ACSS2-coupled KAT2A regulates histone H3 lactylation in gene promoter regions and gene expression
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE278139 | GEO | 2024/10/01
REPOSITORIES: GEO
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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
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).
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Project description:Acetate metabolism is an important metabolic pathway in many types of cancers and is primarily controlled by acetyl-CoA synthetase 2 (ACSS2), an enzyme that catalyzes the conversion of acetate to acetyl-CoA. However, the consequences of inhibiting tumor acetate metabolism on the tumor microenvironment and anti-tumor immunity are unknown. Herein we demonstrate that the growth of ACSS2 deficient triple negative breast cancer is severely impaired when host immunity is intact and, in many instances, ACSS2 deficient tumors are fully cleared by the immune system. Pharmacological inhibition of ACSS2 using a potent small molecule inhibitor reproduces these effects and enhances the efficacy of standard of care chemotherapy for TNBC. Single cell RNA sequencing of vehicle versus ACSS2 inhibitor treated tumors indicates differentiation and activation of T cells suggesting a crosstalk between acetate metabolism and immune cells in the tumor microenvironment. Our data suggest that blocking ACSS2 and acetate metabolism in tumors increases the availability of acetate in the tumor microenvironment. Tumor infiltrating T cells can then use acetate as a fuel source due to the relatively high expression of acetyl-CoA synthetase 1 (ACSS1), which is impervious to ACSS2 inhibitors. In this manner, ACSS1-driven oxidation of acetate in T cells helps to metabolically bolster anti-tumor immune responses. Based on our findings, we propose a completely novel paradigm for ACSS2 inhibitors as metaboimmunomodulators that dually act as inhibitors of tumor cell metabolism and modulators of tumor immunity.
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Project description:Acetate metabolism is an important metabolic pathway in many types of cancers and is primarily controlled by acetyl-CoA synthetase 2 (ACSS2), an enzyme that catalyzes the conversion of acetate to acetyl-CoA. However, the consequences of inhibiting tumor acetate metabolism on the tumor microenvironment and anti-tumor immunity are unknown. Herein we demonstrate that the growth of ACSS2 deficient triple negative breast cancer is severely impaired when host immunity is intact and, in many instances, ACSS2 deficient tumors are fully cleared by the immune system. Pharmacological inhibition of ACSS2 using a potent small molecule inhibitor reproduces these effects and enhances the efficacy of standard of care chemotherapy for TNBC. Single cell RNA sequencing of vehicle versus ACSS2 inhibitor treated tumors indicates differentiation and activation of T cells suggesting a crosstalk between acetate metabolism and immune cells in the tumor microenvironment. Our data suggest that blocking ACSS2 and acetate metabolism in tumors increases the availability of acetate in the tumor microenvironment. Tumor infiltrating T cells can then use acetate as a fuel source due to the relatively high expression of acetyl-CoA synthetase 1 (ACSS1), which is impervious to ACSS2 inhibitors. In this manner, ACSS1-driven oxidation of acetate in T cells helps to metabolically bolster anti-tumor immune responses. Based on our findings, we propose a completely novel paradigm for ACSS2 inhibitors as metaboimmunomodulators that dually act as inhibitors of tumor cell metabolism and modulators of tumor immunity.
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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.
2017-05-01 | GSE76853 | GEO
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.
2017-05-01 | GSE76850 | GEO
Project description:We sequenced mRNA from 24 samples extracted from mouse CA1 tissue to generate the first CA1-specific murine transcriptome and the first CA1-transcriptome in response to environmental novelty under normal and Kat2a-loss-of-function conditions. Samples were divded in 4 groups: A: Control naM-CM-/ve (n=6), B: control novelty-exposed (n=5), C: Kat2a cKO naM-CM-/ve (n=6), D: Kat2a cKO novelty-exposed (n=7). Pairwise comparisons for AvsB, AvsC, BvsD and CvsD were performed using DESeq2.
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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 mammalian spatial object 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, and these hippocampal genes are pre-bound by ACSS2. These results reveal a unique connection between cellular metabolism, gene regulation, and neural plasticity, establishing a link between generation of acetyl-CoA “on-site” at chromatin of critical neuronal genes.
2017-05-01 | GSE90854 | GEO
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 mammalian spatial object 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, and these hippocampal genes are pre-bound by ACSS2. These results reveal a unique connection between cellular metabolism, gene regulation, and neural plasticity, establishing a link between generation of acetyl-CoA “on-site” at chromatin of critical neuronal genes.
2017-05-01 | GSE90853 | GEO
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 mammalian spatial object 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, and these hippocampal genes are pre-bound by ACSS2. These results reveal a unique connection between cellular metabolism, gene regulation, and neural plasticity, establishing a link between generation of acetyl-CoA “on-site” at chromatin of critical neuronal genes.
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