ACSS2 drives senescence-associated secretory phenotype by limiting purine biosynthesis through PAICS acetylation
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ABSTRACT:
PROVIDER: PRJNA1145898 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30172617_1.fastq.gz | Fastqsanger.gz | |||
| SRR30172617_2.fastq.gz | Fastqsanger.gz | |||
| SRR30172618_1.fastq.gz | Fastqsanger.gz | |||
| SRR30172618_2.fastq.gz | Fastqsanger.gz | |||
| SRR30172619_1.fastq.gz | Fastqsanger.gz |
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Project description:Senescence-associated secretory phenotype (SASP), an established feature of cellular senescence, mediates the biological effects of senescent cell on tissue microenvironment and contributes to aging-associated disease progression. The metabolic enzyme ACSS2 produces acetyl-CoA from acetate and epigenetically regulates gene expression through histone acetylation. Whether and how ACSS2 regulates cellular senescence through non-histone acetylation mechanisms remain unclear. Here we show that ACSS2 drives SASP by promoting PAlCS acetylation to restrain purine metabolism. Genetic and pharmacological inhibition, as well as deletion of Acss2 in mice blunts SASP gene expression and abrogates the pro-tumorigenic and immune surveillance functions of senescent cells. Mechanistically, ACSS2 directly interacts and promotes acetylation of PAlCS, a key enzyme for purine metabolism. The acetylation of PAlCS promotes autophagy-mediated degradation of PAlCS to limit purine metabolism and reduces dNTP pools for DNA repair, which exacerbates cytoplasmic chromatin fragment (CCF) accumulation and SASP. Altogether, our work links ACSS2-mediated local acetyI-CoA generation to purine metabolism through PAlCS acetylation that dictates the functionality of SASP, and identify ACSS2 as a potential senomorphic target for healthy aging and to prevent senescence-associated diseases.
2025-02-10 | GSE275173 | GEO
Project description:Senescence-associated secretory phenotype (SASP), an established feature of cellular senescence, mediates the biological effects of senescent cell on tissue microenvironment and contributes to aging-associated disease progression. The metabolic enzyme ACSS2 produces acetyl-CoA from acetate and epigenetically regulates gene expression through histone acetylation. Whether and how ACSS2 regulates cellular senescence through non-histone acetylation mechanisms remain unclear. Here we show that ACSS2 drives SASP by promoting PAlCS acetylation to restrain purine metabolism. Genetic and pharmacological inhibition, as well as deletion of Acss2 in mice blunts SASP gene expression and abrogates the pro-tumorigenic and immune surveillance functions of senescent cells. Mechanistically, ACSS2 directly interacts and promotes acetylation of PAlCS, a key enzyme for purine metabolism. The acetylation of PAlCS promotes autophagy-mediated degradation of PAlCS to limit purine metabolism and reduces dNTP pools for DNA repair, which exacerbates cytoplasmic chromatin fragment (CCF) accumulation and SASP. Altogether, our work links ACSS2-mediated local acetyl-CoA generation to purine metabolism through PAlCS acetylation that dictates the functionality of SASP, and identify ACSS2 as a potential senomorphic target for healthy aging and to prevent senescence-associated diseases.
2025-02-10 | GSE274295 | GEO
Project description:ACSS2 drives senescence-associated secretory phenotype by limiting purine biosynthesis through PAICS acetylation
| PRJNA1149736 | ENA
Project description:Senescence-associated secretory phenotype (SASP) mediates the biological effects of senescent cells on the tissue microenvironment and contributes to ageing-associated disease progression. ACSS2 produces acetyl-CoA from acetate and epigenetically controls gene expression through histone acetylation under various circumstances. However, whether and how ACSS2 regulates cellular senescence remains unclear. Here, we show that pharmacological inhibition and deletion of Acss2 in mice blunts SASP and abrogates the pro-tumorigenic and immune surveillance functions of senescent cells. Mechanistically, ACSS2 directly interacts with and promotes the acetylation of PAICS, a key enzyme for purine biosynthesis. The acetylation of PAICS promotes autophagy-mediated degradation of PAICS to limit purine metabolism and reduces dNTP pools for DNA repair, exacerbating cytoplasmic chromatin fragment accumulation and SASP. Altogether, our work links ACSS2-mediated local acetyl-CoA generation to purine metabolism through PAICS acetylation that dictates the functionality of SASP, and identifies ACSS2 as a potential senomorphic target to prevent senescence-associated diseases.
| S-EPMC11871226 | biostudies-literature
Project description:Senescence-associated secretory phenotype (SASP), an established feature of cellular senescence, mediates the biological impacts of senescent cells on tissue microenvironments and contributes to ageing-associated disease progression. The metabolic enzyme ACSS2 produces acetyl-coA from acetate and epigenetically regulates gene expression mostly through histone acetylation. Whether and how ACSS2 regulates cellular senescence through non-histone acetylation mechanisms remain unclear. We used proximity labeling by turboID combined with LC-MS, identified PAICS, a key enzyme for purine metabolism which interacts with ACSS2. ACSS2 facilitates the acetylation of PAICS and promotes autophagy-mediated degradation of PAICS to limit purine metabolism and reduces dNTP pools for DNA damage repair, which results in cytoplasmic chromatin fragment (CCF) accumulation and SASP.
2025-02-13 | PXD048937 | Pride
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
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:Senescence-associated secretory phenotype (SASP), an established feature of cellular senescence, mediates the biological impacts of senescent cells on tissue microenvironments and contributes to ageing-associated disease progression. We used proximity labeling by turboID combined with LC-MS and identified PAICS, a key enzyme for purine metabolism which interacts with ACSS2. PAICS can be acetylated and the acetylation promotes autophagy-mediated degradation to limit purine metabolism and reduces dNTP pools for DNA damage repair, which results in cytoplasmic chromatin fragment (CCF) accumulation and SASP.
2025-02-13 | PXD048965 | Pride
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: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