title: KLF4 mediates the link between TGF-β1-induced gene transcription and H3 acetylation in vascular smooth muscle cells.
abstract: Transcriptional activation by transcription factors is coupled with histone acetylation and chromatin remodeling. However, the relationship between TGF-β1-induced gene transcription by Krüppel-like factor (KLF)-4 and histone acetylation remains unknown. In our study, KLF4 overexpression or knockdown, respectively increased or decreased H3 acetylation and p300 occupancy, which is concentrated in the region containing TGF-β1 control elements (TCEs) of the genes by TGF-β1 regulation during vascular smooth muscle cell (VSMC) differentiation. Coimmunoprecipitation and glutathione S-transferase pull-down assays showed that phosphatase and tensin homolog (PTEN) formed a complex with KLF4 to inhibit the phosphorylation of the latter in basal conditions. After TGF-β1 signaling activation, PTEN was phosphorylated by p38 MAPK or PI3K/Akt signaling, phosphorylated PTEN lost its ability to dephosphorylate KLF4, and the cofactors interacting with KLF4 switched from PTEN to p300. Then, KLF4-p300 complexes were recruited to KLF4-binding sites of the gene promoter of VSMCs, to acetylate histone H3 and activate transcription. In addition, phosphorylated KLF4 enhanced p300 histone acetyltransferase (HAT) activity via the p38 MAPK pathway, which may be responsible for H3 acetylation. Taken together, the results of our study reveal a novel mechanism whereby KLF4 mediates the link between TGF-β1-induced gene transcription activation and H3 acetylation during VSMC differentiation.
authors.affiliation: *Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, Shijiazhuang, China; and Institute of Chinese Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China.
authors.forename: Ming
authors.initials: M
authors.lastname: He
authors.affiliation: *Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, Shijiazhuang, China; and Institute of Chinese Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zheng
authors.affiliation: *Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, Shijiazhuang, China; and Institute of Chinese Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: *Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, Shijiazhuang, China; and Institute of Chinese Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China.
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Zhang
authors.affiliation: *Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, Shijiazhuang, China; and Institute of Chinese Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China.
authors.forename: Chang
authors.initials: C
authors.lastname: Wang
authors.affiliation: *Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, Shijiazhuang, China; and Institute of Chinese Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Yang
authors.affiliation: *Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, Shijiazhuang, China; and Institute of Chinese Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: *Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, Shijiazhuang, China; and Institute of Chinese Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Wu
authors.affiliation: *Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, Shijiazhuang, China; and Institute of Chinese Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China wjk@hebmu.edu.cn.
authors.forename: Jin-Kun
authors.initials: JK
authors.lastname: Wen
mesh_terms: D000107:Acetylation; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D006657:Histones; C000715468:Klf4 protein, mouse; C000715469:Klf4 protein, rat; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C508961:Tgfb1 protein, mouse; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1
keywords: PTEN; p21 promoter; p300; p38 MAPK; phosphorylation