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Alcohol metabolism directly fuels histone acetylation in the brain [ChIP-Seq]

ABSTRACT: In the adult brain, epigenetic control of gene expression has important roles in the processing of neural activity. Emerging evidence suggests that epigenetic regulation is dependent on metabolic state, implicating specific metabolic factors in neural functions that drive behavior. In neurons, histone acetylation is dependent on the metabolite acetyl-CoA that is produced from acetate by chromatin-bound ACSS21. Here, using in vivo stable isotope labeling in mouse, we show that alcohol metabolism rapidly fuels histone acetylation in the brain by direct deposition of alcohol-derived acetyl groups onto histones in an ACSS2-dependent manner. A similar induction was observed with heavy labeled acetate injection in vivo. Injection of labeled alcohol into a pregnant mouse results in incorporation of labeled acetyl groups into gestating fetal brains, indicating that the acetate passes through the placenta. In isolated primary hippocampal neurons ex vivo, extracellular acetate induced learning and memory-related transcriptional programs that were sensitive to ACSS2 inhibition. Strikingly, alcohol-related associative learning requires ACSS2 in vivo. These findings establish a novel and direct link between alcohol metabolism and neuronal ACSS2-dependent histone acetylation in the brain, providing evidence that dynamic acetate release from liver metabolism may travel to the brain for direct epigenetic regulation in neurons.

ORGANISM(S): Mus musculus

PROVIDER: GSE122186 | GEO | 2019/08/01

REPOSITORIES: GEO

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Alcohol metabolism directly fuels histone acetylation in the brain [RNA-Seq]

Project description:In the adult brain, epigenetic control of gene expression has important roles in the processing of neural activity. Emerging evidence suggests that epigenetic regulation is dependent on metabolic state, implicating specific metabolic factors in neural functions that drive behavior. In neurons, histone acetylation is dependent on the metabolite acetyl-CoA that is produced from acetate by chromatin-bound ACSS21. Here, using in vivo stable isotope labeling in mouse, we show that alcohol metabolism rapidly fuels histone acetylation in the brain by direct deposition of alcohol-derived acetyl groups onto histones in an ACSS2-dependent manner. A similar induction was observed with heavy labeled acetate injection in vivo. Injection of labeled alcohol into a pregnant mouse results in incorporation of labeled acetyl groups into gestating fetal brains, indicating that the acetate passes through the placenta. In isolated primary hippocampal neurons ex vivo, extracellular acetate induced learning and memory-related transcriptional programs that were sensitive to ACSS2 inhibition. Strikingly, alcohol-related associative learning requires ACSS2 in vivo. These findings establish a novel and direct link between alcohol metabolism and neuronal ACSS2-dependent histone acetylation in the brain, providing evidence that dynamic acetate release from liver metabolism may travel to the brain for direct epigenetic regulation in neurons.

2019-08-01 | GSE122181 | GEO

Alcohol metabolism directly fuels histone acetylation in the brain [RNA-Seq II]

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Acetyl-CoA metabolism by ACSS2 regulates neuronal histone acetylation and long-term memory [ChIP-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 directchum 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. Genome-wide examination of histone H3 and H4 acetylation, as well as ACSS2 binding, in undifferentiated CAD cells and differentiated CAD neurons; background adjusted by H3 ChIP or Input.

2017-05-01 | E-GEOD-76850 | biostudies-arrayexpress

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

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.

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ACSS2 and ACLY 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 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.

2024-08-01 | GSE262865 | 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.

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Enzymatic transfer of acetate on histones from lysine reservoir sites to lysine activating sites (ChIP-Seq)

Project description:Histone acetylation, a post-translational modification associated with transcriptional activation, is governed by nuclear acetyl-CoA pools that can vary depending on the metabolic state of the cell. The metabolic enzyme acetyl-CoA synthetase 2 (ACSS2) is proposed to regulate nuclear acetyl-CoA levels, using local acetate to produce acetyl-CoA that is utilized for histone acetylation. We hypothesize that during gene activation, a local transfer of intact acetate occurs between histones to upregulate transcription via sequential action of epigenetic and metabolic enzymes. Here we present converging lines of evidence in support of this acetate transfer to serve rapid gene induction. Using stable isotope labeling, we detect local transfer of intact acetate between histone acetylation sites both in vitro using purified mammalian enzymes and in vivo using quiescence exit in Saccharomyces cerevisiae as a change-of-state model. We delineate the enzymatic components required for this transfer mechanism, finding that ACSS2, histone deacetylase and histone acetyltransferase enzymes are necessary for efficient acetyl-group transfer in vitro. We show that Acs2, the yeast orthologue of ACSS2, is recruited to the genome during quiescence exit, and observe dynamic changes of histone acetylation in the vicinity of Acs2 peaks in vivo. Strikingly, we find that Acs2 is preferentially associated with the most upregulated growth genes, suggesting that acetyl-group transfer might play an important role in increased gene expression. Overall, our data reveal direct transfer of acetate between histone lysine residues to facilitate rapid transcriptional induction, an exchange that may be critical during metabolic alterations and changes in nutrient availability.

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Enzymatic transfer of acetate on histones from lysine reservoir sites to lysine activating sites (RNA-Seq)

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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.

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