Bulk RNA-seq analysis of ATF3 kncokdown on HRMECs
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE249642 | GEO | 2024/12/09
REPOSITORIES: GEO
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Project description:Bulk RNA-seq analysis of ATF3 kncokdown on HRMECs
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Project description:Following acute injury, the capillary vascular bed in the lung must be repaired to reestablish gas exchange between pulmonary endothelial cells (ECs) lining these vessels and the alveolar epithelium. However, the factors that control EC stress response and drive regeneration of pulmonary capillaries remain incompletely understood. Viral infections such as influenza and COVID-19 may indirectly damage lung vasculature through loss of epithelial gas exchange partners or through signaling from infiltrating immune cells. To prevent excessive tissue damage and to renew the endothelium, ECs must both withstand cellular stress and proliferate after injury. Here, we show that the transcription factor and immediate early gene Atf3 is essential for both responses in the mouse lung after influenza infection. Atf3 expression defines a subpopulation of capillary ECs enriched in genes involved in cellular response to stress, angiogenesis, and vascular development. Endothelial loss of ATF3 results in defective alveolar regeneration: in the absence of ATF3, ECs exhibit increased apoptosis and decreased proliferation, resulting in an emphysema-like phenotype with enlarged alveolar airspaces lined with regions of lost vasculature. These data implicate ATF3 as an essential component of the vascular response to acute lung injury that is required for successful lung regeneration.
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Project description:The pathophysiology of retinopathy of prematurity (ROP) is postulated to first involve delayed intraretinal vascularization, followed by intravitreal neovascularization (IVNV). Although intravitreal agents that reduce the bioactivity of vascular endothelial growth factor (VEGF) are used to treat IVNV, concerns exist regarding their effects on intraretinal vascularization. In an experimental ROP model, VEGF receptor 2 (VEGFR2) knockdown in retinal endothelial cells reduced IVNV and promoted intraretinal vascularization, whereas knockdown of a downstream effector, signal transducer and activator of transcription 3 (STAT3) in retinal endothelial cells only reduced IVNV. In this study, we tested the hypothesis that the different pathways involved in VEGF-triggered VEGFR2 signaling and VEGF-triggered STAT3 signaling in retinal endothelial cells would allow us to delineate signaling pathways involved in IVNV from those involved in intraretinal vascularization in ROP. To address our hypothesis, we used RNA-sequencing and pathway enrichment analysis to determine changes in the transcriptome of cultured human retinal microvascular endothelial cells (HRMECs). Of the enriched pathways, inactivation of oncostatin M signaling was predicted by either KDR or STAT3 knockdown in the presence of VEGF. Activation of kinetochore metaphase signaling was predicted by KDR knockdown, whereas inactivation was predicted by STAT3 knockdown in the presence of VEGF. Inactivation of signaling by the Rho family of GTPases was predicted by KDR knockdown, but activation was predicted by STAT3 knockdown in the presence of VEGF. Taken together, our data identified unique signaling pathway differences between VEGF-triggered VEGFR2 and VEGF-triggered STAT3 in HRMECs that might have implications in ROP.
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Project description:The pathophysiology of retinopathy of prematurity (ROP) is postulated to first involve delayed intraretinal vascularization, followed by intravitreal neovascularization (IVNV). Although intravitreal agents that reduce the bioactivity of vascular endothelial growth factor (VEGF) are used to treat IVNV, concerns exist regarding their effects on intraretinal vascularization. In an experimental ROP model, VEGF receptor 2 (VEGFR2) knockdown in retinal endothelial cells reduced IVNV and promoted intraretinal vascularization, whereas knockdown of a downstream effector, signal transducer and activator of transcription 3 (STAT3) in retinal endothelial cells only reduced IVNV. In this study, we tested the hypothesis that the different pathways involved in VEGF-triggered VEGFR2 signaling and VEGF-triggered STAT3 signaling in retinal endothelial cells would allow us to delineate signaling pathways involved in IVNV from those involved in intraretinal vascularization in ROP. To address our hypothesis, we used RNA-sequencing and pathway enrichment analysis to determine changes in the transcriptome of cultured human retinal microvascular endothelial cells (HRMECs). Of the enriched pathways, inactivation of oncostatin M signaling was predicted by either KDR or STAT3 knockdown in the presence of VEGF. Activation of kinetochore metaphase signaling was predicted by KDR knockdown, whereas inactivation was predicted by STAT3 knockdown in the presence of VEGF. Inactivation of signaling by the Rho family of GTPases was predicted by KDR knockdown, but activation was predicted by STAT3 knockdown in the presence of VEGF. Taken together, our data identified unique signaling pathway differences between VEGF-triggered VEGFR2 and VEGF-triggered STAT3 in HRMECs that might have implications in ROP.
