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The importance of the ZBED6-IGF2 axis for metabolic regulation in mouse myoblast cells

Younis, Shady and Naboulsi, Rakan and Wang, Xuan and Cao, Xiaofang and Larsson, Marten and Sargsyan, Ernest and Bergsten, Peter and Welsh, Nils and Andersson, Leif (2020). The importance of the ZBED6-IGF2 axis for metabolic regulation in mouse myoblast cells. FASEB Journal. 34 , 10250-10266
[Journal article]

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Abstract

The transcription factor ZBED6 acts as a repressor of Igf2 and affects directly or indirectly the transcriptional regulation of thousands of genes. Here, we use gene editing in mouse C2C12 myoblasts and show that ZBED6 regulates Igf2 exclusively through its binding site 5 '-GGCTCG-3 ' in intron 1 of Igf2. Deletion of this motif (Igf2(Delta GGCT)) or complete ablation of Zbed6 leads to similar to 20-fold upregulation of the IGF2 protein. Quantitative proteomics revealed an activation of Ras signaling pathway in both Z bed6(-/-) and Igf2(Delta GGCT) myoblasts, and a significant enrichment of mitochondrial membrane proteins among proteins showing altered expression in Z bed6(-/-)myoblasts. BothZbed6(-/-)andIgf2(Delta GGCT)myoblasts showed a faster growth rate and developed myotube hypertrophy. These cells exhibited an increased O-2 consumption rate, due to IGF2 upregulation. Transcriptome analysis revealed similar to 30% overlap between differentially expressed genes in Z bed6(-/-) and Igf2(Delta GGCT) myotubes, with an enrichment of upregulated genes involved in muscle development. In contrast, ZBED6-overexpression in myoblasts led to cell apoptosis, cell cycle arrest, reduced mitochondrial activities, and ceased myoblast differentiation. The similarities in growth and differentiation phenotypes observed in Z bed6(-/-)and Igf2(Delta GGCT) myoblasts demonstrates that ZBED6 affects mitochondrial activity and myogenesis largely through its regulation of IGF2 expression. This study adds new insights how the ZBED6-Igf2 axis affects muscle metabolism.

Authors/Creators:Younis, Shady and Naboulsi, Rakan and Wang, Xuan and Cao, Xiaofang and Larsson, Marten and Sargsyan, Ernest and Bergsten, Peter and Welsh, Nils and Andersson, Leif
Title:The importance of the ZBED6-IGF2 axis for metabolic regulation in mouse myoblast cells
Year of publishing :2020
Volume:34
Page range:10250-10266
Number of Pages:17
Publisher:Wiley Periodicals, Federation of American Societies for Experimental Biology
ISSN:0892-6638
Language:English
Publication Type:Journal article
Article category:Scientific peer reviewed
Version:Published version
Copyright:Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0
Full Text Status:Public
Subjects:(A) Swedish standard research categories 2011 > 1 Natural sciences > 106 Biological Sciences (Medical to be 3 and Agricultural to be 4) > Genetics (medical genetics to be 30107 and agricultural genetics to be 40402)
Keywords:IGF2, mitochondria, myogenesis and gene editing, ZBED6
URN:NBN:urn:nbn:se:slu:epsilon-p-106883
Permanent URL:
http://urn.kb.se/resolve?urn=urn:nbn:se:slu:epsilon-p-106883
Additional ID:
Type of IDID
DOI10.1096/fj.201901321R
Web of Science (WoS)000541805900001
ID Code:17414
Faculty:VH - Faculty of Veterinary Medicine and Animal Science
Department:(VH) > Dept. of Animal Breeding and Genetics
Deposited By: SLUpub Connector
Deposited On:07 Sep 2020 09:41
Metadata Last Modified:07 Sep 2020 09:41

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