Hypoxia-mediated regulation of histone demethylases affects angiogenesis associated functions in endothelial cells
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ABSTRACT:
PROVIDER: PRJNA586868 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10380501.fastq.gz | Fastqsanger.gz | |||
| SRR10380502.fastq.gz | Fastqsanger.gz | |||
| SRR10380503.fastq.gz | Fastqsanger.gz | |||
| SRR10380504.fastq.gz | Fastqsanger.gz | |||
| SRR10380505.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: Jumonji-containing (jmjC) family of proteins are involved in epigenetic gene regulation through histone specific lysine demethylation. Previous studies have demonstrated that the expression of several members of this family is induced by hypoxia. However, the mechanisms by which lysine specific demethylases (KDMs) are regulated under hypoxia and how they affect angiogenesis, the primary method to restore blood oxygen, remains unknown. In this study, we characterized regulation of KDMs using a combination of nascent and mature mRNA profiling. Furthermore, we aimed to identify KDMs that play a role in mediating the VEGF-mediated angiogenic response in endothelial cells. Results: We demonstrated that majority of KDMs were induced by hypoxia and this effect is more prominent upon constitutive activation of HIF2α compared to HIF1α. Half of the changes in mRNAs levels were attributed to transcriptional regulation as evidenced by similar changes at the level of nascent mRNAs, whereas half was likely due to post-transcriptional mechanisms affecting mature mRNA levels. Hypoxia induced genome-wide redistribution of H3K27me3 at 2000 transcriptionally active loci in human umbilical vein endothelial cells (HUVECs). Among these, we further verified the induction of VEGF-A by demethylation of the locus by KDM4B and KDM6B in response to hypoxia. Accordingly, knockdown of KDM4B and KDM6B led to decreased proliferation and tube formation of HUVECs. Conclusions: Hypoxia leads to both transcriptional and post-transcriptional induction of KDMs and wide redistribution of H3K27me3 at active chromatin regions. Main mediator of angiogenesis, VEGFA, is regulated by KDM4B- and KDM6B- mediated demethylation in HUVECs with functional implications for cell proliferation and tube formation. These findings provide novel insights into the regulation of KDMs by hypoxia and the epigenetic regulation of angiogenesis.
2020-09-03 | GSE139678 | GEO
Project description:The CCM endothelium is hypersensitive to angiogenesis and can induce a hypoxic program associated with changes in angiogenesis, inflammation, and endothelial-cell metabolism under normoxic conditions. However, the role of active drivers of angiogenesis as CCM disease modifiers in human disease remains unclear. To examine if hypoxia, a driver of angiogenesis, may contribute to CCM exacerbation, we performed bulk RNA-seq of brain tissue from P50 Pdcd10BECKO mice under normoxia and hypoxia. P50 Pdcd10fl/fl littermate controls under normoxia and hypoxia were used as controls.
2024-09-23 | GSE236163 | GEO
Project description:KAI1 functions as a negative regulator of angiogenesis
| PRJNA471496 | ENA
Project description:Pathological retinal angiogenesis with irregular and fragile vessels (also termed as neovascularization, a response to hypoxia and dysmetabolism) is a leading cause of vision loss in all age groups driven in part by unmet metabolic demand from retinal neurons. Sustaining neural retinal metabolism with an adequate nutrient supply may prevent vision-threatening neovascularization. Low circulating serine levels are associated with neovascularization in macular telangiectasia and altered serine/glycine metabolism is suggested in retinopathy of prematurity. Here we assessed the role of serine metabolism in suppressing hypoxia-driven retinal neovascularization in mice. Systemic serine supplementation decreased, and dietary serine/glycine deficiency worsened retinal neovascularization. Fatty acid oxidation was essential in mediating serine protective effects and serine also increased the levels of phosphatidylcholine, the most abundant phospholipids in the retina. Exogenous serine increased abundance of proteins involved in oxidative phosphorylation in total retinas, as well as increased expression of mitochondrial respiration-related genes and decreased expression of pro-angiogenic genes in rod photoreceptor cluster. Pharmaceutical inhibition of mitochondrial energy production largely attenuated serine suppression of retinal neovascularization. Our data suggested that increasing serine is a potential therapeutic approach for neovascular eye diseases by enhancing retinal mitochondrial function and lipid metabolism to suppress driving factors for uncontrolled angiogenesis.
