HIF1α-glycolysis engages activation-induced cell death to drive IFN-γ induction in hypoxic T cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1064028 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27503500_1.fastq.gz | Fastqsanger.gz | |||
| SRR27503500_2.fastq.gz | Fastqsanger.gz | |||
| SRR27503501_1.fastq.gz | Fastqsanger.gz | |||
| SRR27503501_2.fastq.gz | Fastqsanger.gz | |||
| SRR27503502_1.fastq.gz | Fastqsanger.gz |
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Project description:The role of HIF1a-glycolysis in regulating IFN-g induction in hypoxic T cells is unknown. Given that hypoxia is a common feature in a wide array of pathophysiological contexts such as tumor and that IFN-g is instrumental for protective immunity, it is of great significance to gain a clear idea on this. Combining pharmacological and genetic gain-of-function and loss-of-function approaches, we find that HIF1a-glycolysis controls IFN-g induction in both human and mouse T cells activated under hypoxia. Specific deletion of HIF1a in T cells (HIF1a–/–) and glycolytic inhibition significantly abrogate IFN-g induction. Conversely, HIF1a stabilization in T cells by hypoxia and VHL deletion (VHL–/–) promotes IFN-g production. Mechanistically, reduced IFN-g production in hypoxic HIF1a–/– T cells is due to attenuated activation-induced cell death but not proliferative defect. We further show that depletion of intracellular acetyl-CoA is a key metabolic underlying mechanism. Hypoxic HIF1a–/– T cells are less able to kill tumor cells, and HIF1a–/– tumor-bearing mice are not responsive to immune checkpoint blockade (ICB) therapy, indicating loss of HIF1a in T cells is a major mechanism of therapeutic resistance to ICBs. Importantly, acetate supplementation restores IFN-g production in hypoxic HIF1a–/– T cells and re-sensitizes HIF1a–/– tumor-bearing mice to ICBs, providing an effective strategy to overcome ICB resistance. Taken together, our results highlight T cell HIF1a-anaerobic glycolysis as a principal mediator of IFN-g induction and anti-tumor immunity. Considering that acetate supplementation (i.e., glycerol triacetate (GTA)) is approved to treat infants with Canavan disease, we envision a rapid translation of our findings, justifying further testing of GTA as a repurposed medicine for ICB resistance, a pressing unmet medical need
2024-09-24 | GSE253090 | GEO
Project description:The role of HIF1α-glycolysis in regulating IFN-γ induction in hypoxic T cells is unknown. Given that hypoxia is a common feature in a wide array of pathophysiological contexts such as tumor and that IFN-γ is instrumental for protective immunity, it is of great significance to gain a clear idea on this. Combining pharmacological and genetic gain-of-function and loss-of-function approaches, we find that HIF1α-glycolysis controls IFN-γ induction in both human and mouse T cells activated under hypoxia. Specific deletion of HIF1α in T cells (HIF1α-/-) and glycolytic inhibition significantly abrogate IFN-γ induction. Conversely, HIF1α stabilization in T cells by hypoxia and VHL deletion (VHL-/-) promotes IFN-γ production. Mechanistically, reduced IFN-γ production in hypoxic HIF1α-/- T cells is due to attenuated activation-induced cell death but not proliferative defect. We further show that depletion of intracellular acetyl-CoA is a key metabolic underlying mechanism. Hypoxic HIF1α-/- T cells are less able to kill tumor cells, and HIF1α-/- tumor-bearing mice are not responsive to immune checkpoint blockade (ICB) therapy, indicating loss of HIF1α in T cells is a major mechanism of therapeutic resistance to ICBs. Importantly, acetate supplementation restores IFN-γ production in hypoxic HIF1α-/- T cells and re-sensitizes HIF1α-/- tumor-bearing mice to ICBs, providing an effective strategy to overcome ICB resistance. Taken together, our results highlight T cell HIF1α-anaerobic glycolysis as a principal mediator of IFN-γ induction and anti-tumor immunity. Considering that acetate supplementation (i.e., glycerol triacetate (GTA)) is approved to treat infants with Canavan disease, we envision a rapid translation of our findings, justifying further testing of GTA as a repurposed medicine for ICB resistance, a pressing unmet medical need.
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Project description:SF3B1 promotes glycolysis and tumor malignancy through splicing-independent activation of HIF1α
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Project description:The hypoxia signaling pathway controls hypoxia adaptation and tolerance of organisms, which is regulated by multiple mechanisms. Viral infection elicits various pathophysiological responses in the host. However, whether viral infection can affect the hypoxia response is still largely unknown. In this study, we found that Spring viraemia of carp virus (SVCV) infection in zebrafish caused symptoms similar to those in zebrafish under hypoxic conditions. Further assays indicated that SVCV infection activated the hypoxia signaling pathway in zebrafish. In addition, SVCV infection caused increased glycolysis and ROS levels in cells. Mechanistically, SVCV-G protein interacted with hif1α-a/b and attenuated their K48-linked polyubiquitination, leading to their stabilization and subsequent enhancement of target gene expression. Moreover, treatment with the HIF1α-specific inhibitor PX478 enhanced the antiviral ability against SVCV infection in zebrafish and zebrafish cells. This study reveals a relationship between SVCV infection and the hypoxia signaling pathway in fish, and provides a strategy for reducing the damage of viral disease in the aquaculture industry.
