title: Eukaryotic initiation factor 6 modulates myofibroblast differentiation at transforming growth factor-β1 transcription level via H2A.Z occupancy and Sp1 recruitment.
abstract: 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-β1 (TGF-β1) 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-β1 promoter by H2A.Z (Swiss-Prot P0C0S6) 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-smooth muscle actin (α-SMA)(+) myofibroblasts after skin injury. Overall, our data reveal 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.
authors.affiliation: Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, The Third Military Medical University, Chongqing 400038, People's Republic of China Chongqing Key Laboratory for Disease Proteomics, Chongqing 400038, People's Republic of China.
authors.forename: Si-si
authors.initials: SS
authors.lastname: Yang
authors.affiliation: Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, The Third Military Medical University, Chongqing 400038, People's Republic of China Chongqing Key Laboratory for Disease Proteomics, Chongqing 400038, People's Republic of China.
authors.forename: Jiang-lin
authors.initials: JL
authors.lastname: Tan
authors.affiliation: Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, The Third Military Medical University, Chongqing 400038, People's Republic of China Chongqing Key Laboratory for Disease Proteomics, Chongqing 400038, People's Republic of China.
authors.forename: Dai-song
authors.initials: DS
authors.lastname: Liu
authors.affiliation: Department of Biology, University 'Tor Vergata', Via Ricerca Scientifica, Roma 00133, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Loreni
authors.affiliation: Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, The Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: Xu
authors.initials: X
authors.lastname: Peng
authors.affiliation: Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, The Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: Qing-qing
authors.initials: QQ
authors.lastname: Yang
authors.affiliation: Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, The Third Military Medical University, Chongqing 400038, People's Republic of China Chongqing Key Laboratory for Disease Proteomics, Chongqing 400038, People's Republic of China.
authors.forename: Wei-feng
authors.initials: WF
authors.lastname: He
authors.affiliation: Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, The Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: Zhi-hui
authors.initials: ZH
authors.lastname: Yao
authors.affiliation: Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, The Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: Xiao-Rong
authors.initials: XR
authors.lastname: Zhang
authors.affiliation: Histology and Embryology Section, Department of Life and Reproduction Sciences, University of Verona Medical School, Verona 37134, Venetia, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Dal Prà
authors.affiliation: Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, The Third Military Medical University, Chongqing 400038, People's Republic of China Chongqing Key Laboratory for Disease Proteomics, Chongqing 400038, People's Republic of China logxw@yahoo.com junwupro@126.com.
authors.forename: Gao-xing
authors.initials: GX
authors.lastname: Luo
authors.affiliation: Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, The Third Military Medical University, Chongqing 400038, People's Republic of China Chongqing Key Laboratory for Disease Proteomics, Chongqing 400038, People's Republic of China logxw@yahoo.com junwupro@126.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics* / Q000502:physiology; D002478:Cells, Cultured; D051379:Mice; D008817:Mice, Mutant Strains; D058628:Myofibroblasts / Q000166:cytology* / Q000378:metabolism*; D010448:Peptide Initiation Factors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000235:genetics*
chemical_list: D010448:Peptide Initiation Factors; D016329:Sp1 Transcription Factor; D053773:Transforming Growth Factor beta1; C021019:eIF-6
keywords: Epigenetic regulation; H2A.Z; Myofibroblast differentiation; Sp1; TGF-β1; eIF6