eIF6 modulates myofibroblast differentiation at TGF-β1 transcription level via H2A.Z occupancy and Sp1 recruitment

Eukaryotic initiation factor 6 (eIF6) is a pivotal regulator of ribosomal function, participating in translational control. Previously our data suggest that eIF6 acts as a key binding protein of P311 (a hypertrophic scar-related protein). However, a comprehensive investigation of its functional role and the underlying mechanisms in modulation myofibroblast (a key effector of hypertrophic scar formation) differentiation remains unclear. Here, we identified that eIF6 is a novel regulator of the TGF-β1 expression at transcription level, which has a key role in myofibroblast differentiation. Mechanistically, this effect is associated with eIF6 altering the occupancy of the TGF-β1 promoter by H2A.Z and Sp1. Accordingly, modulation of eIF6 expression in myofibroblasts significantly affects their differentiation via the TGF-β/Smad signaling pathway, which was verified in vivo by the observation that heterozygote eIF6(+/-) mice exhibited enhanced TGF-β1 production coupled with increased α-SMA(+) myofibroblasts after skin injury. Overall, our data reveal that a novel transcriptional regulatory mechanism of eIF6 that acts on facilitating Sp1 recruitment to TGF-β1 promoter via H2A.Z depletion and thus results in increased TGF-β1 transcription, which contributes to myofibroblast differentiation.