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Series GSE139092 Query DataSets for GSE139092
Status Public on Oct 19, 2019
Title VE-Cadherin-Mediated Epigenetic Regulation of Endothelial Gene Expression
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Rationale: The mechanistic foundation of vascular maturation is still largely unknown. Several human pathologies are characterized by deregulated angiogenesis and unstable blood vessels. Solid tumours, for instance, get their nourishment from newly formed structurally abnormal vessels which present wide and irregular inter-endothelial junctions. Expression and clustering of the main endothelial-specific adherens junction protein, vascular endothelial (VE)-cadherin (VEC), upregulate genes with key roles in endothelial differentiation and stability.
Objective: We aim at understanding the molecular mechanisms through which VEC triggers the expression of a set of genes involved in endothelial differentiation and vascular stabilization.
Methods and Results: We compared a VEC-null cell line with the same line reconstituted with VEC wild type cDNA. VEC expression and clustering upregulated endothelial-specific genes with key roles in vascular stabilization including claudin-5, Vascular Endothelial-Protein Tyrosine Phosphatase (VE-PTP) and von Willebrand factor (vWf). Mechanistically VEC exerts this effect by inhibiting Polycomb protein activity on the specific gene promoters. This is achieved by preventing nuclear translocation of FoxO1 and β-catenin, which contribute to Polycomb repressive complex-2 (PRC2) binding to promoter regions of claudin-5, VE-PTP and vWf. VE-cadherin/β-catenin complex also sequesters a core subunit of PRC2 (Ezh2) at the cell membrane, preventing its nuclear translocation. Inhibition of Ezh2/VE-cadherin association increases Ezh2 recruitment to claudin-5, VE-PTP and vWf promoters, causing gene downregulation. RNAseq comparison of VEC-null and VEC-positive cells suggested a more general role of VE-cadherin in activating endothelial genes and triggering a vascular stability-related gene expression program. In pathological angiogenesis of human ovarian carcinomas, reduced VEC expression paralleled decreased levels of Claudin-5 and VE-PTP. Conclusions: These data extend the knowledge of Polycomb-mediated regulation of gene expression to endothelial cell differentiation and vessel maturation. The identified mechanism opens novel therapeutic opportunities to modulate endothelial gene expression and induce vascular normalization through pharmacological inhibition of the Polycomb-mediated repression system. Keywords: Polycomb, endothelial cells, VE-cadherin, vessel maturation, vascular biology, vascular permeability, cell signalling, epigenetics, gene regulation. Downloaded from http://circres.ahajour
Conclusions: These data extend the knowledge of Polycomb-mediated regulation of gene expression to endothelial cell differentiation and vessel maturation. The identified mechanism opens novel therapeutic opportunities to modulate endothelial gene expression and induce vascular normalization through pharmacological inhibition of the Polycomb-mediated repression system
 
Overall design mRNA expression profiles are generated in triplicate from VEC-null cell line and VEC-positive cell line ( VEC-positive cell line were generated by indroducing wild type form of VEC into VEC-null cells)
 
Contributor(s) Morini MF, Giampietro C, Corada M, Pisati F, Lavarone E, Cunha SI, Conze LL, O’Reilly N, Joshi D, Kjaer S, George R, Nye E, Ma A, Jin J, Mitter R, Lupia M, Cavallaro U, Pasini D, Calado DP, Dejana E, Taddei A
Citation(s) 29233846
Submission date Oct 18, 2019
Last update date Nov 06, 2019
Contact name Elisabetta Dejana
E-mail(s) elisabetta.dejana@igp.uu.se
Organization name Uppsala University
Department Immunology, Genetics and Pathology
Street address Dag Hammarskjolds väg 20
City Uppsala
ZIP/Postal code 751 85
Country Sweden
 
Platforms (1)
GPL17021 Illumina HiSeq 2500 (Mus musculus)
Samples (6)
GSM4130785 VEC_null_1
GSM4130786 VEC_null_2
GSM4130787 VEC_null_3
Relations
BioProject PRJNA578378
SRA SRP226214

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Supplementary file Size Download File type/resource
GSE139092_normGeneCounts.txt.gz 526.4 Kb (ftp)(http) TXT
SRA Run SelectorHelp
Raw data are available in SRA
Processed data are available on Series record

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