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Succinyl-CoA synthetase deficiency in mouse forebrain results in hyper-succinylation with perturbed neuronal transcriptional regulation and metabolism (ATAC-Seq)

ABSTRACT: Succinyl-CoA synthetase deficiency in mouse forebrain results in hyper-succinylation with perturbed neuronal transcriptional regulation and metabolism (ATAC-Seq)

PROVIDER: PRJNA860620 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR20336603_1.fastq.gz	Fastqsanger.gz
	SRR20336603_2.fastq.gz	Fastqsanger.gz
	SRR20336604_1.fastq.gz	Fastqsanger.gz
	SRR20336604_2.fastq.gz	Fastqsanger.gz
	SRR20336605_1.fastq.gz	Fastqsanger.gz

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Succinyl-CoA synthetase deficiency in mouse forebrain results in hyper-succinylation with perturbed neuronal transcriptional regulation and metabolism (RNA-Seq)

Project description:Lysine-succinylation is a subtype of protein acylation associated with metabolic regulation of succinyl-CoA in the TCA cycle. Deficiency of succinyl-CoA synthetase (SCS), the TCA-cycle enzyme catalyzing the reversible conversion of succinyl-CoA to succinate, leads to mitochondrial encephalomyopathy in humans and embryonic lethality in mice. This report presents a conditional forebrain-specific knock-out (KO0 mouse model of Sucla2, the gene encoding the ATP-specific beta isoform of SCS, resulting in postnatal deficiency of the entire SCS complex. Results demonstrate that the accumulation of succinyl-CoA in the absence of SCS leads to hyper-succinylation within the cerebral cortex of adult mice. With previous research identifying succinylation marks on histones, and with proteomic evidence of histone lysine-succinylation within the presented model, global chromatin accessibility was surveyed in Sucla2 mutant and control mice via ATAC-sequencing. Data show wide-scale alterations in chromatin landscape and global gene expression. Computational analysis of combined chromatin-accessibility and gene expression data reveal perturbation of neuronal transcriptional regulatory networks in the mutant forebrain, suggesting SCS-related changes in the protein succinylome and chromatin accessibility play a significant role in the neuronal pathogenesis of SCS-deficiency.

2022-07-27 | GSE208691 | GEO

Succinyl-CoA synthetase deficiency in mouse forebrain results in hyper-succinylation with perturbed neuronal transcriptional regulation and metabolism (ATAC-Seq)

2022-07-27 | GSE208690 | GEO

Succinyl-CoA synthetase deficiency in mouse forebrain results in hyper-succinylation with perturbed neuronal transcriptional regulation and metabolism

Project description:Succinyl-CoA synthetase deficiency in mouse forebrain results in hyper-succinylation with perturbed neuronal transcriptional regulation and metabolism

| PRJNA860613 | ENA

Succinyl-CoA synthetase deficiency in mouse forebrain results in hyper-succinylation with perturbed neuronal transcriptional regulation and metabolism

Project description:Lysine-succinylation is a subtype of protein acylation associated with metabolic regulation of succinyl-CoA in the TCA cycle. Deficiency of succinyl-CoA synthetase (SCS), the TCA-cycle enzyme catalyzing the reversible conversion of succinyl-CoA to succinate, leads to mitochondrial encephalomyopathy in humans and embryonic lethality in mice. This report presents a conditional forebrain-specific knock-out (KO) mouse model of Sucla2, the gene encoding the ATP-specific beta isoform of SCS, resulting in postnatal deficiency of the entire SCS complex. Results demonstrate that the accumulation of succinyl-CoA in the absence of SCS leads to hyper-succinylation within the cerebral cortex of adult mice. Using immunoprecipitation (IP) and concomitant mass-spectrometry, a highly enriched succinylated proteome is identified in the Sucla2-deficient forebrain. The Sucla2-deficient changes in the succinylome are largely prevalent in metabolic pathways, including the TCA cycle and the electron transport chain (ETC). Specifically, increased succinylation of Complex I of the ETC correlates with functionally significant deficiency of the enzymatic complex. These results suggest that protein-succinylation plays a role in respiratory chain dysfunction associated with SCS-deficiency in patients.

