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

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 <i>in vivo</i>. Satellite cell-specific <i>Klf5</i> deletion severely impaired muscle regeneration, and myotube formation was suppressed in <i>Klf5</i>-deleted cultured C2C12 myoblasts and satellite cells. <i>Klf5</i> 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.