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Histone deacetylase 3 unconventional splicing mediates endothelial-to-mesenchymal transition through transforming growth factor ?2.


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 HD3?, -?, -?, and -?, respectively. HD3? was confirmed in stem cell differentiation by specific antibody against the sequences from intron 12. Immunofluorescence staining indicated that the HD3? isoform co-localized with CD31-positive or ?-smooth muscle actin-positive cells at different developmental stages of mouse embryos. Overexpression of HD3? reprogrammed human aortic endothelial cells into mesenchymal cells featuring an endothelial-to-mesenchymal transition (EndMT) phenotype. HD3? directly interacts with HDAC3 and Akt1 and selectively activates transforming growth factor ?2 (TGF?2) secretion and cleavage. TGF?2 functioned as an autocrine and/or paracrine EndMT factor. The HD3?-induced EndMT was both PI3K/Akt- and TGF?2-dependent. This study provides the first evidence of the role of HDAC3 splicing in the maintenance of endothelial integrity.

SUBMITTER: Zeng L 

PROVIDER: S-EPMC3814778 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Histone deacetylase 3 unconventional splicing mediates endothelial-to-mesenchymal transition through transforming growth factor β2.

Zeng Lingfang L   Wang Gang G   Ummarino Dario D   Margariti Andriana A   Xu Qihe Q   Xiao Qingzhong Q   Wang Wen W   Zhang Zhongyi Z   Yin Xiaoke X   Mayr Manuel M   Cockerill Gillian G   Li Julie Yi-shuan JY   Chien Shu S   Hu Yanhua Y   Xu Qingbo Q  

The Journal of biological chemistry 20130917 44


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  ...[more]

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