Incorporation of a skeletal muscle-specific enhancer in the regulatory region of Igf1 upregulates IGF1 expression and induces skeletal muscle hypertrophy

Abstract In this study, we upregulated insulin-like growth factor-1 (IGF1) expression specifically in skeletal muscle by engineering an enhancer into its non-coding regions and verified the expected phenotype in a mouse model. To select an appropriate site for introducing a skeletal muscle-specific...

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Autores principales:	Yunlong Zou, Yanjun Dong, Qingyong Meng, Yaofeng Zhao, Ning Li
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/64b4fd0905984a15a720c925ddd1ccfe
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spelling	oai:doaj.org-article:64b4fd0905984a15a720c925ddd1ccfe2021-12-02T15:08:44ZIncorporation of a skeletal muscle-specific enhancer in the regulatory region of Igf1 upregulates IGF1 expression and induces skeletal muscle hypertrophy10.1038/s41598-018-21122-52045-2322https://doaj.org/article/64b4fd0905984a15a720c925ddd1ccfe2018-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-21122-5https://doaj.org/toc/2045-2322Abstract In this study, we upregulated insulin-like growth factor-1 (IGF1) expression specifically in skeletal muscle by engineering an enhancer into its non-coding regions and verified the expected phenotype in a mouse model. To select an appropriate site for introducing a skeletal muscle-specific myosin light chain (MLC) enhancer, three candidate sites that exhibited the least evolutionary conservation were chosen and validated in C2C12 single-cell colonies harbouring the MLC enhancer at each site. IGF1 was dramatically upregulated in only the site 2 single-cell colony series, and it exhibited functional activity leading to the formation of extra myotubes. Therefore, we chose site 2 to generate a genetically modified (GM) mouse model with the MLC enhancer incorporated by CRISPR/Cas9 technology. The GM mice exhibited dramatically elevated IGF1 levels, which stimulated downstream pathways in skeletal muscle. Female GM mice exhibited more conspicuous muscle hypertrophy than male GM mice. The GM mice possessed similar circulating IGF1 levels and tibia length as their WT littermates; they also did not exhibit heart abnormalities. Our findings demonstrate that genetically modifying a non-coding region is a feasible method to upregulate gene expression and obtain animals with desirable traits.Yunlong ZouYanjun DongQingyong MengYaofeng ZhaoNing LiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-13 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yunlong Zou Yanjun Dong Qingyong Meng Yaofeng Zhao Ning Li Incorporation of a skeletal muscle-specific enhancer in the regulatory region of Igf1 upregulates IGF1 expression and induces skeletal muscle hypertrophy
description	Abstract In this study, we upregulated insulin-like growth factor-1 (IGF1) expression specifically in skeletal muscle by engineering an enhancer into its non-coding regions and verified the expected phenotype in a mouse model. To select an appropriate site for introducing a skeletal muscle-specific myosin light chain (MLC) enhancer, three candidate sites that exhibited the least evolutionary conservation were chosen and validated in C2C12 single-cell colonies harbouring the MLC enhancer at each site. IGF1 was dramatically upregulated in only the site 2 single-cell colony series, and it exhibited functional activity leading to the formation of extra myotubes. Therefore, we chose site 2 to generate a genetically modified (GM) mouse model with the MLC enhancer incorporated by CRISPR/Cas9 technology. The GM mice exhibited dramatically elevated IGF1 levels, which stimulated downstream pathways in skeletal muscle. Female GM mice exhibited more conspicuous muscle hypertrophy than male GM mice. The GM mice possessed similar circulating IGF1 levels and tibia length as their WT littermates; they also did not exhibit heart abnormalities. Our findings demonstrate that genetically modifying a non-coding region is a feasible method to upregulate gene expression and obtain animals with desirable traits.
format	article
author	Yunlong Zou Yanjun Dong Qingyong Meng Yaofeng Zhao Ning Li
author_facet	Yunlong Zou Yanjun Dong Qingyong Meng Yaofeng Zhao Ning Li
author_sort	Yunlong Zou
title	Incorporation of a skeletal muscle-specific enhancer in the regulatory region of Igf1 upregulates IGF1 expression and induces skeletal muscle hypertrophy
title_short	Incorporation of a skeletal muscle-specific enhancer in the regulatory region of Igf1 upregulates IGF1 expression and induces skeletal muscle hypertrophy
title_full	Incorporation of a skeletal muscle-specific enhancer in the regulatory region of Igf1 upregulates IGF1 expression and induces skeletal muscle hypertrophy
title_fullStr	Incorporation of a skeletal muscle-specific enhancer in the regulatory region of Igf1 upregulates IGF1 expression and induces skeletal muscle hypertrophy
title_full_unstemmed	Incorporation of a skeletal muscle-specific enhancer in the regulatory region of Igf1 upregulates IGF1 expression and induces skeletal muscle hypertrophy
title_sort	incorporation of a skeletal muscle-specific enhancer in the regulatory region of igf1 upregulates igf1 expression and induces skeletal muscle hypertrophy
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/64b4fd0905984a15a720c925ddd1ccfe
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Incorporation of a skeletal muscle-specific enhancer in the regulatory region of Igf1 upregulates IGF1 expression and induces skeletal muscle hypertrophy

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