GSE208690
Succinyl-CoA synthetase deficiency in mouse forebrain results in hyper-succinylation with perturbed neuronal transcriptional regulation and metabolism (ATAC-Seq)
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. Overall design: Assessment of global chromatin accessibiliy and bulk mRNA-sequencing in murine cortex with enriched protein succinylation resulting from loss of Kreb's Cycle enzyme succinyl-CoA synthetase