2024-10-01 | GSE260453 | GEO
Project description:Background: During eye lens development the fetal vasculature regresses leaving the lens without a direct oxygen source. Both embryonically and throughout adult life, the lens contains a decreasing oxygen gradient from the surface to the core that parallels the natural differentiation of immature surface epithelial cells into mature core transparent fiber cells. These properties of the lens suggest a potential role for hypoxia in the regulation of genes required for mature lens structure and function. Since HIF1α is a master regulator of the hypoxic response, these lens properties also implicate HIF1α as a potential requirement for lens formation and homeostasis. Here, we employed a multiomics approach combining CUT&RUN, RNAseq and ATACseq analysis to establish the genomic complement of lens HIF1α binding sites, genes activated or repressed by HIF1α and the chromatin states of HIF1α-regulated genes. Results: CUT&RUN analysis revealed 8,375 HIF1α-DNA binding complexes in the chick lens genome. 1,190 HIF1α-DNA binding complexes were significantly clustered within chromatin accessible regions (χ2 test p < 1x10-55) identified by ATACseq. Formation of the identified HIF1α-DNA complexes paralleled the activation or repression of 526 genes, 116 of which contained HIF1α binding sites within 10kB of the transcription start sites. Some of the identified HIF1α genes have previously established lens functions while others have novel functions never before examined in the lens. GO and pathway analysis of these genes implicate HIF1α in the control of a wide-variety of cellular pathways potentially critical for lens formation, structure and function including glycolysis, cell cycle regulation, chromatin remodeling, Notch and Wnt signaling, differentiation, development, and transparency. Conclusions: These data establish the first functional map of genomic HIF1α-DNA complexes in the eye lens. They identify HIF1α as an important regulator of a wide-variety of genes previously shown to be critical for lens formation and function and they reveal a requirement for HIF1α in the regulation of a wide-variety of genes not yet examined for lens function. They support a requirement for HIF1α in lens development, structure and function and they provide a basis for understanding the potential roles and requirements for HIF1α in the development, structure and function of more complex tissues.
2021-07-07 | GSE166632 | GEO
Project description:Background: During eye lens development the fetal vasculature regresses leaving the lens without a direct oxygen source. Both embryonically and throughout adult life, the lens contains a decreasing oxygen gradient from the surface to the core that parallels the natural differentiation of immature surface epithelial cells into mature core transparent fiber cells. These properties of the lens suggest a potential role for hypoxia in the regulation of genes required for mature lens structure and function. Since HIF1α is a master regulator of the hypoxic response, these lens properties also implicate HIF1α as a potential requirement for lens formation and homeostasis. Here, we employed a multiomics approach combining CUT&RUN, RNAseq and ATACseq analysis to establish the genomic complement of lens HIF1α binding sites, genes activated or repressed by HIF1α and the chromatin states of HIF1α-regulated genes. Results: CUT&RUN analysis revealed 8,375 HIF1α-DNA binding complexes in the chick lens genome. 1,190 HIF1α-DNA binding complexes were significantly clustered within chromatin accessible regions (χ2 test p < 1x10-55) identified by ATACseq. Formation of the identified HIF1α-DNA complexes paralleled the activation or repression of 526 genes, 116 of which contained HIF1α binding sites within 10kB of the transcription start sites. Some of the identified HIF1α genes have previously established lens functions while others have novel functions never before examined in the lens. GO and pathway analysis of these genes implicate HIF1α in the control of a wide-variety of cellular pathways potentially critical for lens formation, structure and function including glycolysis, cell cycle regulation, chromatin remodeling, Notch and Wnt signaling, differentiation, development, and transparency. Conclusions: These data establish the first functional map of genomic HIF1α-DNA complexes in the eye lens. They identify HIF1α as an important regulator of a wide-variety of genes previously shown to be critical for lens formation and function and they reveal a requirement for HIF1α in the regulation of a wide-variety of genes not yet examined for lens function. They support a requirement for HIF1α in lens development, structure and function and they provide a basis for understanding the potential roles and requirements for HIF1α in the development, structure and function of more complex tissues.
2021-07-07 | GSE166626 | GEO
Project description:CCR7L-inducible lnc-Dpf3 restrains dendritic cell migration by inhibiting HIF1α-mediated glycolysis (mRNA)
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Project description:SF3B1 promotes glycolysis and tumor malignancy through splicing-independent activation of HIF1α [ChIP-Seq]
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Project description:SF3B1 promotes glycolysis and tumor malignancy through splicing-independent activation of HIF1α [RNA-Seq]
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