Open AccessWilms' tumour 1‐associating protein inhibits endothelial cell angiogenesis by m6A‐dependent epigenetic silencing of desmoplakin in brain arteriovenous malformation
Author(s) -
Wang Linjian,
Xue Yimeng,
Li Hao,
Huo Ran,
Yan Zihan,
Wang Jie,
Xu Hongyuan,
Wang Jia,
Cao Yong,
Zhao Jizong
Publication year - 2020
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.15101
Subject(s) - angiogenesis , biology , cancer research , endothelial stem cell , desmoplakin , microbiology and biotechnology , pathology , medicine , cell , in vitro , genetics
Brain arteriovenous malformations (AVMs) are congenital vascular abnormality in which arteries and veins connect directly without an intervening capillary bed. So far, the pathogenesis of brain AVMs remains unclear. Here, we found that Wilms' tumour 1‐associating protein (WTAP), which has been identified as a key subunit of the m6A methyltransferase complex, was down‐regulated in brain AVM lesions. Furthermore, the lack of WTAP could inhibit endothelial cell angiogenesis in vitro. In order to screen for downstream targets of WTAP, we performed RNA transcriptome sequencing (RNA‐seq) and Methylated RNA Immunoprecipitation Sequencing technology (MeRIP‐seq) using WTAP‐deficient and control endothelial cells. Finally, we determined that WTAP regulated Desmoplakin (DSP) expression through m6A modification, thereby affecting angiogenesis of endothelial cells. In addition, an increase in Wilms' tumour 1 (WT1) activity caused by WTAP deficiency resulted in substantial degradation of β‐catenin, which might also inhibit angiogenesis of endothelial cells. Collectively, our findings revealed the critical function of WTAP in angiogenesis and laid a solid foundation for the elucidation of the pathogenesis of brain AVMs.