2022-12-29 | GSE221861 | GEO
Project description:Purpose: Transcriptomics analysis provides a genome-wide digital gene expression profile, which reveals the regulation of gene transcription at the overall level. This study aimed to investigate the underlying mechanism of carnosol against t-BHP-induced Human retinal microvascular endothelial cells (HRMECs) oxidative stress injury. Methods: HRMECs were treated with 10 μM carnosol for 24 h, followed by 300 μM t-BHP for 4 h to simulate the oxidative stress environment in vitro. Oligo dT was used to generate the cDNA library. After constructing the cDNA library, the quality of the library was detected with Agilent biological analyzer, and the cDNA was sequenced with Illumina. Conclusions: Our data provide a systematic perspective for the mechanism of carnosol against HRMECs oxidative stress injury, which lay a foundation for further study on carnosol.
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Project description:Exercise is a powerful driver of physiological angiogenesis during adulthood, but the mechanisms of exercise-induced vascular expansion are poorly understood. We explored endothelial heterogeneity in skeletal muscle and identified two capillary muscle endothelial cells (mEC) populations which are characterized by differential expression of ATF3/4. Spatial mapping showed that ATF3/4 + mECs are enriched in red oxidative muscle areas while ATF3/4 low ECs lie adjacent to white glycolytic fibers. In vitro and in vivo experiments revealed that red ATF3/4 + mECs are more angiogenic when compared to white ATF3/4 low mECs. Mechanistically, ATF3/4 in mECs control genes involved in amino acid uptake and metabolism and metabolically prime red (ATF3/4 + ) mECs for angiogenesis. As a consequence, supplementation of non-essential amino acids and overexpression of ATF4 increased proliferation of white mECs. Finally, deleting Atf4 in ECs impaired exercise-induced angiogenesis. Our findings illustrate that spatial metabolic angiodiversity determines the angiogenic potential of muscle ECs.
2021-06-15 | GSE174785 | GEO
Project description:Maintenance of genetic integrity is essential for survival of all organisms. Activating transcription factor 3 (ATF3) is a member of the c-AMP response element binding (CREB)/ATF family of transcription factors, and is highly inducible by various stress conditions including DNA damage. However, downstream targets and molecular basis underlying pleiotropic effects of ATF3 on the cell fate have been largely unknown. To identify ATF3 targets in the human genome, we carried out chromatin immunoprecipitation-microarray (ChiP-on-chip) and knockdown-expression profiling analysis using two models where ATF3 was either transiently induced or constitutively expressed. We show that ATF3 binds to an unexpectedly large number of targets; 5,984 promoters in HCT116 cells treated with an alkylating agene methyl methanesulfonate (MMS) and 1,423 promoters in LNCaP cells constitutively expressing ATF3. Importantly, targets of MMS-induced ATF3 are highly enriched not only for CREB/ATF motifs but also for binding sites of several stress sensors including DDIT3/CHOP, Egr1, and c-Ets which are concomitantly induced by MMS. Stress-induced ATF3 affects broad but select biological processes including cell cycle, cell death, adhesion, biosynthesis, and receptor signaling pathways. In addition, ATF3 binds to as many as 40% of the p53 targets and preferentially enhances MMS-induced activation of proapoptotic genes such as DR4, DR5, and PUMA, consistent with the proapoptotic effect of ATF3. These data shed new light on the co-regulatory function of ATF3 in the stress-induced transcription factor network. The comprehensive list of genomic targets of ATF3 will facilitate further understanding the role of ATF3 in determining life and death of cells under both physiological and tumour-associated stress conditions. Maintenance of genetic integrity is fundamental to survival of all organisms. DNA damage can be caused by various agents in environment and elicits complex responses in the cell. ATF3 is one of the transcription factors activated by various stress conditions including DNA damage, and has been shown to have pleiotropic effects on life and death of cells depending on the context of experimental conditions. It has been largely unknown, however, which