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
[Research 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 | ||||||
| Series Name/Journal: | FASEB Journal | ||||||
| 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: | Research 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: |
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| 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: | 15 Jan 2021 19:47 |
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