Elevated Endothelial Sox2 Causes Lumen Disruption and Cerebral AVMs
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA532381 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8882360.fastq.gz | Fastqsanger.gz | |||
| SRR8882361.fastq.gz | Fastqsanger.gz | |||
| SRR8882362.fastq.gz | Fastqsanger.gz | |||
| SRR8882363.fastq.gz | Fastqsanger.gz | |||
| SRR8882364.fastq.gz | Fastqsanger.gz |
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Project description: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.
2019-04-12 | GSE129644 | GEO
Project description: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 β-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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Project description:Cerebral organoids have emerged as faithful humanoid avatars for modeling numerous advanced neurodevelopmental and pathological processes and additionally serve as a powerful discovery platform for less well-characterized neurobiological programs. Towards this later prospect, we leveraged mass spectrometry-based proteomics to molecularly profile precursor and more committed neural compartments of both human-derived organoids and mid-gestation fetal brain tissue to define overlapping protein-level programs. Interestingly, this included numerous precursor-enriched transcriptional regulatory proteins that were notably not found to be differentially expressed in previous transcriptomic datasets. Specifically, we show that the RuvB-like 2 (RUVBL2) AAA-type ATPase is preferentially expressed in the SOX2-positive compartment of organoids and chemical inactivation leads to precursor cell displacement and apoptosis within the more mature DCX-positive niche. To explore potential clinicopathological correlates of this disruption in organoid cytoarchitecture, we interrogated various clinical datasets, and identified de novo deletions, missense mutations and a novel recurring tandem duplication involving RUVBL2 in patients diagnosed with neurodevelopmental and autism spectrum disorders. Together, our study demonstrates how cell-type specific and phenotype-level profiling of cerebral organoids can help nominate and implicate previously unappreciated genes in neurodevelopment and disease.
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Project description:The pluripotency transcription factor SOX2 is essential for the maintenance of glioblastoma stem cells (GSC), which drive tumor growth and treatment resistance.To understand how SOX2 is regulated in GSCs, we utilized a proteomic approach and identified the E3 ubiquitin ligase TRIM26 as a direct SOX2-interacting protein. Unexpectedly, we found TRIM26 depletion decreased SOX2 protein levels and increased SOX2 polyubiquitination in patient-derived GSCs, suggesting TRIM26 promotes SOX2 protein stability. Accordingly, TRIM26 knockdown reduced SOX2 transcriptional activity, self-renewal capacity, and in vivo tumorigenicity in multiple GSC lines. Mechanistically, we found TRIM26, via its C-terminal PRYSPRY domain, but independent of its RING domain, stabilizes SOX2 protein by directly inhibiting the interaction of SOX2 with WWP2, which we identify as a bona fide SOX2 E3 ligase in GSCs. Our work identifies E3 ligase competition as a critical mechanism of SOX2 regulation, with functional consequences for GSC identity and maintenance.
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