Pax7BP, a novel Pax7-binding protein, bridges Pax7 and the H3K4 histone methyltransferase complex and mediates the expression of Pax7 target genes in myoblasts.

摘要

Muscle satellite cells (i.e., muscle stem cells) are mainly responsible for postnatal muscle growth and regeneration. Pax7, a transcription factor of the paired-domain-containing proteins, is preferentially expressed in the quiescent muscle satellite cell and proliferating myoblast. In Pax7-/- mice, satellite cells are gradually lost in the first two weeks after birth and Pax7-/- muscles are defective in injury-induced muscle regeneration. However, the exact function of Pax7 remains unclear. To help understand how Pax7 functions in muscle differentiation and regeneration, we carried out a yeast two-hybrid screening to look for Pax7-interacting proteins. Pax7 Binding Protein (Pax7BP), a previously uncharacterized protein, was found to specifically interact with Pax7 in both yeast cells and mouse muscle tissues. Pax7BP is a nuclear protein and ubiquitously expressed. In adult skeletal muscles, Pax7BP is enriched in muscle satellite cells rather than mature myofibers. Pax7 was recently shown to be associated with a H3K4 histone methyltransferase (HMT) complex that is important for the Pax7-mediated gene expression. Pax7BP physically links Pax7 to the HMT complex through WDR5. Importantly, the Pax7-associated HMT activity is absolutely dependent on Pax7BP. Similar to the effects of Pax7 siRNA, knockdown of Pax7BP in primary myoblasts slowed down cell proliferation and inhibited the expression of Id3, a direct target gene of Pax7. Collectively, Pax7BP functions as an adaptor protein to recruit the H3K4 HMT complex to the Pax7 binding sites, resulting in increased transcription of Pax7 target genes and enhanced proliferation of primary myoblast.