Incongruence between transcriptional and vascular pathophysiological cell states I
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PROVIDER: PRJNA955832 | ENA |
REPOSITORIES: ENA
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Project description:Incongruence between transcriptional and vascular pathophysiological cell states
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Project description:Incongruence between transcriptional and vascular pathophysiological cell states II
| PRJNA967006 | ENA
Project description:The Notch pathway is a major regulator of endothelial transcriptional specification. Targeting the Notch receptors or the ligand Dll4 dysregulates angiogenesis. Here, by analyzing single and compound genetic mutants for all Notch signaling members, we find significant differences in the way ligands and receptors regulate liver vascular homeostasis. Loss of Notch receptors caused endothelial hypermitogenic cell-cycle arrest and senescence. Conversely, Dll4 loss triggered a strong Myc-driven transcriptional switch, inducing endothelial proliferation and the tip-cell state. Myc loss suppressed the induction of angiogenesis in the absence of Dll4, without preventing the vascular enlargement and organ pathology. Similarly, inhibition of other pro-angiogenic pathways, including MAPK/ERK and mTor, had no effect on the vascular expansion induced by Dll4 loss; however, anti-VEGFA treatment prevented it without fully suppressing the transcriptional and metabolic programs. This study shows incongruence between single-cell transcriptional states, vascular phenotypes, and related pathophysiology. Our findings also suggest that vascular structure abnormalization, rather than neoplasms, causes the reported anti-Dll4 antibody toxicity.
2023-05-12 | GSE231612 | GEO
Project description:The Notch pathway is a major regulator of endothelial transcriptional specification. Targeting the Notch receptors or the ligand Dll4 induces angiogenesis. Here, by analyzing single and compound genetic mutants for all Notch signaling members, we find significant differences in the way ligands and receptors regulate liver vascular homeostasis. Loss of Notch receptors caused endothelial hypermitogenic cell-cycle arrest and senescence. Conversely, Dll4 loss triggered a strong Myc-driven transcriptional switch inducing endothelial proliferation and the tip-cell state. Myc loss suppressed the induction of angiogenesis in the absence of Dll4, without preventing the vascular enlargement and organ pathology. Similarly, inhibition of other pro-angiogenic pathways, including MAPK/ERK and mTor, had no effect on the vascular expansion induced by Dll4 loss, however, anti-VEGFA treatment prevented it without fully suppressing the transcriptional and metabolic programs. This study shows incongruence between single-cell transcriptional states, vascular phenotypes, and related pathophysiology. Our findings also suggest that the vascular structure abnormalization, rather than neoplasms, causes the reported anti-Dll4 antibody toxicity.
2023-05-12 | GSE229793 | GEO
Project description:The Notch pathway is a major regulator of endothelial transcriptional specification. Targeting the Notch receptors or Delta-like ligand 4 (Dll4) dysregulates angiogenesis. Here, by analyzing single and compound genetic mutants for all Notch signaling members, we find significant differences in the way ligands and receptors regulate liver vascular homeostasis. Loss of Notch receptors caused endothelial hypermitogenic cell-cycle arrest and senescence. Conversely, Dll4 loss triggered a strong Myc-driven transcriptional switch inducing endothelial proliferation and the tip-cell state. Myc loss suppressed the induction of angiogenesis in the absence of Dll4, without preventing the vascular enlargement and organ pathology. Similarly, inhibition of other pro-angiogenic pathways, including MAPK/ERK and mTOR, had no effect on the vascular expansion induced by Dll4 loss; however, anti-VEGFA treatment prevented it without fully suppressing the transcriptional and metabolic programs. This study shows incongruence between single-cell transcriptional states, vascular phenotypes and related pathophysiology. Our findings also suggest that the vascular structure abnormalization, rather than neoplasms, causes the reported anti-Dll4 antibody toxicity.
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Project description:This SuperSeries is composed of the SubSeries listed below.
2023-05-12 | GSE231613 | GEO
Project description:Vascular endothelial dysfunction underlies the genesis and progression of numerous diseases. Whereas the GATA transcription factor GATA-2 is expressed in endothelial cells and is implicated in coronary heart disease, it has been studied predominantly as a master regulator of hematopoiesis. As many questions remain unanswered regarding GATA-2 function in the vascular biology realm, we used ChIP-seq and loss-of-function strategies to define the GATA-2-instigated genetic network in human endothelial cells. By contrast to erythroid cells, GATA-2 occupied a unique target gene ensemble, consisting of genes encoding key determinants of endothelial cell identity and inflammation. GATA-2-occupied sites characteristically contained motifs that bind Activator Protein-1 (AP-1), a pivotal regulator of inflammatory genes. GATA-2 frequently occupied the same chromatin sites as c-JUN and c-FOS, heterodimeric components of AP-1. Though all three components were required for maximal AP-1 target gene expression, GATA-2 was not required for AP-1 chromatin occupancy. GATA-2 conferred maximal phosphorylation of chromatin-bound c-JUN at Ser 73, which stimulates AP-1-dependent transactivation, in a chromosomal context-dependent manner. This work establishes a link between a GATA factor and inflammation, mechanistic insights underlying GATA-2-AP-1 cooperativity, and a rigorous genetic framework for understanding GATA-2 function in normal and pathophysiological vascular states. For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODEDataReleasePolicyFinal2008.pdf Examination of GATA2 ChIP-seq in HUVEC cells.
2011-08-11 | E-GEOD-29531 | biostudies-arrayexpress
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2023-12-12 | GSE228900 | GEO