Zac1, a zinc finger transcription factor, is a direct Pax7 target gene in post-natal myogenesis

Abstract

Pax7 plays an essential role in the commitment, survival and expansion of myogenic progenitors during postnatal muscle growth and regeneration. Recently, our genome-wide expression study in myoblasts identified Myf5 and Zac1 (PlagL1; encoding a zinc-finger transcription factor) as transcripts regulated by Pax7. Zac1 has been previously identified as a tumour suppressor showing anti-proliferative properties through regulation of apoptosis and cell cycle arrest. Zac1 expression paralleled that of Pax7 during myogenic progression, with both genes being expressed at high levels in proliferating primary myoblasts but being rapidly down-regulated during cell-cycle arrest and terminal differentiation. Genome wide protein-DNA interaction profiling and chromatin immunoprecipitation assays have identified a region bound by Pax7 at +11 kb from the Zac1 transcriptional start. This region contains a novel Pax7 consensus sequence that is conserved across species and is functionally activated by the Pax7/FKHR fusion protein. Together these data support the assertion that Zac1 is directly activated by Pax7. Regeneration assays conducted in Zac1-null mice indicate a critical role for Zac1 in mediating efficient regenerative myogenesis. Further elucidation of the functional regulation of Zac1 by Pax7 will provide important insight into the mechanism by which Pax7 defines the cellular phenotype of myogenic progenitors.