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Lipids reprogram metabolism to become a major carbon source for histone acetylation

ABSTRACT: We found that lipid-derived acetyl-CoA is a major source of carbon for histone acetylation. Gene expression profiling of octanoate-treated hepatocytes identified a pattern of upregulated lipid metabolic genes, demonstrating a specific transcriptional response to lipid. These studies expand the landscape of nutrient sensing and uncover how lipids and metabolism are integrated by epigenetic events that control gene expression.

ORGANISM(S): Mus musculus

PROVIDER: GSE87156 | GEO | 2016/09/22

SECONDARY ACCESSION(S): PRJNA343729

REPOSITORIES: GEO

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Lipids reprogram cellular metabolism to become a major carbon source for histone acetylation.

Project description:From McDonnell et. al. Cell Reports 2016: Cells integrate nutrient sensing and metabolism to coordinate proper cellular responses to a particular nutrient source. For example, glucose drives a gene expression program characterized by activating genes involved in its metabolism, in part, by increasing glucose-derived histone acetylation. Here, we find that lipid-derived acetyl-CoA is a major source of carbon for histone acetylation. Using 13C-carbon tracing combined with acetyl-proteomics, we show that up to 90% of acetylation on certain histone lysines can be derived from fatty acid carbon, even in the presence of excess glucose. By repressing both glucose and glutamine metabolism, fatty acid oxidation reprograms cellular metabolism leading to increased lipid-derived acetyl-CoA. Gene expression profiling of octanoate-treated hepatocytes shows a pattern of upregulated lipid metabolic genes, demonstrating a specific transcriptional response to lipid. These studies expand the landscape of nutrient sensing and uncover how lipids and metabolism are integrated by epigenetic events that control gene expression.

2016-12-22 | PXD005040 | Pride

Lipids Reprogram Metabolism to Become a Major Carbon Source for Histone Acetylation.

Project description: Not available

| S-EPMC5123807 | biostudies-literature

Multi-acetylated histones are a source of carbon for lipid synthesis

Project description:Histone modifications commonly integrate environmental stimuli to cellular metabolic outputs by affecting gene expression. Many modifications, including some histone acetylation marks, do not always correlate to transcription, thus pointing towards an alternative role of histone modifications as potential metabolic reservoirs. Using an approach that integrates mass spectrometry- based epi-proteomics and metabolomics with stable isotope tracer studies, we demonstrate that elevated lipids in histone acetyltransferase (HAT)-depleted hepatocytes result from carbon atoms flowing from the deacetylation of multi-acetylated histone H4 to fatty acids. Consistent with this, the enhanced lipid synthesis in HAT-depleted hepatocytes is dependent on the activity of histone deacetylases (HDACs) and acetyl-CoA synthetase ACSS2. Furthermore, we show that during diet-induced lipid synthesis there is a reduction of multi-acetylated histone H4 in hepatocytes and in mouse liver. In addition, overexpression of histone acetyltransferases can reverse diet-induced lipogenesis by blocking lipid droplet accumulation and maintaining the levels of multi-acetylated histone H4. This study unveils an additional link between epigenetics and metabolism whereby histone acetylation reservoirs may serve as a carbon source for lipid synthesis.

2024-02-14 | PXD042624 | Pride

RNA-seq analysis of Schwann cell knockout of ATP citrate lyase (ACLY)

Project description:Formation of myelin by Schwann cells is tightly coupled to nervous system development and is important for neuronal function and long-term maintenance. Perturbation of myelin causes a number of specific disorders that are among the most prevalent diseases affecting the nervous system. Schwann cells synthesize myelin lipids de novo rather than relying on uptake of circulating lipids, and the metabolic sources of myelin formation and maintenance in vivo remain unresolved. One of these questions is how a central metabolite in myelin formation, Acetyl CoA, is generated in myelinating cells. Acetyl CoA-generating pathways are induced at the level of gene expression to support high demands for lipid synthesis and acetylation reactions. However, recent studies have shown that glucose-derived Acetyl CoA itself is not required for myelination, and the requirements of mitochondrially-derived Acetyl CoA has never been tested for myelination in vivo. Several older labeling studies have demonstrated the possibility that cytosolic Acetyl CoA-generating pathways from acetate/ketone bodies satisfy the high demands for lipid synthesis and histone acetylation, and we have employed knockout mice to test the required pathways. Intriguingly, metabolic pathways play different role during the postnatal synthesis of myelin lipids in the postnatal period compared to myelin maintenance postweaning.

