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ACSS2 and ACLY link nutrient-dependent chromatin accessibility to regulation of CD8 T cell effector responses

ABSTRACT: Coordination of cellular metabolism is essential for optimal T cell responses. Here, we identify cytosolic acetyl-CoA production as an essential metabolic node for CD8 T cell function in vivo. We show that acetyl-CoA derived from mitochondrial citrate via the enzyme ATP citrate lyase (Acly) is required for CD8 T cell responses to infection. However, ablation of Acly triggers an alternative, acetate-dependent pathway for acetyl-CoA production in T cells mediated by acyl-CoA synthetase short chain family member 2 (Acss2). Mechanistically, acetate fuels both the TCA cycle and cytosolic acetyl-CoA production, impacting T cell effector responses, acetate-dependent histone acetylation, and effector gene expression by altering chromatin accessibility. When Acly is functional, Acss2 is not required, suggesting acetate is not an obligate metabolic substrate for CD8 T cell function. However, deletion of Acly renders CD8 T cells dependent on acetate (via Acss2) to maintain acetyl-CoA production and effector function. Thus, together Acly and Acss2 coordinate cytosolic acetyl-CoA production in CD8 T cells to maintain chromatin accessibility and T cell effector function.

ORGANISM(S): Mus musculus

PROVIDER: GSE262865 | GEO | 2024/08/01

REPOSITORIES: GEO

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ACLY and ACSS2 link nutrient-dependent chromatin accessibility to regulation of CD8 T cell effector responses [RNA-seq]

Project description:Coordination of cellular metabolism is essential for optimal T cell responses. Here, we identify cytosolic acetyl-CoA production as an essential metabolic node for CD8 T cell function in vivo. We show that CD8 T cell responses to infection depend on acetyl-CoA derived from citrate via the enzyme ATP citrate lyase (ACLY). However, ablation of ACLY triggers an alternative, acetate-dependent pathway for acetyl-CoA production mediated by acyl-CoA synthetase short chain family member 2 (ACSS2). Mechanistically, acetate fuels both the TCA cycle and cytosolic acetyl-CoA production, impacting T cell effector responses, acetate-dependent histone acetylation, and chromatin accessibility at effector gene loci. When ACLY is functional, ACSS2 is not required, suggesting acetate is not an obligate metabolic substrate for CD8 T cell function. However, loss of ACLY renders CD8 T cells dependent on acetate (via ACSS2) to maintain acetyl-CoA production and effector function. Together, ACLY and ACSS2 coordinate cytosolic acetyl-CoA production in CD8 T cells to maintain chromatin accessibility and T cell effector function.

2024-07-04 | GSE270851 | GEO

ACLY and ACSS2 link nutrient-dependent chromatin accessibility to regulation of CD8 T cell effector responses

Project description:Coordination of cellular metabolism is essential for optimal T cell responses. Here, we identify cytosolic acetyl-CoA production as an essential metabolic node for CD8 T cell function in vivo. We show that CD8 T cell responses to infection depend on acetyl-CoA derived from citrate via the enzyme Acly (ATP citrate lyase). However, ablation of Acly triggers an alternative, acetate-dependent pathway for acetyl-CoA production mediated by Acss2 (acyl-CoA synthetase short chain family member 2). Mechanistically, acetate fuels both the TCA cycle and cytosolic acetyl-CoA production, impacting T cell effector responses, acetate-dependent histone acetylation, and chromatin accessibility at effector gene loci. When Acly is functional, Acss2 is not required, suggesting acetate is not an obligate metabolic substrate for CD8 T cell function. However, deletion of Acly renders CD8 T cells dependent on acetate (via Acss2) to maintain acetyl-CoA production and effector function. Thus, together Acly and Acss2 coordinate cytosolic acetyl-CoA production in CD8 T cells to maintain chromatin accessibility and T cell effector function.

