Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1141714 | ENA |
REPOSITORIES: ENA
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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 | GSE122186 | GEO
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 | GSE122384 | GEO
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
Project description:Loss of cell identity and global epigenomic dysregulation are emerging as key contributors to Alzheimer’s disease (AD). The mechanisms by which protective or risk-conferring epigenetic marks are established and maintained are under intense investigation. ACSS2 (Acetyl-CoA Synthetase 2) is a key metabolic enzyme that is nuclear-localized in neurons. In healthy brains, ACSS2 fuels histone acetylation and drives expression of neuronal genes that regulate learning and memory. Here, we examine how loss of ACSS2 contributes to AD-associated cellular, genomic and behavioral outcomes, focusing on long-term steady state changes. Using a mouse model of human pathological AD-Tau injection, we show that loss of ACSS2 exacerbates Tau-related memory impairments, while dietary supplementation of acetate rescues learning in an ACSS2-dependent manner. Combining state-of-the-art proteomic and genomic approaches, we demonstrate that this effect is accompanied by ACSS2-dependent incorporation of acetate into hippocampal histone acetylation, which facilitates gene expression programs related to learning. We identify the most severely affected hippocampal neuronal populations, including pyramidal cells of the perforant pathway and Cajal-Retzius cells. Overall, these results reveal ACSS2 as a neuroprotective metabolic enzyme in key hippocampal neuronal populations, and dysregulation of which may play an important role in the etiology of AD. These findings may guide development of future therapies for AD, other tauopathies and related dementia.
2026-06-18 | GSE294751 | GEO
Project description:Loss of cell identity and global epigenomic dysregulation are emerging as key contributors to Alzheimer’s disease (AD). The mechanisms by which protective or risk-conferring epigenetic marks are established and maintained are under intense investigation. ACSS2 (Acetyl-CoA Synthetase 2) is a key metabolic enzyme that is nuclear-localized in neurons. In healthy brains, ACSS2 fuels histone acetylation and drives expression of neuronal genes that regulate learning and memory. Here, we examine how loss of ACSS2 contributes to AD-associated cellular, genomic and behavioral outcomes, focusing on long-term steady state changes. Using a mouse model of human pathological AD-Tau injection, we show that loss of ACSS2 exacerbates Tau-related memory impairments, while dietary supplementation of acetate rescues learning in an ACSS2-dependent manner. Combining state-of-the-art proteomic and genomic approaches, we demonstrate that this effect is accompanied by ACSS2-dependent incorporation of acetate into hippocampal histone acetylation, which facilitates gene expression programs related to learning. We identify the most severely affected hippocampal neuronal populations, including pyramidal cells of the perforant pathway and Cajal-Retzius cells. Overall, these results reveal ACSS2 as a neuroprotective metabolic enzyme in key hippocampal neuronal populations, and dysregulation of which may play an important role in the etiology of AD. These findings may guide development of future therapies for AD, other tauopathies and related dementia.
2026-02-18 | GSE294261 | GEO
Project description:Loss of cell identity and global epigenomic dysregulation are emerging as key contributors to Alzheimer’s disease (AD). The mechanisms by which protective or risk-conferring epigenetic marks are established and maintained are under intense investigation. ACSS2 (Acetyl-CoA Synthetase 2) is a key metabolic enzyme that is nuclear-localized in neurons. In healthy brains, ACSS2 fuels histone acetylation and drives expression of neuronal genes that regulate learning and memory. Here, we examine how loss of ACSS2 contributes to AD-associated cellular, genomic and behavioral outcomes, focusing on long-term steady state changes. Using a mouse model of human pathological AD-Tau injection, we show that loss of ACSS2 exacerbates Tau-related memory impairments, while dietary supplementation of acetate rescues learning in an ACSS2-dependent manner. Combining state-of-the-art proteomic and genomic approaches, we demonstrate that this effect is accompanied by ACSS2-dependent incorporation of acetate into hippocampal histone acetylation, which facilitates gene expression programs related to learning. We identify the most severely affected hippocampal neuronal populations, including pyramidal cells of the perforant pathway and Cajal-Retzius cells. Overall, these results reveal ACSS2 as a neuroprotective metabolic enzyme in key hippocampal neuronal populations, and dysregulation of which may play an important role in the etiology of AD. These findings may guide development of future therapies for AD, other tauopathies and related dementia.
2026-06-18 | GSE294331 | GEO
Project description:Alcohol intake is a risk factor for development of osteopenia. Ethanol perturbs gene expression in osteoblasts and osteoclasts and disrupts growth plate morphology. Hepatic metabolism of ethanol to acetate elevates concentrations of acetate in the circulation. We investigated whether acetate could mediate the toxicity of ethanol on gene expression in bone and on chondrocyte differentiation. When ethanol and acetate were compared by gavage for four consecutive days, none of eleven genes involved in bone homeostasis showed expression significantly affected by acetate, but the acetate responses significantly correlated with ethanol responses. Intraperitoneal injection with acetate to transiently elevate serum acetate for four consecutive days significantly increased expression of two markers of osteoclast differentiation, calcitonin receptor (Calcr) and Ocstamp. Early chondrogenic differentiation of ATDC5 cells for 7 days in vitro characterized by aggrecan (Acan) and collagen 2a1 (Col2a1) mRNA expression and proteoglycan production was inhibited by both 50 mM ethanol and 5 mM acetate. Ethanol effects were not blocked by the alcohol dehydrogenase inhibitor 4-methylpyrazole. 50 mM ethanol retarded both ATDC5 cell growth and culture medium acidification. Inhibition of chondrogenic differentiation by 5 mM acetate was associated with elevated phosphorylation of Erk1 and Erk2 and decreased expression of transcription factors Sox9 and Runx2. In acetate-exposed cells, blocking of Erk1 and Erk2 phosphorylation with Trametinib prevented further reduction of Acan and Col2a1 mRNA expression. We conclude that ethanol-derived acetate mediates at least part of the induction of Calcr and Ocstamp expression, and that acetate mimics effects of ethanol on early chondrogenic differentiation.
2025-09-24 | GSE287135 | GEO
Project description:We hypothesized that mouse Brpf1 plays critical roles in the morphology and function of hippocampal neurons, and its deficiency leads to learning and memory deficits. To test this, we performed immunofluorescence, whole-cell patch clamp, mRNA-Seq on shBrpf1 infected primary cultured hippocampal neurons to study the effect of Brpf1 knockdown on neuronal morphology, electrophysiological characteristics and gene regulation. In addition, we performed stereotactic injection into adult mouse hippocampus to knockdown Brpf1 in vivo and examined the learning and memory ability by Morris Water Maze. We found that mild knockdown of Brpf1 reduced mEPSC frequency of cultured hippocampal neurons, before any significant changes of dendritic morphology showed. We also found that hippocampal knockdown of Brpf1 reduced the learning and memory ability of mice to some extent. Finally, mRNA-Seq analyses showed that genes related to learning, memory, movement and synaptic transmission (such as C1ql1, Gpr17, Htr1d, Glra1, Cxcl10, Grin2a) were dysregulated upon Brpf1 knockdown. Our results showed that Brpf1 mild knockdown attenuated hippocampal excitatory neurotransmission and reduced learning and memory ability, which helps explain the symptoms of patients with BRPF1 mutations.
2021-05-19 | GSE174600 | GEO