genes and pathways are regulated by stress-induced ATF3. Here we attempted to answer this question by chromatin immunoprecipitation-microarray analysis of downstream targets of ATF3. We show that ATF3 binds to an unexpectedly large number of promoters (nearly 6,000) in a human colorectal cancer cell lineHCT116 treated with an alkylating agent methyl methanesulfonate. Interestingly, the ATF3 targets are highly enriched for binding sites of other stress sensors shedding light on a transcriptional co-regulatory network of DNA damage response. We further show that ATF3 regulates expression of genes in select biological processes including cell cycle, cell death, adhesion, metabolism, signal transduction, and the p53 pathway. The comprehensive list of ATF3 targets provides new insight into a highly inter-connected network of stress-induced transcription factors around ATF3. ChIP-chip samples: Comparison of ATF3-IP and whole genome DNA (control) Gene expression samples: HCT116 cells pre-transfected with either control siRNA or ATF3 knockdown siRNA and stimulated by methyl methanesulfonate (MMS) for 0, 6, 12, and 24 hours
2010-10-01 | E-GEOD-18457 | biostudies-arrayexpress
Project description:Purpose: To investigate the expression and function of apolipoprotein C3 (APOC3) in diabetic retinopathy (DR). Methods: The quantitative expression of APOC3 in aqueous humor of patients with DR was detected using our proteomic datasets (PXD046630 and PXD053634). A multiplex immunoassay was used to examine the level of APOC3 in serum of patients with DR. Western blot, immunohistochemistry and enzyme-linked immunosorbent assays were used to measure APOC3 expression in liver, duodenum, retina and serum of db/db mice and oxygen induced retinopathy (OIR) mice, and in the human retinal microvascular endothelial cells (hRMECs) exposed to high glucose, hypoxia or both of them. Cell proliferation, migration and tube formation assays were used to assessed the phenotypic characteristics of hRMECs treated with recombinant APOC3 (r-APOC3), hypoxia and both of them. RNA sequence analysis and inhibition assay were conducted to explore the pathway in r-APOC3 and hypoxia stimulation. Results: APOC3 expression were significantly increased in aqueous humor and serum of patients with DR, as well as in liver, duodenum, serum, and retina of db/db mice and OIR mice, while did not markedly change in both hRMECs and their conditioned medium when exposed to high glucose, hypoxia or both of them. r-APOC3 combined with hypoxia significantly enhanced the proliferation, migration and tube formation of hRMECs, and promoted the upregulation of MYC, VEGF and IL6. Inhibition of MYC expression alleviated the phenotypic changes in hRMECs treated with r-APOC3 combined with hypoxia. Purpose: To investigate the expression and function of apolipoprotein C3 (APOC3) in diabetic retinopathy (DR). Methods: The quantitative expression of APOC3 in aqueous humor of patients with DR was detected using our proteomic datasets (PXD046630 and PXD053634). A multiplex immunoassay was used to examine the level of APOC3 in serum of patients with DR. Western blot, immunohistochemistry and enzyme-linked immunosorbent assays were used to measure APOC3 expression in liver, duodenum, retina and serum of db/db mice and oxygen induced retinopathy (OIR) mice, and in the human retinal microvascular endothelial cells (hRMECs) exposed to high glucose, hypoxia or both of them. Cell proliferation, migration and tube formation assays were used to assessed the phenotypic characteristics of hRMECs treated with recombinant APOC3 (r-APOC3), hypoxia and both of them. RNA sequence analysis and inhibition assay were conducted to explore the pathway in r-APOC3 and hypoxia stimulation. Results: APOC3 expression were significantly increased in aqueous humor and serum of patients with DR, as well as in liver, duodenum, serum, and retina of db/db mice and OIR mice, while did not markedly change in both hRMECs and their conditioned medium when exposed to high glucose, hypoxia or both of them. r-APOC3 combined with hypoxia significantly enhanced the proliferation, migration and tube formation of hRMECs, and promoted the upregulation of MYC, VEGF and IL6. Inhibition of MYC expression alleviated the phenotypic changes in hRMECs treated with r-APOC3 combined with hypoxia.
2024-12-09 | GSE283578 | GEO