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Wilms' tumour 1-associating protein inhibits endothelial cell angiogenesis by m6A-dependent epigenetic silencing of desmoplakin in brain arteriovenous malformation.

ABSTRACT: 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 ?-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.

SUBMITTER: Wang LJ

PROVIDER: S-EPMC7205785 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Wilms' tumour 1-associating protein inhibits endothelial cell angiogenesis by m6A-dependent epigenetic silencing of desmoplakin in brain arteriovenous malformation.

Wang Lin-Jian LJ Xue Yimeng Y Li Hao H Huo Ran R Yan Zihan Z Wang Jie J Xu Hongyuan H Wang Jia J Cao Yong Y Zhao Ji-Zong JZ

Journal of cellular and molecular medicine 20200413 9

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 sc ...[more]

PMID: 32281240

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Project description:BACKGROUND:Pulmonary arteriovenous malformations are abnormal direct connections between the pulmonary artery and pulmonary vein which result in a right-to-left shunt. They are associated with substantial morbidity and mortality mainly from the effects of paradoxical emboli. Potential complications include stroke, cerebral abscess, pulmonary haemorrhage and hypoxaemia. Embolisation is an endovascular intervention based on the occlusion of the feeding arteries the pulmonary arteriovenous malformations thus eliminating the abnormal right-to-left-shunting. This is an update of a previously published review. OBJECTIVES:To determine the efficacy and safety of embolisation in patients with pulmonary arteriovenous malformations including a comparison with surgical resection and different embolisation devices. SEARCH METHODS:We searched the Cystic Fibrosis and Genetic Disorders Group's Trials Register; date of last search: 10 April 2017.We also searched the following databases: the Australian New Zealand Clinical Trials Registry; ClinicalTrials.gov; International Standard Randomised Controlled Trial Number Register; International Clinical Trials Registry Platform Search Portal (last searched 27 August 2017). to be updatedWe checked cross-references and searched references from review articles. SELECTION CRITERIA:Trials in which individuals with pulmonary arteriovenous malformations were randomly allocated to embolisation compared to no treatment, surgical resection or embolisation using a different embolisation device. DATA COLLECTION AND ANALYSIS:Studies identified for potential inclusion were independently assessed for eligibility by two authors, with excluded studies further checked by a third author. No trials were identified for inclusion in the review and hence no analysis was performed. MAIN RESULTS:There were no randomised controlled trials included in the review; one ongoing trial has been identified which may be eligible for inclusion in the future. AUTHORS' CONCLUSIONS:There is no evidence from randomised controlled trials for embolisation of pulmonary arteriovenous malformations. However, randomised controlled trials are not always feasible on ethical grounds. Accumulated data from observational studies suggest that embolisation is a safe procedure which reduces morbidity and mortality. A standardised approach to reporting with long-term follow-up through registry studies can help to strengthen the evidence for embolisation in the absence of randomised controlled trials.

Dataset Information

Wilms' tumour 1-associating protein inhibits endothelial cell angiogenesis by m6A-dependent epigenetic silencing of desmoplakin in brain arteriovenous malformation.

Publications

Wilms' tumour 1-associating protein inhibits endothelial cell angiogenesis by m6A-dependent epigenetic silencing of desmoplakin in brain arteriovenous malformation.

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