Browsing by Subject "ATAC sequencing"

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    Loss of succinyl-CoA synthetase in mouse forebrain results in hypersuccinylation with perturbed neuronal transcription and metabolism
    (Elsevier, 2023) Lancaster, Makayla S.; Kim, Byungwook; Doud, Emma H.; Tate, Mason D.; Sharify, Ahmad D.; Gao, Hongyu; Chen, Duojiao; Simpson, Ed; Gillespie, Patrick; Chu, Xiaona; Miller, Marcus J.; Wang, Yue; Liu, Yunlong; Mosley, Amber L.; Kim, Jungsu; Graham, Brett H.; Medical and Molecular Genetics, School of Medicine
    Lysine succinylation is a subtype of protein acylation associated with metabolic regulation of succinyl-CoA in the tricarboxylic acid cycle. Deficiency of succinyl-CoA synthetase (SCS), the tricarboxylic acid cycle enzyme catalyzing the interconversion of succinyl-CoA to succinate, results in mitochondrial encephalomyopathy in humans. This report presents a conditional forebrain-specific knockout (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 accumulation of succinyl-CoA in the absence of SCS leads to hypersuccinylation within the murine cerebral cortex. Specifically, increased succinylation is associated with functionally significant reduced activity of respiratory chain complex I and widescale alterations in chromatin landscape and gene expression. Integrative analysis of the transcriptomic data also reveals perturbations in regulatory networks of neuronal transcription in the KO forebrain. Together, these findings provide evidence that protein succinylation plays a significant role in the pathogenesis of SCS deficiency.