Mucosal-Associated Invariant T Cell Effector Function Is an Intrinsic Cell Property That Can Be Augmented by the Metabolic Cofactor α-Ketoglutarate
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ABSTRACT:
PROVIDER: PRJNA691878 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13428017_1.fastq.gz | Fastqsanger.gz | |||
| SRR13428017_2.fastq.gz | Fastqsanger.gz | |||
| SRR13428018_1.fastq.gz | Fastqsanger.gz | |||
| SRR13428018_2.fastq.gz | Fastqsanger.gz | |||
| SRR13428019_1.fastq.gz | Fastqsanger.gz |
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Project description:Mucosal-associated invariant T (MAIT) cells are an innate-like population of unconventional T cells that respond rapidly to vitamin B metabolite antigens or cytokine stimulation. Due to this reactivity and surface expression of CD45RO+, CD45RA−, CD127+, they are described as effector memory cells. Yet, there is a lack of uniformity in the MAIT cell effector response. it is unclear what factors contribute to setting MAIT cells effector capacity and whether it is fixed or can be modified. To address this, we have taken a systematic approach to examine MAIT cells effector capacity across healthy individuals in response to ligand and cytokine stimulation. We demonstrate the heterogenous nature of MAIT cells effector capacity, and that the ability to produce an effector response was not directly attributable to TCR clonotype or coreceptor expression. Global gene transcription analysis revealed that the MAIT cells effector capacity produced in response to TCR stimulation was associated with the expression of the epigenetic regulator lysine demethylase 6B (KDM6B). Addition of a KDM6B inhibitor does not alter MAIT cell effector function. However, addition of the KDM6B cofactor α-ketoglutarate greatly enhanced MAIT cells effector capacity in a KDM6B-dependent manner. These results demonstrate that the MAIT cells effector response is epigenetically regulated and can be targeted for enhancement.
2021-01-14 | GSE164740 | GEO
Project description:Phosphoinositide-3 kinase (PI3K)/AKT signaling participates in cellular proliferation, survival, and tumorigenesis as well as cellular reprogramming including generation of induced pluripotent stem cells (iPSCs). In this study, we revealed that activation of AKT in somatic cells undergoing reprogramming enhances epigenetic reprogramming. Activated AKT in reprogramming cells triggers elevated anabolic glucose metabolism, and, accordingly, increases the level of α-ketoglutarate (αKG) which is an essential cofactor for the enzymatic activity of the 5-methylcytosine (5mC) dioxygenase TET. Additionally, the level of TET was upregulated. Consistent with upregulated KG production and TET, we observed a genome-wide increase in 5-hydorxymethylcytosine (5hmC) which is an intermediate in the DNA demethylation process. Moreover, DNA methylation level at ES-cell super-enhancers of pluripotency-related genes was significantly decreased, leading upregulation of associated genes. Taken together, our results indicate that AKT signaling is associated with epigenetic regulation by hyperactivating TET at catalytical and transcriptional levels during the somatic cell reprogramming.
2021-09-29 | GSE161399 | GEO
Project description:Phosphoinositide-3 kinase (PI3K)/AKT signaling participates in cellular proliferation, survival, and tumorigenesis as well as cellular reprogramming including generation of induced pluripotent stem cells (iPSCs). In this study, we revealed that activation of AKT in somatic cells undergoing reprogramming enhances epigenetic reprogramming. Activated AKT in reprogramming cells triggers elevated anabolic glucose metabolism, and, accordingly, increases the level of α-ketoglutarate (αKG) which is an essential cofactor for the enzymatic activity of the 5-methylcytosine (5mC) dioxygenase TET. Additionally, the level of TET was upregulated. Consistent with upregulated KG production and TET, we observed a genome-wide increase in 5-hydorxymethylcytosine (5hmC) which is an intermediate in the DNA demethylation process. Moreover, DNA methylation level at ES-cell super-enhancers of pluripotency-related genes was significantly decreased, leading upregulation of associated genes. Taken together, our results indicate that AKT signaling is associated with epigenetic regulation by hyperactivating TET at catalytical and transcriptional levels during the somatic cell reprogramming.
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Project description:AKT signaling promotes epigenetic reprogramming via upregulation of TET and its cofactor, alpha-ketoglutarate during iPSC generation.
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Project description:AKT signaling promotes epigenetic reprogramming via upregulation of TET and its cofactor, alpha-ketoglutarate during iPSC generation
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Project description:In order to propagate a solid tumor, cancer cells must adapt to and survive under various tumor microenvironment (TME) stresses, such as hypoxia or lactic acidosis. To systematically identify genes that modulate cancer cell survival under stresses, we performed genome-wide shRNA screens under hypoxia or lactic acidosis. We discovered that genetic depletion of acetyl-CoA carboxylase (ACACA or ACC1) or ATP citrate lyase (ACLY) protected cancer cells from hypoxia-induced apoptosis. Additionally, loss of ACLY or ACC1 reduced levels and activities of the oncogenic transcription factor ETV4. Silencing ETV4 also protected cells from hypoxia-induced apoptosis and led to remarkably similar transcriptional responses as with silenced ACLY or ACC1, including an anti-apoptotic program. Metabolomic analysis found that while α-ketoglutarate levels decrease under hypoxia in control cells, α-ketoglutarate is paradoxically increased by hypoxia when ACC1 or ACLY are depleted. Supplementation with α-ketoglutarate rescued the hypoxia-induced apoptosis and recapitulated the decreased expression and activity of ETV4 via an epigenetic mechanism. Therefore, ACC1 and ACLY regulate the levels of ETV4 under hypoxia via increased α-ketoglutarate. These results reveal that ACC1/ACLY- α-ketoglutarate-ETV4 is a novel means by which metabolic states regulate transcriptional output for life vs. death decisions under hypoxia. Since many lipogenic inhibitors are under investigation as cancer therapeutics, our findings suggest that the use of these inhibitors will need to be carefully considered with respect to oncogenic drivers, tumor hypoxia, progression and dormancy. More broadly, our screen provides a framework for studying additional tumor cell stress-adaption mechanisms in the future. DESIGN: H1975 lung cancer cells transduced with a scramble shRNA hairpin or two different shRNAs against ACLY, ACC1, or ETV4 under hypoxia.