2024-02-01 | GSE252209 | GEO

Characterization of lysine acetylation in Toxoplasma gondii proteome lacking acetyl-CoA transporter 1 (AT1).

Project description:Acetyl-CoA participates in post-translational modification of proteins, central carbon and lipid metabolism in several cell compartments. In mammals, the acetyl-CoA transporter 1 (AT1) facilitates the flux of cytosolic acetyl-CoA into the endoplasmic reticulum (ER), enabling the acetylation of proteins of the secretory pathway, in concert with dedicated acetyltransferases including Nat8. However, the implication of the ER acetyl-CoA pool in acetylation of ER-transiting proteins and their relevance throughout the parasites’ life cycle is unknown. Here, we evaluated the impact of blocking putative cytosolic acetyl-CoA import on acetylation of proteins through KO of the homologue of AT1 in the parasite Toxoplasma gondii.

2022-07-25 | PXD030932 | Pride

RNA-sequencing analysis of glucose and acetate regulated transcripts in glioblastoma cells

Project description:Our studies indicate that glucose and acetate can regulate histone acetylation by altering the acetyl-CoA concentrations in the cell. The purpose of this study was to to determine whether specific gene sets correlated with acetyl-CoA availability. We conclude that 10% of glucose-regulated genes are acetyl-CoA regulated genes (genes suppressed or induced by low glucose and reversed by acetate). Acetate usually regulated gene expression in the same direction as glucose, suggesting that acetyl-CoA is a key mediator of glucose-dependent gene expression. The experiments were performed in quadruplicates for each condition with a total of 12 samples

2014-08-05 | E-GEOD-57488 | biostudies-arrayexpress

Cytosolic acetyl-CoA promotes histone acetylation predominantly at H3K27 in Arabidopsis

Project description:Acetyl-Coenzyme A (acetyl-CoA) is a central metabolite and the acetyl source for protein acetylation, particularly histone acetylation that promotes gene expression. However, the effect of acetyl-CoA levels on histone acetylation status in plants remains unknown. Here, we show that malfunctioned cytosolic acetyl-CoA carboxylase1 (ACC1) in Arabidopsis leads to elevated levels of acetyl-CoA and promotes histone hyperacetylation predominantly at lysine 27 of histone H3 (H3K27). The increase of H3K27 acetylation (H3K27ac) is dependent on ATP-citrate lyase which cleaves citrate to acetyl-CoA in the cytoplasm, and requires histone acetyltransferase GCN5. A comprehensive analysis of the transcriptome and metabolome in combination with the genome-wide H3K27ac profiles of acc1 mutants, demonstrate the dynamic changes of H3K27ac, gene transcripts and metabolites occurring in the cell by the increased levels of acetyl-CoA. This study suggests that H3K27ac is an important link between cytosolic acetyl-CoA level and gene expression in response to the dynamic metabolic environments in plants.

2017-09-25 | GSE79524 | GEO

Nucleoside-Diphosphate Kinase 1 and 2 (Nme1/2) are major cellular co-enzyme A/acetyl-CoA binding factors

Project description:Co-enzyme A is the essential cellular carrier of the acetyl group, largely used in fatty acid synthesis and lysine post-translational modifications of proteins. Following the analysis of the cellular CoA-binding proteome, we identified Nme1/2 as major abundant cytoplasmic CoA-binding proteins. We report a novel mechanism that controls fatty acids synthesis involving ATP-dependent acetyl-CoA binding by Nucleoside Diphosphate Kinases 1 and 2 (Nme1/2).

2023-08-01 | PXD029159 | Pride

The ageing epigenome regulates stem cell fate via mitochondrial-derived vesicles delivery of citrate carrier to lysosomes [CUT&RUN]

Project description:We report that upon ageing MSC exhibit reduced metabolic rates, with lower lipid biosynthesis and elevated acetyl-CoA levels. However, aged cells display chromatin compaction and histone hypo-acetylation, particularly on enhancers of genes involved in osteogenesis. This is due to the lower levels of citrate carrier, resulting in impaired acetyl-CoA export from mitochondria to the cytosol, which concomitantly affects histone acetylation and osteogenesis. CiC gets degraded in the aged cells via an MVD-lysosomal pathway, which establishes a strong connection between mitochondrial quality control, chromatin and stemness.

2021-07-08 | GSE155714 | GEO

The ageing epigenome regulates stem cell fate via mitochondrial-derived vesicles delivery of citrate carrier to lysosomes [CUT&RUN_H3AC]

2021-07-08 | GSE173358 | GEO

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