Mitochondrial fatty acid oxidation regulates monocytic type I interferon signaling via histone acetylation.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1175027 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31047500_1.fastq.gz | Fastqsanger.gz | |||
| SRR31047500_2.fastq.gz | Fastqsanger.gz | |||
| SRR31047501_1.fastq.gz | Fastqsanger.gz | |||
| SRR31047501_2.fastq.gz | Fastqsanger.gz | |||
| SRR31047502_1.fastq.gz | Fastqsanger.gz |
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Project description:Although lipid-derived acetyl-CoA is a major carbon source for histone acetylation, the contribution of fatty acid -oxidation (FAO) to this process remains poorly characterized. To investigate this, we generated mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1, distal FAO enzyme) knockout macrophages. 13C-carbon tracing confirmed reduced FA-derived carbon incorporation into histone H3 and RNA-seq identified diminished interferon stimulated gene expression in the absence of ACAT1. Chromatin accessibility at Stat1 locus was diminished in ACAT1-/- cells. CHIP analysis demonstrated reduced acetyl-H3 binding to Stat1 promoter/enhancer regions and increasing histone acetylation rescued Stat1 expression. IFNβ release was blunted in ACAT1-/- and recovered by ACAT1 reconstitution. Furthermore, ACAT1-dependent histone acetylation required an intact acetylcarnitine shuttle. Finally, obese subjects’ monocytes exhibited increased ACAT1 and histone acetylation levels. Thus, our study identifies a novel link between FAO-mediated epigenetic control of type 1 interferon signaling and uncovers a potential mechanistic link between obesity and type I inferon signaling.
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Project description:Metabolic remodeling is one of the earliest events that occur during the early differentiation of embryonic stem cells (ESCs), but how these metabolic changes are regulated and participate in the cell differentiation is still largely undissected. Here, we define the fatty acid metabolism as a key player in definitive endoderm (DE) differentiation from human ESCs. During DE differentiation, lipogenesis is decreased while fatty acid β oxidation is enhanced. This dynamic is due to the phosphorylation of lipogenic enzyme acetyl-CoA carboxylase (ACC), which is mediated by AMP-activated protein kinase (AMPK) and inhibits the de novo fatty acid synthesis. More importantly, inhibition of fatty acid synthesis by either its inhibitors or AMPK agonist, significantly promotes the human endoderm differentiation, while blockade of the fatty acid oxidation by genetic manipulation or chemical antagonists impairs the differentiation. The de novo fatty acid synthesis inhibition and fatty acid β oxidation maintaining contribute to the accumulation of cellular acetyl-CoA, which is the essential substrate for protein acetylation. Further study reveals that SMAD3 acetylation and the subsequent subcellular localization exhibit significant change upon interfering fatty acid metabolism. Mechanistically, the accumulation of cellular acetyl-CoA guarantees the acetylation of key transcription factor SMAD3, which further causes the nuclear localization and activation of SMAD signaling pathway to promote DE differentiation. Thus, our current study reveals a fatty acid synthesis/oxidation shift during early differentiation and presents an instructive role of fatty acid metabolism in regulating human early endoderm differentiation.
2023-07-02 | GSE217992 | GEO
Project description:Although lipid-derived acetyl-coenzyme A (CoA) is a major carbon source for histone acetylation, the contribution of fatty acid β-oxidation (FAO) to this process remains poorly characterized. To investigate this, we generated mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1, distal FAO enzyme) knockout macrophages. 13C-carbon tracing confirmed reduced FA-derived carbon incorporation into histone H3, and RNA sequencing identified diminished interferon-stimulated gene expression in the absence of ACAT1. Chromatin accessibility at the Stat1 locus was diminished in ACAT1-/- cells. Chromatin immunoprecipitation analysis demonstrated reduced acetyl-H3 binding to Stat1 promoter/enhancer regions, and increasing histone acetylation rescued Stat1 expression. Interferon-β release was blunted in ACAT1-/- and recovered by ACAT1 reconstitution. Furthermore, ACAT1-dependent histone acetylation required an intact acetylcarnitine shuttle. Last, obese subjects' monocytes exhibited increased ACAT1 and histone acetylation levels. Thus, our study identifies an intriguing link between FAO-mediated epigenetic control of type I interferon signaling and uncovers a potential mechanistic nexus between obesity and type I interferon signaling.
