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Pyruvate dehydrogenase complex integrates the metabolome and epigenome in memory CD8+ T cell differentiation in vitro [ChIP-Seq]

ABSTRACT: Modulation of metabolic flux through pyruvate dehydrogenase complex (PDC) plays an important role in T cell activation and differentiation. PDC sits at the transition between glycolysis and the tricarboxylic acid cycle and is a major producer of acetyl-CoA, marking it as a potential metabolic and epigenetic node. To understand the role of pyruvate dehydrogenase complex in T cell differentiation, we generated mice deficient in T cell pyruvate dehydrogenase E1A (Pdha) subunit using a CD4-cre recombinase-based strategy. Herein, we show that genetic ablation of PDC activity in T cells (TPdh-/-) leads to marked perturbations in glycolysis, the tricarboxylic acid cycle, and OXPHOS. Due to depressed OXPHOS, TPdh-/- T cells became dependent upon substrate level phosphorylation via glycolysis. Due to the block of PDC activity, histone acetylation was reduced, including H3K27, a critical site for CD8+ T cell memory differentiation. Transcriptional and functional profiling revealed abnormal CD8+ memory T cell differentiation in vitro. Collectively, our data indicate that PDC integrates the metabolome and epigenome in memory T cell differentiation. Targeting this metabolic and epigenetic node can have widespread ramifications on cellular function.

ORGANISM(S): Mus musculus

PROVIDER: GSE231433 | GEO | 2023/08/07

REPOSITORIES: GEO

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Pyruvate dehydrogenase complex integrates the metabolome and epigenome in memory CD8+ T cell differentiation in vitro [RNA-Seq]

Project description:Modulation of metabolic flux through pyruvate dehydrogenase complex (PDC) plays an important role in T cell activation and differentiation. PDC sits at the transition between glycolysis and the tricarboxylic acid cycle and is a major producer of acetyl-CoA, marking it as a potential metabolic and epigenetic node. To understand the role of pyruvate dehydrogenase complex in T cell differentiation, we generated mice deficient in T cell pyruvate dehydrogenase E1A (Pdha) subunit using a CD4-cre recombinase-based strategy. Herein, we show that genetic ablation of PDC activity in T cells (TPdh-/-) leads to marked perturbations in glycolysis, the tricarboxylic acid cycle, and OXPHOS. Due to depressed OXPHOS, TPdh-/- T cells became dependent upon substrate level phosphorylation via glycolysis. Due to the block of PDC activity, histone acetylation was reduced, including H3K27, a critical site for CD8+ T cell memory differentiation. Transcriptional and functional profiling revealed abnormal CD8+ memory T cell differentiation in vitro. Collectively, our data indicate that PDC integrates the metabolome and epigenome in memory T cell differentiation. Targeting this metabolic and epigenetic node can have widespread ramifications on cellular function.

2023-08-07 | GSE231553 | GEO

Pyruvate dehydrogenase complex integrates the metabolome and epigenome in memory T cell differentiation in vitro [ATAC-Seq]

Project description:The chromatin landscape was assessed in effector and memory T-cells obtained from wildtype and pyruvate dehydrogenase knockout mouse. Disruption of the metabolic processes involving pyruvate dehydrogenase can affect T-cell differentiation through epigenetic and metabolic mechanisms.

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Transcription profiling of human Burkittas lymphoma cell line, P493-6 to identify hypoxia responsive genes

Project description:Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia. We found that HIF-1 also actively suppresses glucose metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA. Forced PDK1 expression in hypoxic HIF-1Î±-null cells increases ATP levels, attenuates hypoxic ROS generation and rescues these cells from hypoxia-induced apoptosis. These studies reveal a novel hypoxia-induced metabolic switch that shunts glucose metabolites from the mitochondria to glycolysis to maintain ATP production and to prevent toxic ROS production. Experiment Overall Design: We sought to determine by microarray analysis of gene expression the genes responsive to hypoxia using the human B lymphocyte cell line, P493-6. Hypoxia-responsive genes were globally assessed in cells incubated in 0.1% O2 for 29 hours at which the highest HIF-1 levels were obtained

2008-06-12 | E-GEOD-4086 | biostudies-arrayexpress

Hypoxia responsive genes in human Burkitt’s lymphoma cell line, P493-6.

Project description:Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia. We found that HIF-1 also actively suppresses glucose metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA. Forced PDK1 expression in hypoxic HIF-1α-null cells increases ATP levels, attenuates hypoxic ROS generation and rescues these cells from hypoxia-induced apoptosis. These studies reveal a novel hypoxia-induced metabolic switch that shunts glucose metabolites from the mitochondria to glycolysis to maintain ATP production and to prevent toxic ROS production. Keywords: Hypoxia responsive, case control

2006-03-16 | GSE4086 | GEO

Stimulation of glycolysis via the pyruvate dehydrogenase axis promotes cardiomyocyte proliferation after injury in adult zebrafish.

