Genome wide analysis of differential gene expression of PFKFB3 under- or overexpression upon inhibition or activation of notch signaling in endothelial cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Bert Cruys
PROVIDER: E-GEOD-45750 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Analysis of gene expression profiles upon PFKFB3 under- or overexpression during inhibition or activation of notch signaling. With this experiment we aimed to identify whether alterations in PFKFB3 could influence the expression pattern of angiogenic genes in conditions that favor a tip- or stalk cell gene signature.
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Project description:To identify previously unknown determinants of endothelial cell sprouting, we defined and exploited a pharmacological strategy for the manipulation of angiogenic cell behavior in vivo. Whereas high vascular endothelial growth factor receptor (Vegfr) signaling is known to promote tip cell (TC) specification, activation of the Notch receptor via its ligand Delta-like 4 (Dll4) represses the TC phenotype to promote stalk cell (SC) fate. Conversely, suppression of Notch activity upon antagonistic interaction with its ligand Jagged1 pro- motes TC formation. Hence, specification of TCs involves tight spatiotemporal control of Vegfr/Notch signaling. Consequently, we hypothesized that the pharmacological manipulation of Vegfr/Notch signaling selectively during zebrafish intersegmental vessel (ISV) angiogenesis would enable the precise control of angiogenic EC behavior and sprouting- associated gene expression in vivo. For more information, see Herbert et al., 2012, PMID 22921365.
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Project description:Corepressors negatively regulate gene expression by chromatin compaction. Targeted regulation of gene expression could provide a means to control endothelial cell phenotype. We hypothesize that by targeting corepressor proteins, endothelial angiogenic function can be improved. To study this, the expression and function of nuclear corepressors in human umbilical vein endothelial cells (HUVEC) and in murine organ culture was studied. RNA-seq revealed that nuclear receptor corepressor 1 (NCoR1), Silencing Mediator of Retinoid and Thyroid hormone receptors (SMRT) and repressor element-1 silencing transcription factor (REST) are the highest expressed corepressors in HUVECs. Knockout and knockdown strategies demonstrated that the depletion of NCoR1 increased the angiogenic capacity of endothelial cells, whereas depletion of SMRT or REST did not. Interestingly, the effect was VEGF signaling independent. NCoR1 depletion significantly upregulated angiogenesis-associated genes, especially tip cell genes, including ESM1, DLL4 and NOTCH4, as observed by RNA- and ATAC-seq. Confrontation assays comparing cells with and without NCoR1-deficiency revealed that loss of NCoR1 promotes a tip-cell position during spheroid sprouting. Moreover, a proximity ligation assay identified NCoR1 as a direct binding partner of the Notch-signaling-related transcription factor RBPJk. Luciferase assays showed that siRNA-mediated knockdown of NCoR1 promotes RBPJk activity. Furthermore, NCoR1 downregulation prompts upregulation of several elements in the Notch signaling cascade. Downregulation of NOTCH4, but not NOTCH1, prevented the positive effect of NCoR1 knockdown on spheroid outgrowth. Collectively, these data indicate that decreasing NCOR1 expression is an attractive approach to promote angiogenic function.
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Project description:Corepressors negatively regulate gene expression by chromatin compaction. Targeted regulation of gene expression could provide a means to control endothelial cell phenotype. We hypothesize that by targeting corepressor proteins, endothelial angiogenic function can be improved. To study this, the expression and function of nuclear corepressors in human umbilical vein endothelial cells (HUVEC) and in murine organ culture was studied. RNA-seq revealed that nuclear receptor corepressor 1 (NCoR1), Silencing Mediator of Retinoid and Thyroid hormone receptors (SMRT) and repressor element-1 silencing transcription factor (REST) are the highest expressed corepressors in HUVECs. Knockout and knockdown strategies demonstrated that the depletion of NCoR1 increased the angiogenic capacity of endothelial cells, whereas depletion of SMRT or REST did not. Interestingly, the effect was VEGF signaling independent. NCoR1 depletion significantly upregulated angiogenesis-associated genes, especially tip cell genes, including ESM1, DLL4 and NOTCH4, as observed by RNA- and ATAC-seq. Confrontation assays comparing cells with and without NCoR1-deficiency revealed that loss of NCoR1 promotes a tip-cell position during spheroid sprouting. Moreover, a proximity ligation assay identified NCoR1 as a direct binding partner of the Notch-signaling-related transcription factor RBPJk. Luciferase assays showed that siRNA-mediated knockdown of NCoR1 promotes RBPJk activity. Furthermore, NCoR1 downregulation prompts upregulation of several elements in the Notch signaling cascade. Downregulation of NOTCH4, but not NOTCH1, prevented the positive effect of NCoR1 knockdown on spheroid outgrowth. Collectively, these data indicate that decreasing NCOR1 expression is an attractive approach to promote angiogenic function.
