Klf5 regulates muscle differentiation by directly targeting muscle-specific genes in cooperation with MyoD in mice

Elife. 2016 Oct 15;5:e17462. doi: 10.7554/eLife.17462.

Abstract

Krüppel-like factor 5 (Klf5) is a zinc-finger transcription factor that controls various biological processes, including cell proliferation and differentiation. We show that Klf5 is also an essential mediator of skeletal muscle regeneration and myogenic differentiation. During muscle regeneration after injury (cardiotoxin injection), Klf5 was induced in the nuclei of differentiating myoblasts and newly formed myofibers expressing myogenin in vivo. Satellite cell-specific Klf5 deletion severely impaired muscle regeneration, and myotube formation was suppressed in Klf5-deleted cultured C2C12 myoblasts and satellite cells. Klf5 knockdown suppressed induction of muscle differentiation-related genes, including myogenin. Klf5 ChIP-seq revealed that Klf5 binding overlaps that of MyoD and Mef2, and Klf5 physically associates with both MyoD and Mef2. In addition, MyoD recruitment was greatly reduced in the absence of Klf5. These results indicate that Klf5 is an essential regulator of skeletal muscle differentiation, acting in concert with myogenic transcription factors such as MyoD and Mef2.

Keywords: Krüppel-like factor; developmental biology; mouse; muscle differentiation; muscle regeneration; satellite cell; stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiotoxins / administration & dosage
  • Cell Differentiation / genetics*
  • Cell Proliferation / genetics
  • Kruppel-Like Transcription Factors / genetics*
  • MEF2 Transcription Factors / genetics
  • Mice
  • Muscle Development / genetics
  • Muscle, Skeletal / growth & development
  • Muscle, Skeletal / metabolism
  • MyoD Protein / genetics*
  • MyoD Protein / metabolism
  • Protein Binding
  • Regeneration / genetics
  • Satellite Cells, Skeletal Muscle

Substances

  • Cardiotoxins
  • Klf5 protein, mouse
  • Kruppel-Like Transcription Factors
  • MEF2 Transcription Factors
  • Mef2a protein, mouse
  • MyoD Protein
  • MyoD1 myogenic differentiation protein

Grant support

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.