Project description:Cardiac metabolism plays a crucial role in producing sufficient energy to sustain cardiac contractions. However, the role of metabolism in cardiomyocyte proliferation remains unclear. Working with the adult zebrafish heart regeneration model, we first find an increase in the levels of mRNAs encoding enzymes regulating glucose and pyruvate metabolism, including pyruvate kinase M1/2 (Pkm) and pyruvate dehydrogenase kinases (Pdks), specifically in tissues bordering the damaged area. We proceed to show that impaired glycolysis decreases the number of proliferating cardiomyocytes following cardiac injury. These observations are further supported by analyses using loss-of-function models for the metabolic regulators Pkm2a and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (Ppargc1a). Cardiomyocyte-specific loss- and gain-of-function manipulations of pyruvate metabolism using Pdk3 and a catalytic subunit of the pyruvate dehydrogenase complex (PDC) reveal its importance in cardiomyocyte dedifferentiation and proliferation. Furthermore, we find that PDK activity can modulate cell cycle progression and protrusive activity in mammalian cardiomyocytes in culture. Our findings reveal new roles for cardiac metabolism and the PDK-PDC axis in cardiomyocyte behavior following cardiac injury.

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Stimulation of glycolysis promotes cardiomyocyte proliferation after injury in adult zebrafish

Project description:Cardiac metabolism plays a crucial role in producing sufficient energy to sustain cardiac function. However, the role of metabolism in different aspects of cardiomyocyte regeneration remains unclear. Working with the adult zebrafish heart regeneration model, we first find an increase in the levels of mRNAs encoding enzymes regulating glucose and pyruvate metabolism, including pyruvate kinase M1/2 (Pkm) and pyruvate dehydrogenase kinases (Pdks), especially in tissues bordering the damaged area. We further find that impaired glycolysis decreases the number of proliferating cardiomyocytes following injury. These observations are supported by analyses using loss-of-function models for the metabolic regulators Pkma2 and peroxisome proliferator-activated receptor gamma coactivator 1 alpha. Cardiomyocyte-specific loss- and gain-of-function manipulations of pyruvate metabolism using Pdk3 as well as a catalytic subunit of the pyruvate dehydrogenase complex (PDC) reveal its importance in cardiomyocyte dedifferentiation and proliferation after injury. Furthermore, we find that PDK activity can modulate cell cycle progression and protrusive activity in mammalian cardiomyocytes in culture. Our findings reveal new roles for cardiac metabolism and the PDK-PDC axis in cardiomyocyte behavior following cardiac injury.

2020-07-13 | PXD016235 | Pride

Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions (ATAC-Seq)

Project description:Pyruvate dehydrogenase (PDH) is the central enzyme connecting glycolysis and the tricarboxylic acid (TCA) cycle. The importance of PDH function in Th17 cells is unknown. Here, we show that PDH is essential for the generation of a unique glucose-derived citrate pool needed for Th17 cell proliferation, survival and effector function. In vivo, mice harboring a T cell-specific deletion of PDH were less susceptible to developing experimental autoimmune encephalomyelitis. Mechanistically, the absence of PDH in Th17 cells increased glutaminolysis, glycolysis, and lipid uptake in an mTOR-dependent manner. However, cellular citrate remained critically low in mutant Th17 cells, which interfered with oxidative phosphorylation (OXPHOS), lipid synthesis and histone acetylation crucial for the transcription of Th17 signature genes. Increasing cellular citrate in PDH-deficient Th17 cells restored their metabolism and function, identifying a metabolic feedback loop within central carbon metabolism that may offer possibilities for therapeutically targeting Th17 cell-driven autoimmunity.

2023-03-02 | GSE222878 | GEO

Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions (RNA-Seq II)

2023-03-02 | GSE222881 | GEO

Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions (RNA-Seq I)

2023-03-02 | GSE222880 | GEO

Gene expression in activated WT or PDK4 -/- CD4+ T cells

Project description:Activation of CD4+ T cells requires metabolic reprograming to sustain demands of cellular building blocks and ATP. Pyruvate dehydrogenase kinase (PDK) is an enzyme regulating pyruvate dehydrogenase complex subunit alpha 1 (PDHE1-alpha), which converts pyruvate to acetyl-CoA. Gene expression analysis of TCR-stimulated CD4+ T cells with PDK4 deletion exhibited the reduced calcium signaling and aerobic glycolysis pathway.

2022-11-01 | GSE161653 | GEO

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