The ZBED6-IGF2 axis has a major effect on growth of skeletal muscle and internal organs in placental mammals

Shady Younis, Milena Schönke, Julie Massart, Rikke Hjortebjerg, Elisabeth Sundström, Ulla Gustafson, Marie Björnholm, Anna Krook, Jan Frystyk, Juleen R. Zierath, Leif Andersson*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

A single nucleotide substitution in the third intron of insulin-like growth factor 2 (IGF2) is associated with increased muscle mass and reduced subcutaneous fat in domestic pigs. This mutation disrupts the binding of the ZBED6 transcription factor and leads to a threefold up-regulation of IGF2 expression in pig skeletal muscle. Here, we investigated the biological significance of ZBED6-IGF2 interaction in the growth of placental mammals using two mouse models, ZBED6 knock-out (Zbed6-/-) and Igf2 knock-in mice that carry the pig IGF2 mutation. These transgenic mice exhibit markedly higher serum IGF2 concentrations, higher growth rate, increased lean mass, and larger heart, kidney, and liver; no significant changes were observed for white adipose tissues. The changes in body and lean mass were most pronounced in female mice. The phenotypic changes were concomitant with a remarkable up-regulation of Igf2 expression in adult tissues. Transcriptome analysis of skeletal muscle identified differential expression of genes belonging to the extracellular region category. Expression analysis using fetal muscles indicated a minor role of ZBED6 in regulating Igf2 expression prenatally. Furthermore, transcriptome analysis of the adult skeletal muscle revealed that this elevated expression of Igf2 was derived from the P1 and P2 promoters. The results revealed very similar phenotypic effects in the Zbed6 knock-out mouse and in the Igf2 knock-in mouse, showing that the effect of ZBED6 on growth of muscle and internal organs is mediated through the binding site in the Igf2 gene. The results explain why this ZBED6 binding site is extremely well conserved among placental mammals.

Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number9
Pages (from-to)E2048-E2057
ISSN0027-8424
DOIs
Publication statusPublished - 27. Feb 2018

Keywords

  • IGF2
  • Metabolic regulation
  • Mouse
  • Muscle growth
  • ZBED6
  • Up-Regulation
  • Transcriptome
  • Male
  • Muscle, Skeletal/growth & development
  • Insulin-Like Growth Factor II/physiology
  • Conserved Sequence
  • Female
  • Binding Sites
  • Promoter Regions, Genetic
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Repressor Proteins/genetics
  • DNA Transposable Elements
  • Mice, Knockout
  • Phenotype
  • Animals
  • Sequence Analysis, RNA
  • Alleles
  • CpG Islands
  • Mice

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