Histone Deacetylase 3 Unconventional Splicing Mediates Endothelial-to-mesenchymal Transition through Transforming Growth Factor β2

Lingfang Zeng, Gang Wang, Dario Ummarino, Andriana Margariti, Qihe Xu, Qingzhong Xiao, Wen Wang, Zhongyi Zhang, Xiaoke Yin, Manuel Mayr, Gillian Cockerill, Julie Yi-shuan Li, Shu Chien, Yanhua Hu, Qingbo Xu

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)

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 ?-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. TGF?2 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.
Original languageEnglish
Article numberN/A
Pages (from-to)31853-31866
Number of pages14
JournalJournal of Neuroscience, Journal of Biological Chemistry
Volume288
Issue number44
DOIs
Publication statusPublished - 1 Nov 2013

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