study we characterize an additional layer of regulation involving miR483 encoded by another Igf2 intron. We found a highly significant up-regulation of miR483 expression when the ZBED6-Igf2 axis is disrupted in transgenic mice. Furthermore, CRISPR/Cas9 mediated knock-out of miR483 in C2C12 myoblast cells, both wild-type and cells with disrupted ZBED6-Igf2 axis (Igf2 dGGCT), resulted in down-regulation of Igf2 expression and a reduced proliferation rate. This was further validated using miR483 mimics and inhibitors. RNA-seq analysis revealed a significant enrichment of genes involved in the PI3K-Akt signaling pathway among genes down-regulated in miR483 −/− cells, including Igf2 down-regulation. The opposite pattern was observed in Igf2 dGGCT cells, where Igf2 is up-regulated. Our data suggest a positive feedback between miR483 and Igf2 promoter activity, strongly affecting how ZBED6 controls Igf2 expression in various cell types.Rakan NaboulsiMårten LarssonLeif AnderssonShady YounisNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rakan Naboulsi Mårten Larsson Leif Andersson Shady Younis ZBED6 regulates Igf2 expression partially through its regulation of miR483 expression
description	Abstract The expression of Igf2 in mammals shows a complex regulation involving multiple promoters and epigenetic mechanisms. We previously identified a novel regulatory mechanism based on the interaction between the transcriptional factor ZBED6 and Igf2 intron. Disruption of the ZBED6-Igf2 interaction leads to a dramatic up-regulation of IGF2 expression postnatally. In the current study we characterize an additional layer of regulation involving miR483 encoded by another Igf2 intron. We found a highly significant up-regulation of miR483 expression when the ZBED6-Igf2 axis is disrupted in transgenic mice. Furthermore, CRISPR/Cas9 mediated knock-out of miR483 in C2C12 myoblast cells, both wild-type and cells with disrupted ZBED6-Igf2 axis (Igf2 dGGCT), resulted in down-regulation of Igf2 expression and a reduced proliferation rate. This was further validated using miR483 mimics and inhibitors. RNA-seq analysis revealed a significant enrichment of genes involved in the PI3K-Akt signaling pathway among genes down-regulated in miR483 −/− cells, including Igf2 down-regulation. The opposite pattern was observed in Igf2 dGGCT cells, where Igf2 is up-regulated. Our data suggest a positive feedback between miR483 and Igf2 promoter activity, strongly affecting how ZBED6 controls Igf2 expression in various cell types.
format	article
author	Rakan Naboulsi Mårten Larsson Leif Andersson Shady Younis
author_facet	Rakan Naboulsi Mårten Larsson Leif Andersson Shady Younis
author_sort	Rakan Naboulsi
title	ZBED6 regulates Igf2 expression partially through its regulation of miR483 expression
title_short	ZBED6 regulates Igf2 expression partially through its regulation of miR483 expression
title_full	ZBED6 regulates Igf2 expression partially through its regulation of miR483 expression
title_fullStr	ZBED6 regulates Igf2 expression partially through its regulation of miR483 expression
title_full_unstemmed	ZBED6 regulates Igf2 expression partially through its regulation of miR483 expression
title_sort	zbed6 regulates igf2 expression partially through its regulation of mir483 expression
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/b3207640c18a4a53ac68ecdbbeda91e0
work_keys_str_mv	AT rakannaboulsi zbed6regulatesigf2expressionpartiallythroughitsregulationofmir483expression AT martenlarsson zbed6regulatesigf2expressionpartiallythroughitsregulationofmir483expression AT leifandersson zbed6regulatesigf2expressionpartiallythroughitsregulationofmir483expression AT shadyyounis zbed6regulatesigf2expressionpartiallythroughitsregulationofmir483expression
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ZBED6 regulates Igf2 expression partially through its regulation of miR483 expression

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