2024-07-04 | GSE267377 | GEO

The proto-oncogene tyrosine kinase c-SRC facilitates glioblastoma progression by remodeling fatty acid synthesis

Project description:Increased fatty acid synthesis benefits glioblastoma malignancy. However, the coordinated regulation of cytosolic acetyl-CoA production, the exclusive substrate for fatty acid synthesis, remains unclear. Here, we show that proto-oncogene tyrosine kinase c-SRC is activated in glioblastoma and remodels cytosolic acetyl-CoA production for fatty acid synthesis. Firstly, acetate is an important substrate for fatty acid synthesis in glioblastoma. c-SRC phosphorylates acetyl-CoA synthetase ACSS2 at Tyr530 and Tyr562 to stimulate the conversion of acetate to acetyl-CoA in cytosol. Secondly, c-SRC inhibits citrate-derived acetyl-CoA synthesis by phosphorylating ATP-citrate lyase ACLY at Tyr682. ACLY phosphorylation shunts citrate to IDH1-catalyzed NADPH production to provide reducing equivalent for fatty acid synthesis. The c-SRC-unresponsive double-mutation of ACSS2 and ACLY significantly reduces fatty acid synthesis and hampers glioblastoma progression. In conclusion, this remodeling fulfills the dual needs of glioblastoma cells for both acetyl-CoA and NADPH in fatty acid synthesis and provides evidence for glioma treatment by c-SRC inhibition.

2024-07-29 | PXD054314 | Pride

Nutrient-driven histone code determines exhausted CD8+ T cell fates [ChIP-seq]

Project description:To investigate the role of ACSS2 and ACLY in the regulation of epigenetic states of CD8+ T cells in cancer and chronic viral infections Exhausted T cells (TEX) in cancer and chronic viral infections undergo metabolic and epigenetic remodeling, impairing protective capabilities. However, the impact of nutrient metabolism on epigenetic modifications that control TEX differentiation remains unclear. Our study reveals that TEX cells shift from acetate to citrate metabolism by downregulating acetyl-CoA synthetase 2 (ACSS2) while maintaining ATP-citrate lyase (ACLY) activity. This metabolic switch increases citrate-dependent histone acetylation, mediated by histone acetyltransferase KAT2A-ACLY interactions, at TEX signature-genes while reducing acetate-dependent histone acetylation, dependent on p300-ACSS2 complexes, at effector and memory T cell genes. Nuclear ACSS2 overexpression or ACLY inhibition prevents TEX differentiation and enhances tumor-specific T cell responses. These findings unveil a nutrient-driven histone code governing CD8+ T cell differentiation, with implications for metabolic- and epigenetic-based T cell therapies

2024-12-11 | GSE235005 | GEO

Nutrient-driven histone code determines exhausted CD8+ T cell fates [RNA-seq]

Project description:To investigate the role of ACSS2NLS in the regulation of CD8+ T cell responses in B16-GP33 tumor model Exhausted T cells (TEX) in cancer and chronic viral infections undergo metabolic and epigenetic remodeling, impairing protective capabilities. However, the impact of nutrient metabolism on epigenetic modifications that control TEX differentiation remains unclear. Our study reveals that TEX cells shift from acetate to citrate metabolism by downregulating acetyl-CoA synthetase 2 (ACSS2) while maintaining ATP-citrate lyase (ACLY) activity. This metabolic switch increases citrate-dependent histone acetylation, mediated by histone acetyltransferase KAT2A-ACLY interactions, at TEX signature-genes while reducing acetate-dependent histone acetylation, dependent on p300-ACSS2 complexes, at effector and memory T cell genes. Nuclear ACSS2 overexpression or ACLY inhibition prevents TEX differentiation and enhances tumor-specific T cell responses. These findings unveil a nutrient-driven histone code governing CD8+ T cell differentiation, with implications for metabolic- and epigenetic-based T cell therapies

2024-12-11 | GSE235006 | GEO

Hepatic ACLY deficiency and bempedoic acid drive divergent responses to dietary lipid

