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Status |
Public on Apr 12, 2019 |
Title |
Elevated Endothelial Sox2 Causes Lumen Disruption and Cerebral AVMs |
Organism |
Mus musculus |
Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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Summary |
Lumen integrity in vascularization requires fully differentiated endothelial cells (ECs). Here, we report that endothelial-mesenchymal transitions (EndMTs) emerged in ECs of cerebral arteriovenous malformation (AVMs) and caused disruption of the lumen or lumen disorder. We show that excessive Sry-box 2 (Sox2) signaling was responsible for the EndMTs in cerebral AVMs. EC-specific suppression of Sox2 normalized endothelial differentiation and lumen formation, and improved the cerebral AVMs. Epigenetic studies showed that induction of Sox2 altered the cerebral-endothelial transcriptional landscape, and identified jumonji domain-containing protein 5 (JMJD5) as a direct target of Sox2. Sox2 interacted with JMJD5 to induce EndMTs in cerebral ECs. Furthermore, we utilized a high throughput system to identify the beta-adrenergic antagonist pronethalol as an inhibitor of Sox2 expression. Treatment with pronethalol stabilized endothelial differentiation and lumen formation, which limited the cerebral AVMs.
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Overall design |
Discovery of histone modifications and Sox2 binding in cerebral endothelial cells (ECs) from Mgp knockout and wild type mice.
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Contributor(s) |
Yao J, Wu X |
Citation(s) |
31232700 |
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Submission date |
Apr 11, 2019 |
Last update date |
Aug 27, 2019 |
Contact name |
Yucheng Yao |
Organization name |
UCLA
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Street address |
650 Charles Young Dr East, CHS A2-237
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City |
Los Angeles |
State/province |
CA |
ZIP/Postal code |
90095 |
Country |
USA |
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Platforms (1) |
GPL21493 |
Illumina HiSeq 3000 (Mus musculus) |
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Samples (6)
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Relations |
BioProject |
PRJNA532381 |
SRA |
SRP192021 |