2022-06-21 | MSV000089697 | MassIVE

Succinyl-CoA synthetase deficiency in mouse forebrain results in hyper-succinylation with perturbed neuronal transcriptional regulation and metabolism (RNA-Seq)

Project description:Succinyl-CoA synthetase deficiency in mouse forebrain results in hyper-succinylation with perturbed neuronal transcriptional regulation and metabolism (RNA-Seq)

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Succinyl-CoA synthetase deficiency in mouse forebrain results in hyper-succinylation with perturbed neuronal transcriptional regulation and metabolism

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-07-27 | GSE208692 | GEO

Nuclear GTPSCS functions as a lactyl-CoA synthetase to promote histone lactylation and glioma progression [RNA-Seq]

Project description:Histone lysine lactylation is a physiologically relevant epigenetic pathway that can be stimulated by the Warburg effect and L-lactate. Nevertheless, the mechanism by which cells use L-lactate to generate lactyl-CoA, the cofactor for the modification, and how this process is regulated remain unknown. Here we report identification of GTPSCS as a robust lactyl-CoA synthetase using biochemistry and cell biology approaches. The mechanism of this catalytic activity was elucidated using the crystallographic structure of GTPSCS in complex with L-lactate, followed by mutagenesis experiments. GTPSCS translocates into the nucleus and interacts with p300 to form a functional lactyltransferase to elevate histone lactylation, but not histone succinylation. This process is dependent on not only a nuclear localization signal in the GTPSCS G1 subunit, but also acetylation at G2 subunit residue K73 which mediates the interaction with p300. GTPSCS-p300 collaboration synergistically regulates histone H3K18la, subsequently enhancing the expression of GDF15. This process promotes the proliferation of glioma cells and facilitates tumor formation in mice. In addition, GTPSCS is upregulated in glioma and correlates with glioma malignancy, while histone H3K18la, and GDF15 levels are positively associated with glioma malignancy and poor prognosis in GBM patients. The GTPSCS-lactyltransferase-histone Kla axis thus represents an epigenetic pathway linking lactate metabolism with an oncogenic gene expression pattern in glioma.

2024-11-26 | GSE248703 | GEO

Nuclear GTPSCS functions as a lactyl-CoA synthetase to promote histone lactylation and glioma progression [ChIP-seq]

2024-11-26 | GSE247800 | GEO

Nuclear GTPSCS functions as a lactyl-CoA synthetase to promote histone lactylation

Project description:Histone lysine lactylation is a physiologically and pathologically relevant epigenetic pathway that can be stimulated by the Warburg effect and L-lactate. Nevertheless, the mechanism by which cells use L-lactate to generate lactyl-CoA, the cofactor for the modification, and how this process is regulated remain unknown. Here we report identification of GTPSCS as a lactyl-CoA synthetase in the nucleus using biochemistry and cell biology approaches. The mechanism of this catalytic activity was elucidated using the crystallographic structure of GTPSCS in complex with L-lactate, followed by mutagenesis experiments. GTPSCS translocates into the nucleus and interacts with p300 to form a functional lactyltransferase to elevate histone lactylation, but not histone succinylation. This process is dependent on not only a nuclear localization signal in the GTPSCS G1 subunit, but also acetylation at G2 subunit residue K73 which mediates the interaction with p300. GTPSCS-p300 collaboration synergistically regulates histone H3K18la, subsequently enhancing the expression of GDF15. This process promotes the proliferation and radioresistance of gliomas. The GTPSCS represents the inaugural enzyme that can catalyze lactyl-CoA synthesis for epigenetic histone lactylation and regulate oncogenic gene expression patterns in glioma.

2024-12-02 | PXD056791 | Pride

Protein Succinylation resulting from succinyl-coA ligase deficiency

Project description:Protein hyper-succinylation in fibroblasts and myotubes derived from patients with mutations in succinyl-coA ligase.

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