Project description:ATP citrate lyase (ACLY) synthesizes acetyl-CoA for de novo lipogenesis (DNL), which is elevated in non-alcoholic fatty liver disease. Hepatic ACLY is inhibited by the LDL-cholesterol lowering drug bempedoic acid (BPA), which has been shown to improve steatosis in mice. However, the acetyl-CoA synthetase ACSS2 can compensate for ACLY deficiency to support DNL, potentially complicating the targeting of ACLY. We show that hepatic loss of both ACLY and ACSS2 reduces DNL. Nevertheless, even when ACSS2 is suppressed by dietary or genetic means, we find that steatosis is counterintuitively exacerbated with hepatic ACLY deficiency in mice fed a Western diet (WD), linked to reduced expression of PPARa target genes controlling fatty acid oxidation. Conversely, BPA treatment increased fat catabolism and ameliorated WD-mediated lipid accumulation in both WT and liver ACLY knockout mice. Thus, hepatic ACLY plays an unexpected role in restraining diet-dependent lipid accumulation, and BPA improves steatosis independent of ACLY.

2024-08-01 | GSE247358 | GEO

The acetylcarnitine shuttle links mitochondrial metabolism to histone acetylation and lipogenesis

Project description:To understand the contribution of acetyl-CoA generating enzymes to epigenetic regulation we generated ACLY knockout, ACSS2 knockout, and ACLY/ACSS2 double knockout cell lines

2023-05-10 | GSE223966 | GEO

Acetyl-CoA metabolism by ACSS2 regulates neuronal histone acetylation and long-term memory [RNA-seq]

Project description:Metabolic production of acetyl-CoA has been linked to histone acetylation and gene regulation, however the mechanisms are largely unknown. We show that the metabolic enzyme acetyl-CoA synthetase 2 (ACSS2) is a critical and direct regulator of histone acetylation in neurons and of long-term mammalian memory. We observe increased nuclear ACSS2 in differentiating neurons in vitro. Genome-wide, ACSS2 binding corresponds with increased histone acetylation and gene expression of key neuronal genes. These data indicate that ACSS2 functions as a chromatin-bound co-activator to increase local concentrations of acetyl-CoA and to locally promote histone acetylation for transcription of neuron-specific genes. Remarkably, in vivo attenuation of hippocampal ACSS2 expression in adult mice impairs long-term spatial memory, a cognitive process reliant on histone acetylation. ACSS2 reduction in hippocampus also leads to a defect in upregulation of key neuronal genes involved in memory. These results reveal a unique connection between cellular metabolism and neural plasticity, and establish a link between generation of acetyl-CoA and neuronal chromatin regulation. Global survey of gene expression in CAD cells and differentiated CAD neurons following lentiviral knockdown of ACSS2 or ATP citrate lyase (ACL) (and control = scramble hairpin); survey of hippocampal gene expression changes associated with retrieval of fear memory, after ACSS2-AAV knockdown or in EGFP-AAV control (comparison of 0h vs. 1h post-memory retrieval).

2017-05-01 | E-GEOD-76853 | biostudies-arrayexpress

Long Noncoding RNA TINCR-mediated Regulation of Acetyl-CoA Metabolism Promotes Nasopharyngeal Carcinoma Progression and Chemoresistance

Project description:Our present study showed that lncRNA TINCR have impact on the ubiquitination-mediated degradation level of ACLY protein in nasopharyngeal carcinoma. Silencing of TINCR lead to downregulation of ACLY protein level. ACLY is a cytosolic homotetrameric enzyme catalyzing the ATP-dependent conversion of citrate and coenzyme A (CoA) to oxaloacetate and acetyl-CoA, a precursor for lipid biosynthesis, including cholesterol, free fatty acid and phospholipid. Meanwhile, the cellular acetyl-CoA pool is also required for acetylation reactions that modify proteins such as histone acetylation, including Histone H3 acetylation K27 (H3K27ac). To select the shared genes that were regulated by TINCR and were in response to acetyl-CoA alteration, we conducted RNA-seq in HONE-1 cells with or without TINCR or ACLY silencing, as well as H3K27ac Chromatin Immunoprecipitation sequencing (ChIP-seq) in HONE-1 cells with or without ACLY silencing. We also performed CLIP-seq in HONE-1 and SUNE-1 cells to validate the TINCR-ACLY interaction and identify the binding sites of TINCR with ACLY.

2022-09-25 | GSE137977 | GEO

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2024-10-16 | GSE271035 | GEO

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