Dataset Information

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]

PMID: 24045946

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Project description:Epithelial-mesenchymal transition (EMT) occurs in several disease states, including renal fibrosis and carcinogenesis. Myofibroblasts produced from EMT of renal tubular cells are responsible for the deposition of extracellular matrix components in a large portion of renal interstitial fibrosis. Transforming growth factor-beta (TGF-beta) plays an essential role in the EMT of renal tubular cells, but the molecular mechanism governing this process remains largely unknown. In this study, we found that RGC-32 (response gene to complement 32) is critical for TGF-beta-induced EMT of human renal proximal tubular cells (HPTCs). RGC-32 is not normally expressed in the HPTCs. However, TGF-beta stimulation markedly activates RGC-32 while inducing an EMT, as shown by the induction of smooth muscle alpha-actin (alpha-SMA) and extracellular matrix proteins collagen I and fibronectin, as well as the reduction of epithelial marker E-cadherin. TGF-beta function is mediated by several signaling pathways, but RGC-32 expression in HPTCs appears to be mainly regulated by Smad. Functionally, RGC-32 appears to mediate TGF-beta-induced EMT of HPTCs. Blockage of RGC-32 using short hairpin interfering RNA significantly inhibits TGF-beta induction of myofibroblast marker gene alpha-SMA while repressing the expression of E-cadherin. In contrast, overexpression of RGC-32 induces alpha-SMA expression while restoring E-cadherin. RGC-32 also inhibits the expression of another adherens junction protein, N-cadherin, suggesting that RGC-32 alone induces the phenotypic conversion of renal epithelial cells to myofibroblasts. Additional studies show that RGC-32 stimulates the production of extracellular matrix components fibronectin and collagen I. Mechanistically, RGC-32 induces EMT via the activation of other transcription factors such as Snail and Slug. RGC-32 knockdown inhibits the expression of Snail and Slug during TGF-beta-induced EMT. Taken together, our data demonstrate for the first time that RGC-32 plays a critical role in TGF-beta-induced EMT of renal tubular cells.

Dataset Information

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

Publications

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

Similar Datasets

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