Journal
JOURNAL OF CELL SCIENCE
Volume 128, Issue 21, Pages 3977-3989Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.174870
Keywords
eIF6; Myofibroblast differentiation; TGF-beta 1; Sp1; H2A.Z; Epigenetic regulation
Categories
Funding
- National High-Tech R&D Program (863 Program) [2012AA020504]
- National Natural Science Foundation of China [81372082, 81373155, 81401603]
- Key Project of Military Plan [AWS11J012-05]
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Eukaryotic initiation factor 6 (eIF6) is a pivotal regulator of ribosomal function, participating in translational control. Previously our data suggested that eIF6 acts as a key binding protein of P311 (a hypertrophic scar-related protein; also known as NREP). However, a comprehensive investigation of its functional role and the underlying mechanisms in modulation of myofibroblast (a key effector of hypertrophic scar formation) differentiation remains unclear. Here, we identified that eIF6 is a novel regulator of transforming growth factor-beta 1 (TGF-beta 1) expression at transcription level, which plays a key role in myofibroblast differentiation. Mechanistically, this effect is associated with eIF6 altering the occupancy of the TGF-beta 1 promoter by H2A.Z (Swiss-Prot P0C0S6) and Sp1. Accordingly, modulation of eIF6 expression in myofibroblasts significantly affects their differentiation via the TGF-beta/Smad signaling pathway, which was verified in vivo by the observation that heterozygote eIF6(+/-) mice exhibited enhanced TGF-beta 1 production coupled with increased alpha-smooth muscle actin (alpha-SMA)(+) myofibroblasts after skin injury. Overall, our data reveal a novel transcriptional regulatory mechanism of eIF6 that acts on facilitating Sp1 recruitment to TGF-beta 1 promoter via H2A.Z depletion and thus results in increased TGF-beta 1 transcription, which contributes to myofibroblast differentiation.
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