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Project description:Corepressors negatively regulate gene expression by chromatin compaction. Targeted regulation of gene expression could provide a means to control endothelial cell phenotype. We hypothesize that by targeting corepressor proteins, endothelial angiogenic function can be improved. To study this, the expression and function of nuclear corepressors in human umbilical vein endothelial cells (HUVEC) and in murine organ culture was studied. RNA-seq revealed that nuclear receptor corepressor 1 (NCoR1), Silencing Mediator of Retinoid and Thyroid hormone receptors (SMRT) and repressor element-1 silencing transcription factor (REST) are the highest expressed corepressors in HUVECs. Knockout and knockdown strategies demonstrated that the depletion of NCoR1 increased the angiogenic capacity of endothelial cells, whereas depletion of SMRT or REST did not. Interestingly, the effect was VEGF signaling independent. NCoR1 depletion significantly upregulated angiogenesis-associated genes, especially tip cell genes, including ESM1, DLL4 and NOTCH4, as observed by RNA- and ATAC-seq. Confrontation assays comparing cells with and without NCoR1-deficiency revealed that loss of NCoR1 promotes a tip-cell position during spheroid sprouting. Moreover, a proximity ligation assay identified NCoR1 as a direct binding partner of the Notch-signaling-related transcription factor RBPJk. Luciferase assays showed that siRNA-mediated knockdown of NCoR1 promotes RBPJk activity. Furthermore, NCoR1 downregulation prompts upregulation of several elements in the Notch signaling cascade. Downregulation of NOTCH4, but not NOTCH1, prevented the positive effect of NCoR1 knockdown on spheroid outgrowth. Collectively, these data indicate that decreasing NCOR1 expression is an attractive approach to promote angiogenic function. This SuperSeries is composed of the SubSeries listed below.
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Project description:NCoR1 limits angiogenic capacity by altering Notch signaling
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Project description:Tight control of cell fate choices is crucial for proper vessel development. Here we show that Rnf20, the major E3 ubiquitin ligase of histone H2B, plays a key role in the tight control of VEGF-Notch signaling, which is crucial for proper vessel growth and patterning, as well as for the dynamic tip-stalk cell fate at the vascular front. We demonstrate that Rnf20 is dynamically expressed in the developing retina and controls vessel growth through two distinct modes of action. On the one hand, it restricts gene activation by the endothelial transcription factor ERG and on the other, it orchestrates large-scale mRNA processing events, which change the bioavailability and function of critical pro-angiogenic factors. We show that Rnf20 plays a key role for the upregulation of both VEGFR2 through alternative polyadenylation and VEGFA through intron inclusion, as well as for suppressing the ability of Notch1 to bind to chromatin. Interestingly, perturbations of RNF20 have been associated with complex cardiovascular malformations in human patients, suggesting that delineating the mechanisms that control Rnf20 expression and activity may provide new insights into diseases caused by vascular dysfunction.
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Project description:Tight control of cell fate choices is crucial for proper vessel development. Here we show that Rnf20, the major E3 ubiquitin ligase of histone H2B, plays a key role in the tight control of VEGF-Notch signaling, which is crucial for proper vessel growth and patterning, as well as for the dynamic tip-stalk cell fate at the vascular front. We demonstrate that Rnf20 is dynamically expressed in the developing retina and controls vessel growth through two distinct modes of action. On the one hand, it restricts gene activation by the endothelial transcription factor ERG and on the other, it orchestrates large-scale mRNA processing events, which change the bioavailability and function of critical pro-angiogenic factors. We show that Rnf20 plays a key role for the upregulation of both VEGFR2 through alternative polyadenylation and VEGFA through intron inclusion, as well as for suppressing the ability of Notch1 to bind to chromatin. Interestingly, perturbations of RNF20 have been associated with complex cardiovascular malformations in human patients, suggesting that delineating the mechanisms that control Rnf20 expression and activity may provide new insights into diseases caused by vascular dysfunction.
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