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Inhibition of ACSS2-mediated crotonylation alleviates kidney fibrosis via IL- 1β-dependent macrophage activation and tubular cell senescence

ABSTRACT: Inhibition of ACSS2-mediated crotonylation alleviates kidney fibrosis via IL- 1β-dependent macrophage activation and tubular cell senescence

PROVIDER: PRJNA1028116 | ENA |

REPOSITORIES: ENA

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	SRR26385024_1.fastq.gz	Fastqsanger.gz
	SRR26385024_2.fastq.gz	Fastqsanger.gz
	SRR26385025_1.fastq.gz	Fastqsanger.gz
	SRR26385025_2.fastq.gz	Fastqsanger.gz
	SRR26385026_1.fastq.gz	Fastqsanger.gz

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Inhibition of ACSS2-mediated crotonylation alleviates kidney fibrosis via IL- 1β-dependent macrophage activation and tubular cell senescence

Project description:Chronic kidney disease (CKD) is characterized by sustained inflammation and progressive fibrosis, however therapies to slow CKD progression are limited. Histone lysine crotonylation (Kcr) as a novel post-translational modification is widespread as acetylation (Kac), but its roles in CKD are largely unknown. In the study, we firstly reported that the nuclear histone Kcr in tubular epithelial cells was significantly elevated in fibrotic kidney of patients and mice, which was positively correlated with the progression of disease. Interestingly, abnormal increase of histone 3 lysine 9 crotonylation (H3K9cr) in kidneys of unilateral ureteric obstruction (UUO) and folic acid nephropathy (FAN) was completely different to the stable expression of H3K9ac, indicating that H3K9cr may exert extraordinary functions in kidney fibrosis. By screening these crotonylated/acetylated factors, crotonyl-CoA-producing enzyme ACSS2 (acyl-CoA synthetase short chain family member 2) remarkably promoted H3K9cr without influencing H3K9ac to trigger proinflammatory cytokine IL-1β transcription. Furthermore, genetic and pharmacologic inhibition of ACSS2 both attenuated kidney injury and fibrosis, as well as suppressed H3K9cr-mediated IL-1β expression, which thus to alleviate IL-1β-dependent macrophage activation and tubular cell senescence. Collectively, our finding uncovers that H3K9cr plays a critical, previously unrecognized role in kidney fibrosis, where ACSS2 represents an attractive target for strategies that aim to slow fibrotic kidney disease progression

2024-02-08 | GSE245390 | GEO

Inhibition of ACSS2-mediated crotonylation alleviates kidney fibrosis via IL- 1β-dependent macrophage activation and tubular cell senescence [ChIP-Seq]

2024-02-08 | GSE253032 | GEO

Inhibition of ACSS2-mediated crotonylation alleviates kidney fibrosis via IL- 1β-dependent macrophage activation and tubular cell senescence [ChIP-Seq]

Project description:Inhibition of ACSS2-mediated crotonylation alleviates kidney fibrosis via IL- 1β-dependent macrophage activation and tubular cell senescence [ChIP-Seq]

| PRJNA1063680 | ENA

Inhibition of ACSS2-mediated histone crotonylation alleviates kidney fibrosis via IL-1β-dependent macrophage activation and tubular cell senescence.

Project description:Histone lysine crotonylation (Kcr), as a posttranslational modification, is widespread as acetylation (Kac); however, its roles are largely unknown in kidney fibrosis. In this study, we report that histone Kcr of tubular epithelial cells is abnormally elevated in fibrotic kidneys. By screening these crotonylated/acetylated factors, a crotonyl-CoA-producing enzyme ACSS2 (acyl-CoA synthetase short chain family member 2) is found to remarkably increase histone 3 lysine 9 crotonylation (H3K9cr) level without influencing H3K9ac in kidneys and tubular epithelial cells. The integrated analysis of ChIP-seq and RNA-seq of fibrotic kidneys reveal that the hub proinflammatory cytokine IL-1β, which is regulated by H3K9cr, play crucial roles in fibrogenesis. Furthermore, genetic and pharmacologic inhibition of ACSS2 both suppress H3K9cr-mediated IL-1β expression, which thereby alleviate IL-1β-dependent macrophage activation and tubular cell senescence to delay renal fibrosis. Collectively, our findings uncover that H3K9cr exerts a critical, previously unrecognized role in kidney fibrosis, where ACSS2 represents an attractive drug target to slow fibrotic kidney disease progression.

| S-EPMC11016098 | biostudies-literature

Histone crotonylation

Project description:Histone crotonylation

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ACSS2 alleviates alcoholic liver disease via modulating hepcidin-mediated systemic iron homeostasis and hepatic ferroptosis

Project description:Alcoholic liver disease (ALD) is one of the most prevalent types of liver disease associated with high morbidity and mortality, caused by hepatotoxicity originating from alcohol metabolism, but current therapeutic drugs are still limited. The role of ACSS2 as an enzyme that metabolizes acetate in ALD remains unknown. Our study aimed to investigate the function of ACSS2 and its potential mechanism in ALD progression.