2015-12-10 | E-GEOD-61286 | biostudies-arrayexpress
Project description:In the mouse thymus, invariant γδ T cells are generated at well-defined times during development and acquire effector functions before exiting the thymus. However, whether such thymic programming can occur in human is not known. Here we analyzed human fetal and post-natal γδ thymocytes and investigated the role of hematopoietic-stem-and-precursor-cells (HSPC) in the generation of human γδ T cells. Unlike post-natal γδ thymocytes, fetal γδ thymocytes were functionally programmed (e.g. IFNγ, granzymes), expressed low levels of terminal-deoxynucleotidyl-transferase (TdT) and were highly enriched for invariant/public germline-encoded CDR3 sequences (TRGV8-TRJP1-CATWDTTGWFKIF, TRDV2-TRDD3-CACDTGGY and TRDV1-TRDD3-CALGELGD, previously shown to be expanded in cytomegalovirus infection) composed of short-homology-repeat-containing gene segments. Furthermore, these unique characteristics were due to an intrinsic property of fetal HSPC caused by high expression of the RNA-binding protein Lin28b. In conclusion, our data indicate that the human fetal thymus generates, in a HSPC/Lin28b-dependent manner, invariant γδ T cells with programmed effector functions.
2019-11-21 | GSE128163 | GEO
Project description:the RNA binding property of FSCN1
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Project description:Tet3 is an Fe2+-dependent enzyme that oxidizes genomic 5-methylcytosine to 5-hydroxymethylcytosine with the help of alpha-ketoglutarate and oxygen. It is the most abundant Tet enzyme in differentiated tissues including brain. Adult brain contains the highest 5-hydroxymethylcytosine levels. How alpha-ketoglutarate is made available for the oxidation of mC in brain cells and how the Tet activity is linked to neural activity are unsolved questions. Our experiments with full mouse brains show that Tet3 interacts in the nucleus directly with selected enzymes of the mitochondrial citric acid cycle. This leads to the formation of isocitrate. Tet3 also interacts with aspartate aminotransferase, which produces oxaloacetate. Although oxaloacetate and isocitrate are biosynthetic alpha-ketoglutarate precursors, they function as inhibitors of Tet3 and are needed to protect the reactive Fe2+ center from degrading DNA. The supply of Tet3 with alpha-ketoglutarate is established by a direct interaction of Tet3 with glutamate dehydrogenase (Glud1), which converts the neurotransmitter glutamate directly into alpha-ketoglutarate. This links Tet3 function to neural activity.
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Project description:The tumor suppressor p53 is mutated in the majority of human cancers, including pancreatic ductal adenocarcinoma (PDAC)1,2. Wild-type p53 accumulates in response to cellular stress and acts to regulate the expression of genes that influence cell fate and constrain tumorigenesis2. p53 also can modulate cellular metabolism3, though it remains unclear how the metabolic effects of p53 influence tumor suppression or whether the metabolic consequences of p53 loss play a role in disease maintenance. Here, we show that restoring endogenous p53 function in cancer cells derived from a mouse model of PDAC driven by oncogenic Kras and a regulatable p53 short hairpin RNA (shRNA) rewires glucose and glutamine metabolism to support the accumulation of the metabolite alpha-ketoglutarate, an obligate substrate for several enzymes that regulate chromatin methylation. p53 restoration induces transcriptional programs characteristic of pre-neoplastic differentiation, an effect that can be partially recapitulated by addition of cell permeable alpha-ketoglutarate. Consequently, enforcing alpha-ketoglutarate accumulation in p53 deficient cells by inhibiting expression of oxoglutarate dehydrogenase (Ogdh), the enzyme that consumes alpha-ketoglutarate in the tricarboxylic acid cycle, reduces tumor-initiating capacity and promotes tumor differentiation in vivo. In both mouse and human pancreatic cancer, decreasing levels of the alpha-ketoglutarate-dependent chromatin modification 5-hydroxymethylcytosine (5hmC) marks progression from prenoplastic to de-differentiated malignant lesions. p53 restoration or Ogdh suppression promotes accumulation of 5hmC specifically in differentiated tumor cells in vivo. Together, these results nominate alpha-ketoglutarate as an effector of p53-mediated tumor suppression that promotes pre-neoplastic differentiation and suppresses malignant progression.
2019-09-09 | GSE114263 | GEO