Alcohol metabolism directly fuels histone acetylation in the brain [RNA-Seq II]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA504860 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8180270.fastq.gz | Fastqsanger.gz | |||
| SRR8180280.fastq.gz | Fastqsanger.gz | |||
| SRR8180271.fastq.gz | Fastqsanger.gz | |||
| SRR8180281.fastq.gz | Fastqsanger.gz | |||
| SRR8180272.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 21 |
Similar Datasets
Project description:Alcohol metabolism directly fuels histone acetylation in the brain
| PRJNA503891 | ENA
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:Alcohol metabolism directly fuels histone acetylation in the brain [RNA-Seq]
| PRJNA503885 | ENA
Project description:Alcohol metabolism directly fuels histone acetylation in the brain [ChIP-Seq]
| PRJNA503893 | ENA
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 | GSE122181 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below. Reviewers: for a UCSC Genome Browser session of the chIP-seq and the ex vivo RNA-seq, please see: https://genome.ucsc.edu/cgi-bin/hgTracks?hgS_doOtherUser=submit&hgS_otherUserName=Gdonahue&hgS_otherUserSessionName=Alcohol%20Metabolism%20Publication
2019-08-01 | GSE122188 | GEO
Project description:Alcohol consumption induces hepatocyte damage through complex processes involving oxidative stress and disrupted metabolism. Combined, these factors alter proteomic and epigenetic marks providing a critical opportunity to identify therapeutic targets. Indeed, alcohol-induced protein acetylation is a key post-translational modification (PTM) that regulates hepatic metabolism and is associated with the pathogenesis of alcohol-associated liver disease (ALD). Interestingly, recent evidence suggests lysine acetylation occurs when a proximal cysteine residue is within ~15 Å of a lysine residue, referred to as a cysteine-lysine (Cys-Lys) pair. Here, acetylation can occur through the transfer of an acetyl moiety via an S à N acetyl transfer reaction. Alcohol-mediated hepatic redox stress is known to occur coincident with lysine acetylation, but the biochemical mechanisms related to cysteine and lysine crosstalk within ALD remain unexplored. A chronic murine model of ALD was employed to quantify hepatic cysteine redox and lysine acetylation, revealing that alcohol metabolism significantly reduced the cysteine proteome and increased protein acetylation. Interrogating both cysteine redox and lysine acetylation datasets, 1,281 proteins were mapped by AlphaFold2 to quantify distances between 557,815 cysteine and lysine residues. This process identified 388,698 Cys-Lys pairs that were further used to evaluate thiol redox signaling. Our analysis reveals that alcohol metabolism induces redox changes and acetylation selectively on proximal Cys-Lys pairs with an odds ratio of 1.89 (p< 0.0001). We also identified key redox signaling hubs embedded in metabolic pathways associated with ALD, including lipid metabolism, the TCA cycle, and the electron transport chain. Specific protein targets embedded across these pathways include Echs1, Glrx5, Decr2, and Adh1, among many others. Interestingly, these proximal Cys-Lys exist as four major protein motifs represented by the number of Cys and Lys residues that are pairing (Cysx-Lysx). These motifs include Cys1:Lys1, Cysx:Lys1, Cys1:Lysx and Cysx:Lysx each with a unique microenvironment likely indicative of the mode of enzymatic regulation occurring. The motifs are composed of functionally relevant amino acids altered within ALD, identifying sites of therapeutic potential. Furthermore, these unique Cys-Lys redox signatures are translationally relevant as revealed by orthologous comparison with severe alcohol-associated hepatitis (SAH) explants, revealing numerous pathogenic thiol redox signals in these patients.
2024-12-17 | PXD054686 | Pride
Project description:Post-translational acetylation of proteins at lysine side chains by the central metabolite acetyl-CoA, is a crucial regulator of proteostasis. Ethanol metabolism in the liver induces protein acetylation and disrupts hepatic substrate metabolism. While acetylation can influence gene transcription, enzyme activity, and stability of proteins, the role of ethanol-induced acetylation in hepatic metabolism is still unclear. We used a 2H2O-based metabolic labeling approach to investigate the impact of ethanol-induced acetylation on liver metabolism in a murine model of chronic ethanol-induced liver injury. Mice were fed an ethanol containing diet for 25 days; liver proteins and acetylation patterns were monitored during the final 21 days of 2H2O labeling. The proteome, acetylome, and targeted metabolic profiling were conducted to evaluate ethanol-induced alterations in hepatic metabolism. Ethanol consumption induced hepatic steatosis, inflammation, and oxidative stress. It led to reduced turnover of mitochondrial proteins and increased turnover of cytosolic stress response proteins and metabolic enzymes. Ethanol elevated acetylation levels of mitochondrial metabolic enzymes and nuclear histones, with no significant changes in the cytosol. Acetylation stabilized mitochondrial proteins but destabilized histones. Ethanol-induced reduced mitochondrial protein turnover, linked to increased acetylation, led to hepatic protein accumulation. Impaired proteasomal and lysosomal degradation contributed to alcohol-induced hepatic proteopathy. These changes were associated with altered levels of acyl-CoAs and acyl-carnitines, amino acids, and tricarboxylic acid (TCA) cycle intermediates, reflecting impaired fatty acid oxidation, nitrogen disposal and citric acid cycle activities. In conclusion, ethanol-induced alterations in acetylome dynamics could modify hepatic substrate metabolism and contribute to liver injury in alcohol-associated liver disease through acetylation-dependent epigenetic changes and the regulation of metabolic enzymes.
2025-08-04 | PXD055349 | Pride
Project description:Alcohol is among the most widely consumed dietary substances. While excessive alcohol consumption damages the liver, heart and brain, clinical observations also suggest that alcohol has strong immunoregulatory properties. However, little is known about the mechanistic effects of alcohol on the immune system. T cell functions such as migration, immune synapse formation and activation depend on the reorganization of the cytoskeleton. In this study, we show that acetate, the metabolite of alcohol, effectively inhibits the migratory capacity of T cells through increased tissue acetate levels that lead to acetylation of cortactin, a protein that binds filamentous actin and facilitates branching. Current knowledge of cortactin’s role in T cells is limited. Here we demonstrate and confirm that primary mouse and human T cells express cortactin and acetylation of cortactin inhibits actin filament binding leading to reduced filament branching, lamellipodia formation and T cell migration. Mutated acetylation-resistant cortactin rescued the acetate-induced inhibition of T cell migration. Primary mouse cortactin knock-out T cells exhibited severely reduced T cell migration. Furthermore, acetate-induced cytoskeletal changes effectively inhibited activation, proliferation, and immune synapse formation in T cells exposed to acetate at tissue concentrations reached by alcohol consumption. In summary, these data show that acetate, the key metabolite of alcohol, is inhibiting T cell mediated immune responses by modulating the biomechanics of T cells through their cytoskeletal function.
2023-10-24 | PXD037723 | Pride