title: Histone deacetylase 3 unconventional splicing mediates endothelial-to-mesenchymal transition through transforming growth factor β2.
abstract: Histone deacetylase 3 (HDAC3) plays a critical role in the maintenance of endothelial integrity and other physiological processes. In this study, we demonstrated that HDAC3 undergoes unconventional splicing during stem cell differentiation. Four different splicing variants have been identified, designated as HD3α, -β, -γ, and -δ, respectively. HD3α was confirmed in stem cell differentiation by specific antibody against the sequences from intron 12. Immunofluorescence staining indicated that the HD3α isoform co-localized with CD31-positive or α-smooth muscle actin-positive cells at different developmental stages of mouse embryos. Overexpression of HD3α reprogrammed human aortic endothelial cells into mesenchymal cells featuring an endothelial-to-mesenchymal transition (EndMT) phenotype. HD3α directly interacts with HDAC3 and Akt1 and selectively activates transforming growth factor β2 (TGFβ2) secretion and cleavage. TGFβ2 functioned as an autocrine and/or paracrine EndMT factor. The HD3α-induced EndMT was both PI3K/Akt- and TGFβ2-dependent. This study provides the first evidence of the role of HDAC3 splicing in the maintenance of endothelial integrity.
authors.affiliation: From the Cardiovascular Division, King's College London BHF Centre, 125 Cold Harbour Lane, London SE5 9NU, United Kingdom.
authors.forename: Lingfang
authors.initials: L
authors.lastname: Zeng
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.forename: Dario
authors.initials: D
authors.lastname: Ummarino
authors.forename: Andriana
authors.initials: A
authors.lastname: Margariti
authors.forename: Qihe
authors.initials: Q
authors.lastname: Xu
authors.forename: Qingzhong
authors.initials: Q
authors.lastname: Xiao
authors.forename: Wen
authors.initials: W
authors.lastname: Wang
authors.forename: Zhongyi
authors.initials: Z
authors.lastname: Zhang
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Yin
authors.forename: Manuel
authors.initials: M
authors.lastname: Mayr
authors.forename: Gillian
authors.initials: G
authors.lastname: Cockerill
authors.forename: Julie Yi-shuan
authors.initials: JY
authors.lastname: Li
authors.forename: Shu
authors.initials: S
authors.lastname: Chien
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Hu
authors.forename: Qingbo
authors.initials: Q
authors.lastname: Xu
mesh_terms: D017398:Alternative Splicing / Q000502:physiology*; D000818:Animals; D019898:Autocrine Communication / Q000502:physiology*; D002460:Cell Line; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006655:Histone Deacetylases / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D019899:Paracrine Communication / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D053781:Transforming Growth Factor beta2 / Q000235:genetics / Q000378:metabolism*; D000099186:Histone Deacetylase 3
chemical_list: D006655:Histone Deacetylases; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D053781:Transforming Growth Factor beta2; D000099186:Histone Deacetylase 3; C509041:TGFB2 protein, human; C509042:Tgfb2 protein, mouse; C494918:AKT1 protein, human; C514862:Akt1 protein, mouse
keywords: Cardiovascular; Endothelial Cell; Epithelial to Mesenchymal Transition; Histone Deacetylase; Transforming Growth Factor beta (TGFbeta)
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