N6-methyladenosine methyltransferase METTL3 affects the phenotype of cerebral arteriovenous malformation via modulating Notch signaling pathway
Open Access
- 9 May 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Journal of Biomedical Science
- Vol. 27 (1), 1-13
- https://doi.org/10.1186/s12929-020-00655-w
Abstract
Cerebral arteriovenous malformation (AVM) is a serious life-threatening congenital cerebrovascular disease. Specific anatomical features, such as nidus size, location, and venous drainage, have been validated to affect treatment outcomes. Until recently, molecular biomarkers and corresponding molecular mechanism related to anatomical features and treatment outcomes remain unknown. RNA N6-methyladenosine (m6A) Methyltransferase METTL3 was identified as a differentially expressed gene in groups with different lesion sizes by analyzing the transcriptome sequencing (RNA-seq) data. Tube formation and wound healing assays were performed to investigate the effect of METTL3 on angiogenesis. In addition, Methylated RNA Immunoprecipitation Sequencing technology (MeRIP-seq) was performed to screen downstream targets of METTL3 in endothelial cells and to fully clarify the specific underlying molecular mechanisms affecting the phenotype of cerebral AVM. In the current study, we found that the expression level of METTL3 was reduced in the larger pathological tissues of cerebral AVMs. Moreover, knockdown of METTL3 significantly affected angiogenesis of the human endothelial cells. Mechanistically, down-regulation of METTL3 reduced the level of heterodimeric Notch E3 ubiquitin ligase formed by DTX1 and DTX3L, thereby continuously activating the Notch signaling pathway. Ultimately, the up-regulated downstream genes of Notch signaling pathway dramatically affected the angiogenesis of endothelial cells. In addition, we demonstrated that blocking Notch pathway with DAPT could restore the phenotype of METTL3 deficient endothelial cells. Our findings revealed the mechanism by which m6A modification regulated the angiogenesis and might provide potential biomarkers to predict the outcome of treatment, as well as provide suitable pharmacological targets for preventing the formation and progression of cerebral AVM.Keywords
Funding Information
- “13th Five-Year Plan” National Science and Technology supporting plan (2015BAI12B04)
- Beijing Science and Technology Supporting Plan (D16110000381605)
- Beijing Municipal Administration of Hospitals’ Mission plan (SML20150501)
This publication has 51 references indexed in Scilit:
- Target Gene Analysis by Microarrays and Chromatin Immunoprecipitation Identifies HEY Proteins as Highly Redundant bHLH RepressorsPLoS Genetics, 2012
- Historical Perspective of Treatments of Cranial Arteriovenous Malformations and Dural Arteriovenous FistulasNeurosurgery Clinics of North America, 2012
- Notch4 Normalization Reduces Blood Vessel Size in Arteriovenous MalformationsScience Translational Medicine, 2012
- Integration of a Notch-dependent mesenchymal gene program and Bmp2-driven cell invasiveness regulates murine cardiac valve formationJCI Insight, 2010
- Notch1 activation in mice causes arteriovenous malformations phenocopied by ephrinB2 and EphB4 mutantsgenesis, 2010
- Notch-1 signalling is activated in brain arteriovenous malformations in humansBrain, 2009
- Endothelial Notch signaling is upregulated in human brain arteriovenous malformations and a mouse model of the diseaseLaboratory Investigation, 2009
- The Canonical Notch Signaling Pathway: Unfolding the Activation MechanismCell, 2009
- Chapter 17 Messenger RNA Half‐Life Measurements in Mammalian CellsMethods in Enzymology, 2008
- Developmental patterning of the cardiac atrioventricular canal by Notch and Hairy-related transcription factorsDevelopment, 2006