Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1212340 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32041479_1.fastq.gz | Fastqsanger.gz | |||
| SRR32041479_2.fastq.gz | Fastqsanger.gz | |||
| SRR32041480_1.fastq.gz | Fastqsanger.gz | |||
| SRR32041480_2.fastq.gz | Fastqsanger.gz | |||
| SRR32041481_1.fastq.gz | Fastqsanger.gz |
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Project description:Exosomes serve as signaling messengers that facilitate intercellular communication through delivering molecular cargo. Here, we observed elevated levels of exosomal periostin (POSTN) in blood plasma of patients with proliferative diabetic retinopathy (PDR). Monocytes-derived exosomal POSTN was increased under high glucose condition, and deletion of Postn in myeloid cells reduced retinal neovascularization. Monocytes isolated from the blood of PDR patients exhibited heightened glycolytic activity and elevated histone lactylation levels, particularly H4K8 lactylation (H4K8la). Knockout of Hexokinase 2 (Hk2) in myeloid cells led to reduced H4K8la and POSTN levels and inhibited retinal neovascularization. Exogenous exosomal POSTN partially reversed the angiogenic defects caused by Postn or Hk2 deletion in myeloid cells. Mechanistically, exosomal POSTN stabilized hypoxia-inducible factor 1-alpha (HIF1-α) and upregulated the expression of angiogenic genes. Notably, treatment with metformin reduced retinal neovascularization by decreasing monocytes glycolysis and lowering exosomal POSTN levels. In summary, these findings underscore the critical role of circulating exosomal POSTN in retinal neovascularization and highlight its potential as a therapeutic target for angiogenic retinopathies.
2025-01-20 | PXD059956 |
Project description:While angiogenesis serves as a cornerstone of embryogenesis and a defining feature of pathological progression, a critical gap persists in understanding how metabolic signaling precisely converges with nuclear reprogramming to ignite vascular growth. Here, we demonstrate that glucose-derived lactate via glycolysis induces site-specific lactylation at lysine 412 (K412) of histone deacetylase 1 (HDAC1), triggering transcriptional activation of pro-angiogenic genes such as VEGFA. Mechanistically, HDAC2 forms a nuclear complex with HDAC1 to suppress its lactylation modification in the cytoplasm, whereas alanyl-tRNA synthetase (AARS1) promotes its lactylation in cytoplasm to prevent HDAC1 nuclear translocation, leading to nuclear accumulation of H3K56 acetylation and chromatin remodeling that selectively activates angiogenesis-related transcriptional programs. In zebrafish models, HDAC1-K412 mutation caused embryonic lethality, and site-specific lactylation dynamically increased during cardiac development. In the HDAC1 K412A mutation knock-in mouse model, the results showed that this site prevents vascular proliferation in the retinas of streptozotocin (STZ)-induced diabetic mice. Pharmacologically, we found that the HDAC1 activator Exifone suppressed its lactylation and inhibited vascular growth. Strikingly, Exifone attenuates pathological neovascularization in embryonic chick models and halts aberrant vascular proliferation within the retinal vasculature of STZ-diabetic mice. Our findings reveal HDAC1 lactylation as a metabolic-epigenetic nexus governing angiogenesis, providing mechanistic insights into not only obscures developmental principles but hampers therapeutic targeting of aberrant vascularization in diseases ranging from cancer to diabetes.
2025-11-04 | GSE305252 | GEO
Project description:While angiogenesis serves as a cornerstone of embryogenesis and a defining feature of pathological progression, a critical gap persists in understanding how metabolic signaling precisely converges with nuclear reprogramming to ignite vascular growth. Here, we demonstrate that glucose-derived lactate via glycolysis induces site-specific lactylation at lysine 412 (K412) of histone deacetylase 1 (HDAC1), triggering transcriptional activation of pro-angiogenic genes such as VEGFA. Mechanistically, HDAC2 forms a nuclear complex with HDAC1 to suppress its lactylation modification in the cytoplasm, whereas alanyl-tRNA synthetase (AARS1) promotes its lactylation in cytoplasm to prevent HDAC1 nuclear translocation, leading to nuclear accumulation of H3K56 acetylation and chromatin remodeling that selectively activates angiogenesis-related transcriptional programs. In zebrafish models, HDAC1-K412 mutation caused embryonic lethality, and site-specific lactylation dynamically increased during cardiac development. In the HDAC1 K412A mutation knock-in mouse model, the results showed that this site prevents vascular proliferation in the retinas of streptozotocin (STZ)-induced diabetic mice. Pharmacologically, we found that the HDAC1 activator Exifone suppressed its lactylation and inhibited vascular growth. Strikingly, Exifone attenuates pathological neovascularization in embryonic chick models and halts aberrant vascular proliferation within the retinal vasculature of STZ-diabetic mice. Our findings reveal HDAC1 lactylation as a metabolic-epigenetic nexus governing angiogenesis, providing mechanistic insights into not only obscures developmental principles but hampers therapeutic targeting of aberrant vascularization in diseases ranging from cancer to diabetes.
2025-11-04 | GSE305251 | GEO
Project description:Macrophages are critical components of the immunosuppressive microenvironment that restrict anti-cancer immunity in glioblastoma (GBM). However, how GBM shapes the regulatory function of macrophages remains elusive. Here, we report that monocyte-derived macrophages (MDM), but not yolk-sac derived microglia (MG), exhibited potent immunosuppressive activity, which was mediated by a population of glycolytic GLUT1+MDM, in an IL10-dependent manner. GBM-derived factors reprogrammed MDM towards glycolytic cells with enhanced avidity for glucose, which was mostly used to generate lactate. In turn, intracellular lactate caused lactylation of histone lysine residues that promoted MDM immunosuppressive activity via regulation of Il10 expression. GBM-primed activation of PERK supported glucose metabolism and regulated GLUT1 expression through ATF4 in MDM. PERK-deletion in MDM abrogated histone lactylation and suppressive activity, thereby promoting polyfunctional T cell-infiltration of tumors. In combination with immunotherapy, PERK-deletion blocked GBM progression. Our study demonstrates that glucose-driven histone lactylation controls MDM immunosuppressive function; all in a PERK-dependent manner.