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Project description:Metabolic remodeling is one of the earliest events that occur during the early differentiation of embryonic stem cells (ESCs), but how these metabolic changes are regulated and participate in the cell differentiation is still largely undissected. Here, we define the fatty acid metabolism as a key player in definitive endoderm (DE) differentiation from human ESCs. During DE differentiation, lipogenesis is decreased while fatty acid β oxidation is enhanced. This dynamic is due to the phosphorylation of lipogenic enzyme acetyl-CoA carboxylase (ACC), which is mediated by AMP-activated protein kinase (AMPK) and inhibits the de novo fatty acid synthesis. More importantly, inhibition of fatty acid synthesis by either its inhibitors or AMPK agonist, significantly promotes the human endoderm differentiation, while blockade of the fatty acid oxidation by genetic manipulation or chemical antagonists impairs the differentiation. The de novo fatty acid synthesis inhibition and fatty acid β oxidation maintaining contribute to the accumulation of cellular acetyl-CoA, which is the essential substrate for protein acetylation. Further study reveals that SMAD3 acetylation and the subsequent subcellular localization exhibit significant change upon interfering fatty acid metabolism. Mechanistically, the accumulation of cellular acetyl-CoA guarantees the acetylation of key transcription factor SMAD3, which further causes the nuclear localization and activation of SMAD signaling pathway to promote DE differentiation. Thus, our current study reveals a fatty acid synthesis/oxidation shift during early differentiation and presents an instructive role of fatty acid metabolism in regulating human early endoderm differentiation.
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Project description:Lymphatic vessels are involved in fluid drainage and are critical for health. To date, only genetic signaling pathways have been implicated in lymphatic development, and a role for metabolism has not been described. Here, we report that transcription factor Prox1 increases fatty acid ß-oxidation (FAO) through upregulation of CPT1a, a rate-controlling step of FAO. Lymphatic endothelial cells (LECs) oxidize fatty acids to proliferate and migrate. By providing acetyl-CoA, FAO is also critical for the maintenance of differentiated LECs through the regulation of histone acetylation of key lymphangiogenic genes. Loss of CPT1a in LEC precursors causes lymphatic defects in vivo, while restoration of acetyl-CoA by supplementing acetate to replenish cellular acetyl-CoA levels rescues this process.
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Project description:Long-chain fatty acid β-oxidation regulates embryonic development by H3K18 acetylation in mice [RNA-seq]
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Project description:Fatty acids are not only important as energy sources, but also playing crucial roles in maintaining cellular homeostasis.Inhibition of long-chain fatty acid β-oxidation (LCFAO) results in preimplantation developmental arrest, downregulated expressions of S phase-related genes, and loss of H3K18ac modification. By profiling the landscape of H3K18ac, we show that H3K18ac is enriched on the promoter regions of S phase-related genes and correlates with their expression. Taken together, we demonstrate that LCFAO could regulate mouse preimplantation development by H3K18ac, providing new evidence for metabolic-epigenetic crosstalk in regulating embryonic development.
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Project description:Fatty acids are not only important as energy sources, but also playing crucial roles in maintaining cellular homeostasis.Inhibition of long-chain fatty acid β-oxidation (LCFAO) results in preimplantation developmental arrest, downregulated expressions of S phase-related genes, and loss of H3K18ac modification. By profiling the landscape of H3K18ac, we show that H3K18ac is enriched on the promoter regions of S phase-related genes and correlates with their expression. Taken together, we demonstrate that LCFAO could regulate mouse preimplantation development by H3K18ac, providing new evidence for metabolic-epigenetic crosstalk in regulating embryonic development.
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