2024-08-28 | GSE267638 | GEO

Acetyl-CoA metabolism by ACSS2 regulates neuronal histone acetylation and long-term memory [RNA-seq]

Project description:Metabolic production of acetyl-CoA has been linked to histone acetylation and gene regulation, however the mechanisms are largely unknown. We show that the metabolic enzyme acetyl-CoA synthetase 2 (ACSS2) is a critical and direct regulator of histone acetylation in neurons and of long-term mammalian memory. We observe increased nuclear ACSS2 in differentiating neurons in vitro. Genome-wide, ACSS2 binding corresponds with increased histone acetylation and gene expression of key neuronal genes. These data indicate that ACSS2 functions as a chromatin-bound co-activator to increase local concentrations of acetyl-CoA and to locally promote histone acetylation for transcription of neuron-specific genes. Remarkably, in vivo attenuation of hippocampal ACSS2 expression in adult mice impairs long-term spatial memory, a cognitive process reliant on histone acetylation. ACSS2 reduction in hippocampus also leads to a defect in upregulation of key neuronal genes involved in memory. These results reveal a unique connection between cellular metabolism and neural plasticity, and establish a link between generation of acetyl-CoA and neuronal chromatin regulation. Global survey of gene expression in CAD cells and differentiated CAD neurons following lentiviral knockdown of ACSS2 or ATP citrate lyase (ACL) (and control = scramble hairpin); survey of hippocampal gene expression changes associated with retrieval of fear memory, after ACSS2-AAV knockdown or in EGFP-AAV control (comparison of 0h vs. 1h post-memory retrieval).

2017-05-01 | E-GEOD-76853 | biostudies-arrayexpress

Acetyl-CoA metabolism by ACSS2 regulates neuronal histone acetylation and long-term memory [ChIP-seq]

Project description:Metabolic production of acetyl-CoA has been linked to histone acetylation and gene regulation, however the mechanisms are largely unknown. We show that the metabolic enzyme acetyl-CoA synthetase 2 (ACSS2) is a critical and directchum regulator of histone acetylation in neurons and of long-term mammalian memory. We observe increased nuclear ACSS2 in differentiating neurons in vitro. Genome-wide, ACSS2 binding corresponds with increased histone acetylation and gene expression of key neuronal genes. These data indicate that ACSS2 functions as a chromatin-bound co-activator to increase local concentrations of acetyl-CoA and to locally promote histone acetylation for transcription of neuron-specific genes. Remarkably, in vivo attenuation of hippocampal ACSS2 expression in adult mice impairs long-term spatial memory, a cognitive process reliant on histone acetylation. ACSS2 reduction in hippocampus also leads to a defect in upregulation of key neuronal genes involved in memory. These results reveal a unique connection between cellular metabolism and neural plasticity, and establish a link between generation of acetyl-CoA and neuronal chromatin regulation. Genome-wide examination of histone H3 and H4 acetylation, as well as ACSS2 binding, in undifferentiated CAD cells and differentiated CAD neurons; background adjusted by H3 ChIP or Input.

2017-05-01 | E-GEOD-76850 | biostudies-arrayexpress

HIV latency is reversed by ACSS2-driven histone crotonylation.

Project description:Eradication of HIV-1 (HIV) is hindered by stable viral reservoirs. Viral latency is epigenetically regulated. While the effects of histone acetylation and methylation at the HIV long-terminal repeat (LTR) have been described, our knowledge of the proviral epigenetic landscape is incomplete. We report that a previously unrecognized epigenetic modification of the HIV LTR, histone crotonylation, is a regulator of HIV latency. Reactivation of latent HIV was achieved following the induction of histone crotonylation through increased expression of the crotonyl-CoA-producing enzyme acyl-CoA synthetase short-chain family member 2 (ACSS2). This reprogrammed the local chromatin at the HIV LTR through increased histone acetylation and reduced histone methylation. Pharmacologic inhibition or siRNA knockdown of ACSS2 diminished histone crotonylation-induced HIV replication and reactivation. ACSS2 induction was highly synergistic in combination with either a protein kinase C agonist (PEP005) or a histone deacetylase inhibitor (vorinostat) in reactivating latent HIV. In the SIV-infected nonhuman primate model of AIDS, the expression of ACSS2 was significantly induced in intestinal mucosa in vivo, which correlated with altered fatty acid metabolism. Our study links the HIV/SIV infection-induced fatty acid enzyme ACSS2 to HIV latency and identifies histone lysine crotonylation as a novel epigenetic regulator for HIV transcription that can be targeted for HIV eradication.

| S-EPMC5824862 | biostudies-literature

ACSS2 alleviates alcoholic liver disease via modulating hepcidin-mediated systemic iron homeostasis and hepatic ferroptosis

Project description:ACSS2 alleviates alcoholic liver disease via modulating hepcidin-mediated systemic iron homeostasis and hepatic ferroptosis

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