2024-05-06 | GSE260700 | GEO
Project description:Histone lactylation, an epigenetic modification, promotes tumor growth and immune evasion in various cancers. Our study found increased pan-lysine lactylation and H3K18la in gastric tissues, linked to poor prognosis. Inhibiting glycolysis and silencing lactate dehydrogenase reduced H3K18la, boosting CD8+ T-cell activity against gastric cancer. H3K18la activated HAS2 transcription, enhancing MYC nuclear transport and PD-L1 expression..Our data provide a molecular framework for Histone lactylation in the process of gastric cancer.
2025-09-30 | GSE295142 | GEO
Project description:Background: As a widespread post-transcriptional RNA modification, N5-methylcytosine (m5C) is implicated in a variety of cellular responses and processes that regulate RNA metabolism. Despite this, a clear understanding of m5C modification’s role and mechanism in angiogenesis is still lacking. Methods: Single-cell RNA sequencing data was analyzed to determine expression of m5C methylase NSUN2. m5C levels were determined by mRNA isolation and anti-m5C dot blot in both hypoxia-induced endothelial cells (ECs) and laser-induced choroidal neovascularization (CNV). In addition, endothelial cell and endothelium‐specific NSUN2‐knockout mouse model were used to investigate the effect of NSUN2 silence on angiogenic phenotype. Genome-wide multiomics analyses were performed to identify the functional target of NSUN2, including proteomic analysis, transcriptome screening and m5C-methylated RNA immunoprecipitation sequencing (m5C-meRIP-seq). CUT&Tag sequencing was performed to test the histone lactylation signal in the promoter region of NSUN2. Finally, AAV-mediated short hairpin RNAi knockdown of NSUN2 gene expression (AAV-shNSUN2) was constructed to investigate the effect of inhibiting CNV. Results: First, we discovered that m5C methylase NSUN2 expression level and mRNA m5C level were significantly higher in CNV-ECs than in normal ECs. NSUN2 knockdown in ECs inhibited proliferative, migration, and tube formation activities of ECs. Moreover, compared with EC NSUN2flox/flox mice, EC-specific NSUN2-deficient (EC NSUN2-/-) mice displayed less retinal vascular leakage after laser induction. Through multiomics analyses, we subsequently identified A-kinase anchoring protein 2 (AKAP2), a scaffolding protein which isolate Protein kinase A (PKA) to specific subcellular locations through binding to its regulatory subunit, as a downstream candidate target of NSUN2 in ECs. Overexpression of exogenous AKAP2 markedly reversed the inhibitory phenotypes in NSUN2-deficient ECs. Interestingly, laser induced NSUN2 up-regulation was driven by lactate-mediated lactylation on histone H3K18. In CNV models, AAV-mediated repression of NSUN2 modulated highly retinal vascular leakage and choroidal thickness. Conclusion: Overall, our findings indicate that NSUN2 is a novel therapeutic target for choroidal neovascularization.
2024-05-19 | GSE267661 | GEO
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:Emerging evidence suggests a link between the circadian clock and retinopathies though the causality has not been established. Circadian clocks in the mammalian retina regulate a diverse range of retinal functions that allow the retina to adapt to the light-dark cycle. We report that clock genes are expressed in the embryonic retina, and the embryonic retina requires light cues to maintain robust circadian expression of the core clock gene, Bmal1. Deletion of Bmal1 and Per2 from the retinal neurons results in retinal angiogenic defects similar to when animals are maintained under constant light conditions. Using two different models to assess pathological neovascularization, we show that neuronal Bmal1 deletion reduces neovascularization with reduced vascular leakage, suggesting that a dysregulated circadian clock primarily drives neovascularization. Chromatin immunoprecipitation sequencing analysis suggests that semaphorin signaling is the dominant pathway regulated by Bmal1. Our data indicate that therapeutic silencing of the retinal clock could be a common approach for the treatment of certain retinopathies like diabetic retinopathy and retinopathy of prematurity.
2022-07-01 | GSE207271 | GEO
Project description:The elevated lactate in the joint microenvironment of patients with rheumatoid arthritis (RA) is crucial for disease progression, although the underlying mechanism remains to be elucidated. In this study, we observed significantly increased global lactylation levels within fibroblast-like synoviocytes (FLS) of RA patients compared to HC (healthy controls), and lactylated proteins were enriched in histones. Furthermore, we found that anti-lactated histone antibodies were detected in almost RA patients and positively correlated with Disease Activity Score 28 (DAS28). Then we identified NFATc2 as a key target gene regulated by histone H3 lysine 9 lactylation (H3K9la) using CUT&Tag combined with RNA-seq. Functional studies revealed that NFATc2 promotes migration of RA-FLSs. Additionally, using server combined immune-deficiency (SCID) and collagen-induced arthritis (CIA) mouse models, we demonstrated that NFATc2 exacerbates RA disease progression through enhanced FLS cartilage invasion function. Collectively, our findings suggest that upregulated target gene NFATc2 by lactate-dependent histone lactylation, can be used as a potential therapeutic target for intervention, anti-lactated histone autoantibodies is promising as a diagnostic marker for RA.
2025-01-06 | GSE284763 | GEO