Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1209812 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31973884_1.fastq.gz | Fastqsanger.gz | |||
| SRR31973884_2.fastq.gz | Fastqsanger.gz | |||
| SRR31973885_1.fastq.gz | Fastqsanger.gz | |||
| SRR31973885_2.fastq.gz | Fastqsanger.gz | |||
| SRR31973886_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:Blood vessel growth and remodelling are essential during embryonic development and disease pathogenesis. The diversity of endothelial cells (ECs) is transcriptionally evident and ECs undergo dynamic changes in gene expression during vessel growth and remodelling.Here, we investigated the role of the histone acetyltransferase HBO1 (KAT7), which is important for activating genes during development and histone H3 lysine 14 acetylation (H3K14ac). Loss of HBO1 and H3K14ac impaired developmental sprouting angiogenesis and reduced pathological EC overgrowth in the retinal endothelium. Single-cell RNA-sequencing of retinal ECs revealed an increased abundance of tip cells in Hbo1 deleted retinas, which lead to EC overcrowding in the retinal sprouting front and prevented efficient tip cell migration. We found that H3K14ac was highly abundant in the endothelial genome in both intra- and intergenic regions suggesting that the role of HBO1 is as a genome organiser that promotes efficient tip cell behaviour necessary for sprouting angiogenesis.
2021-09-30 | GSE161236 | GEO
Project description:Diabetic retinopathy (DR), a leading cause of irreversible vision loss in the working-age population, is an inflammatory, neuro-vascular complication of diabetes with poorly understood mechanism. N6-methyladenosine (m6A) modification plays crucial roles in biological and pathological events, while its role in DR remain elusive. Herein, we identified the pathological involvement of m6A demethylase FTO in DR. FTO expression was elevated in proliferative membranes of DR patients, endothelial cells (EC) under diabetic stress, and retinal vessels of diabetic murine models. FTO overexpression in EC promoted EC cycle progression and tip cell formation to facilitate angiogenesis in vitro, in mice and in zebrafish. FTO also regulated EC-pericyte crosstalk to trigger diabetes-induced microvascular leakage, and mediated EC-microglia crosstalk to induce retinal inflammation and subsequent neurodegeneration in vivo and in vitro. Mechanistically, FTO regulated EC features depending on its demethylation activity via modulating CDK2 mRNA stability with YTHDF2 as the reader. Moreover, FTO up-regulation in EC under diabetic conditions was driven by lactic acid mediated histone lactylation. FB23-2, which inhibits FTO’s m6A demethylase activity, suppressed diabetes associated endothelial phenotypes in vitro and in vivo. Noteworthy, we developed a novel macrophage membrane coated and PLGA-Dil based nanoplatform encapsulating FB23-2 for systemic administration, and confirmed its targeting and therapeutic efficacy in mice. Collectively, our study demonstrated an FTO-mediated regulatory network that coordinates EC biology and retinal homeostasis in DR, providing a promising nanotherapeutic approach for DR treatment. Diabetic retinopathy (DR), a leading cause of irreversible vision loss in the working-age population, is an inflammatory, neuro-vascular complication of diabetes with poorly understood mechanism. N6-methyladenosine (m6A) modification plays crucial roles in biological and pathological events, while its role in DR remain elusive. Herein, we identified the pathological involvement of m6A demethylase FTO in DR. FTO expression was elevated in proliferative membranes of DR patients, endothelial cells (EC) under diabetic stress, and retinal vessels of diabetic murine models. FTO overexpression in EC promoted EC cycle progression and tip cell formation to facilitate angiogenesis in vitro, in mice and in zebrafish. FTO also regulated EC-pericyte crosstalk to trigger diabetes-induced microvascular leakage, and mediated EC-microglia crosstalk to induce retinal inflammation and subsequent neurodegeneration in vivo and in vitro. Mechanistically, FTO regulated EC features depending on its demethylation activity via modulating CDK2 mRNA stability with YTHDF2 as the reader. Moreover, FTO up-regulation in EC under diabetic conditions was driven by lactic acid mediated histone lactylation. FB23-2, which inhibits FTO’s m6A demethylase activity, suppressed diabetes associated endothelial phenotypes in vitro and in vivo. Noteworthy, we developed a novel macrophage membrane coated and PLGA-Dil based nanoplatform encapsulating FB23-2 for systemic administration, and confirmed its targeting and therapeutic efficacy in mice. Collectively, our study demonstrated an FTO-mediated regulatory network that coordinates EC biology and retinal homeostasis in DR, providing a promising nanotherapeutic approach for DR treatment.
2023-05-15 | GSE232135 | 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
Project description:Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma
| PRJNA1082724 | ENA