Wilms' tumour 1‐associating protein inhibits endothelial cell angiogenesis by m6A‐dependent epigenetic silencing of desmoplakin in brain arteriovenous malformation
Open Access
- 13 April 2020
- journal article
- research article
- Published by Wiley in Journal of Cellular and Molecular Medicine
- Vol. 24 (9), 4981-4991
- https://doi.org/10.1111/jcmm.15101
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 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.Keywords
Funding Information
- Beijing Municipal Administration of Hospitals (SML20150501)
This publication has 70 references indexed in Scilit:
- ALKBH5 Is a Mammalian RNA Demethylase that Impacts RNA Metabolism and Mouse FertilityMolecular Cell, 2013
- Comprehensive Analysis of mRNA Methylation Reveals Enrichment in 3′ UTRs and near Stop CodonsCell, 2012
- N6-Methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTONature Chemical Biology, 2011
- Deconstructing the skin: cytoarchitectural determinants of epidermal morphogenesisNature Reviews Molecular Cell Biology, 2011
- Brain Arteriovenous Malformation Pathogenesis: A Response-to-Injury ParadigmActa Neurochirurgica Supplementum, 2011
- The DesmosomeCold Spring Harbor Perspectives in Biology, 2009
- An integrated genome screen identifies the Wnt signaling pathway as a major target of WT1Proceedings of the National Academy of Sciences of the United States of America, 2009
- Chapter 17 Messenger RNA Half‐Life Measurements in Mammalian CellsMethods in Enzymology, 2008
- THE WNT SIGNALING PATHWAY IN DEVELOPMENT AND DISEASEAnnual Review of Cell and Developmental Biology, 2004
- The New York Islands AVM StudyStroke, 2003