2025-05-07 | PXD056490 | Pride
Project description:Differential lncRNA expression upon hypoxia affects splicing efficiency
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Project description:Hypoxia increases neuroinflammation and angiogenesis gene programs in CCM disease
| PRJNA989155 | ENA
Project description:Objective: Pathological retinal angiogenesis is vision threatening. In mouse oxygen-induced retinopathy (OIR) we sought to define mitochondrial respiration changes longitudinally during hyperoxia-induced vessel loss and with hypoxia-induced neovascularization (NV), and test interventions to address those changes to prevent NV. Methods: OIR was induced in C57BL/6J mice and retinal vasculature was examined at maximum neovessel formation. We assessed total proteome change and the ratio of mitochondrial/nuclear DNA copy numbers (mtDNA/nDNA) of OIR vs. control retinas, and mitochondrial oxygen consumption rates (OCR) in ex vivo OIR vs. control retinas (BaroFuse). Pyruvate vs. vehicle control was supplemented in OIR mice either prior to or during neovessel formation. Results: In OIR vs. control retinas proteomics identified decreased retinal mitochondrial respiration and synaptic formation pathway proteins at peak neovascularization. mtDNA/nDNA was decreased during hypoxia-induced neovessel growth (as was OCR) suggesting impaired mitochondrial respiration. Pyruvate administration during but not prior to neovessel formation (in line with compromised mitochondrial activity) suppressed NV in vivo. Conclusions: Mitochondrial energetics are suppressed during retinal NV in OIR. Appropriately timed supplementation of energy substrates (pyruvate) may be a novel approach in neovascular retinal diseases.
2025-05-06 | PXD051410 | Pride
Project description:Estrogen receptor β affects hypoxia response in colorectal cancer cells
| PRJNA956954 | ENA
Project description:Pathologic retinal neovascularization is a potentially blinding consequence seen in many common diseases including diabetic retinopathy, retinopathy of prematurity, and retinal vascular occlusive diseases, among others. The use of therapeutics targeting pro-angiogenesis factors such as vascular endothelial growth factor (VEGF) has proven to be highly effective, however considerable side effects exist and serial anti-VEGF treatment has been shown to decrease effectiveness over time. Characterization of additional regulators of neovascularization is needed to further understand neovascular disease and identify possible new therapeutic targets. This study investigates epithelial membrane protein 2 (EMP2) and its role as a possible modulator of angiogenesis in human retinal pigment epithelium (RPE) under hypoxia. EMP2 is highly expressed in human RPE and RPE cell lines. Adult retinal pigment epithelial cell line-19 (ARPE-19) cells were genetically modified to either overexpress EMP2 (OE) or knock down EMP2 (KD) and expression at the RNA and protein level was evaluated using RNA sequencing and western blot respectively. Protein expression was evaluated under both normoxic conditions and conditions of hypoxic stress with 0.5% O2. EMP2 expression was found to positively correlate with expression of the pro-angiogenesis factors hypoxia inducible factor 1-alpha (HIF-1a) and VEGF for both RNA and protein. EMP2 mediated changes in ARPE-19 cells was also found to alter the secretion of a paracrine factor(s) in conditioned media that can regulate human umbilical vein endothelial cells (HUVEC) endothelial cell migration and capillary tube formation in in vitro functional angiogenesis assays. This study identifies EMP2 as a potentially important mediator of angiogenesis in the human RPE, a tissue involved in abnormal retinal neovascularization in a number of diseases. EMP2 levels positively correlate with those of the potent pro-angiogenesis mediators HIF-1a and VEGF, however the mechanism of this relationship remains to be clarified. This study supports further investigation of EMP2 as a promising novel target for therapeutic treatment of pathologic neovascularization in the retina.
2020-06-03 | GSE151610 | GEO
Project description:The neural stem cell (NSC) niche controls the expansion and differentiation of NSCs. Blood vessels are part of this neurogenic niche, but their functional significance for the regulation of NSC differentiation and the mechanisms involved remain unclear. Here, we report that blood vessel formation in the developing mouse and ferret cortex coincided with induction of NSC differentiation in time and space. Moreover, selective inhibition of brain angiogenesis in vessel-specific Gpr124 null embryos caused hypoxia and increased NSC expansion at the expense of differentiation. The hypoxia-inducible factor (HIF)-1Îą mediated this process, as the level of HIF-1Îą controlled NSC differentiation. Niche blood vessels regulated NSC differentiation at least in part by providing oxygen, as exposure to increased ambient oxygen levels rescued NSC differentiation in hypoxic brains of Gpr124 deficient embryos. Our findings establish a novel oxygen-dependent mechanism of how blood vessels regulate NSC differentiation.
2016-02-04 | E-MTAB-3941 | biostudies-arrayexpress