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ATP-citrate lyase regulates chromatin-dependent activation and maintenance of the myofibroblast gene program and cardiac fibrosis

ABSTRACT: ATP-citrate lyase regulates chromatin-dependent activation and maintenance of the myofibroblast gene program and cardiac fibrosis

PROVIDER: PRJNA970472 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24474174_1.fastq.gz	Fastqsanger.gz
	SRR24474174_2.fastq.gz	Fastqsanger.gz
	SRR24474175_1.fastq.gz	Fastqsanger.gz
	SRR24474175_2.fastq.gz	Fastqsanger.gz
	SRR24474176_1.fastq.gz	Fastqsanger.gz

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ATP-citrate lyase regulates chromatin-dependent activation and maintenance of the myofibroblast gene program and cardiac fibrosis

Project description:Differentiation of cardiac fibroblasts (CFs) to myofibroblasts is necessary for matrix remodeling and fibrosis in heart failure. We previously reported mitochondrial calcium signaling drives α-ketoglutarate-dependent histone demethylation, promoting the myofibroblast gene program. Here, we investigated the role of ATP-citrate lyase (ACLY), a key enzyme for acetyl-CoA biosynthesis, in histone acetylation regulating myofibroblast formation and persistence in cardiac fibrosis. Inactivation of ACLY prevented, and importantly reversed, myofibroblasts towards quiescence. Genetic deletion of Acly in activated myofibroblasts prevented fibrosis and preserved cardiac function in murine pressure-overload. TGFβ stimulation enhanced ACLY nuclear localization and increased H3K27ac at fibrotic gene loci. Pharmacological inhibition of ACLY or forced nuclear expression of dominant-negative ACLY mutant prevented myofibroblast formation and H3K27ac. Our data indicate nuclear ACLY activity is necessary for myofibroblast differentiation and persistence by maintaining histone acetylation at TGFβ-induced myofibroblast genes. These findings provide novel clinical rational to prevent and reverse pathological fibrosis. CUT&RUN Sequencing for H3K27ac on the role of ACLY in myofibroblast differentiaton.

2024-05-16 | GSE232010 | GEO

The role of ATP citrate lyase in myelin formation and maintenance

Project description:Schwann cell-specific knockout of ATP citrate lyase (ACLY) revealed that this pathway is important for myelin maintenance rather than formation, and ACLY is required to maintain expression of a myelin-associated gene program.

2024-05-03 | MSV000094670 | MassIVE

Toll-like receptor signaling rewires macrophage metabolism and promotes histone acetylation via ATP-citrate lyase

Project description:TLR activation induces inflammatory responses in macrophages by activating temporally defined transcriptional cascades within the first hours after stimulation. Whether concurrent changes in the cellular metabolism that occur upon TLR activation influence the quality of the transcriptional responses remain unknown. Here we investigated how macrophages adopt their metabolism early after activation to regulate TLR-inducible gene induction. Macrophages increase glucose metabolism and adopt fluxes through the TCA cycle to foster Citrate synthesis. We concomitantly observe activation of ATP-Citrate Lyase (Acly), resulting in augmented acetyl-CoA synthesis and histone acetylation. To investigate which genes and genes classes require ATP-citrate lyase activity for induction we stimulated bone marrow derived macrophages with LPS after ATP-citrate lyase inhibition.

2019-12-16 | GSE129497 | GEO

Macrophage ATP citrate lyase deficiency stabilizes atherosclerotic plaques

Project description:Macrophage ATP citrate lyase deficiency stabilizes atherosclerotic plaques

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GNPS - The role of ATP citrate lyase in myelin formation and maintenance

2024-05-03 | MSV000094670 | GNPS

Selective autophagic degradation of ATP citrate lyase maintains citrate homeostasis and promotes oocyte maturation

Project description:Selective autophagic degradation of ATP citrate lyase maintains citrate homeostasis and promotes oocyte maturation

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Selective autophagic degradation of ATP citrate lyase maintains citrate homeostasis and promotes oocyte maturation

Project description:Autophagy is a cellular and energy homeostatic mechanism that contributes to maintain the number of primordial follicles, germ cell survival, and anti-ovarian aging. However, it remains unknown whether autophagy in granulosa cells affects the oocyte maturation. Here, we show a clear tendency of reduced autophagy level in human granulosa cell from women of advanced maternal age, implying a potential negative correlation between autophagy level and oocyte quality. We therefore established a co-culture system and show that either pharmacological inhibition or genetic ablation of autophagy in granulosa cells negatively affect the oocyte quality and fertilization ability. Moreover, our metabolomics analysis indicates that the adverse impact of autophagy impairment on oocyte quality is mediated by downregulated citrate levels, while exogenous supplementation of citrate can significantly restore the oocyte maturation. In molecular level, we found ATP citrate lyase (Acly), which is a crucial enzyme catalyzing the cleavage of citrate, was preferentially associated with K63-linked ubiquitin chains and recognized by the autophagy receptor protein SQSTM1/p62 for the selective autophagic degradation. In human follicles, autophagy levels in granulosa cells was downregulated with maternal aging, accompanied by decreased citrate in the follicular fluid, implying a potential correlation between citrate metabolism and oocyte quality. We also show that elevated citrate levels in porcine follicular fluid promote oocyte maturation. Collectively, our data reveal that autophagy in granulosa cells is a beneficial mechanism to maintain a certain degree of citrate by selectively targeting Acly during oocyte maturation.

2023-01-09 | GSE190697 | GEO

Macrophage ATP citrate lyase deficiency stabilizes atherosclerotic plaques

Project description:Macrophages represent a major immune cell population in atherosclerotic plaques and play central role in the progression of this lipid-driven chronic inflammatory disease. Targeting immunometabolism is proposed as a strategy to revert aberrant macrophage activation to improve disease outcome. Here, we show ATP citrate lyase (Acly) to be activated in inflammatory macrophages and human atherosclerotic plaques. We demonstrate that myeloid Acly deficiency induces a stable plaque phenotype characterized by increased collagen deposition and fibrous cap thickness, along with a smaller necrotic core. In-depth functional, lipidomic, and transcriptional characterization indicate deregulated fatty acid and cholesterol biosynthesis and reduced liver X receptor (LXR) activation within the macrophages in vitro. This results in macrophages that are more prone to undergo apoptosis, whilst presenting increased phagocytosis of apoptotic cells. Together, our results indicate that targeting macrophage metabolism improves atherosclerosis outcome and we reveal Acly as a promising therapeutic target to stabilize atherosclerotic plaques.

2020-02-18 | GSE126690 | GEO

The role of ATP citrate lyase in myelin formation and maintenance

Project description:Formation of myelin by Schwann cells is tightly coupled to peripheral 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, yet one unresolved matter is how Acetyl CoA, a central metabolite in lipid formation is generated during myelin formation and maintenance. Recent studies have shown that glucose-derived Acetyl CoA itself is not required for myelination. Moreover, the importance of mitochondrially-derived Acetyl CoA has never been tested for myelination in vivo. Therefore, we have developed a Schwann cell-specific knockout of the ATP Citrate Lyase (Acly) gene to determine the importance of mitochondrial metabolism to supply Acetyl CoA in nerve development. Intriguingly, the ACLY pathway is important for myelin maintenance rather than myelin formation. In addition, ACLY is required to maintain expression of a myelin-associated gene program and to inhibit activation of the latent Schwann cell injury program.

2024-03-25 | MSV000094403 | MassIVE

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

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

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