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

Autor: Rakan Naboulsi, Peter Bergsten, Xiaofang Cao, Shady Younis, Mårten Larsson, Nils Welsh, Ernest Sargsyan, Leif Andersson, Xuan Wang
Rok vydání: 2019
Předmět:
0301 basic medicine
animal structures
endocrine system diseases
Transcription
Genetic
Muscle Fibers
Skeletal
Apoptosis
Mitochondrion
Biology
Biochemistry
Cell Line
Transcriptome
Myoblasts
03 medical and health sciences
myogenesis and gene editing
Mice
0302 clinical medicine
Genetics (medical genetics to be 30107 and agricultural genetics to be 40402)
Downregulation and upregulation
Insulin-Like Growth Factor II
Transcriptional regulation
Genetics
Myocyte
Animals
Genetik
Molecular Biology
Transcription factor
Myogenesis
IGF2
ZBED6
Cell Differentiation
Cell Cycle Checkpoints
female genital diseases and pregnancy complications
Cell biology
Mitochondria
Up-Regulation
mitochondria
Repressor Proteins
030104 developmental biology
Gene Expression Regulation
C2C12
030217 neurology & neurosurgery
Biotechnology
Signal Transduction
Zdroj: FASEB journal : official publication of the Federation of American Societies for Experimental BiologyREFERENCES. 34(8)
ISSN: 1530-6860
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: