Chromatin Succinylation Correlates with Active Gene Expression and Is Perturbed by Defective TCA Cycle Metabolism

• Published in: iScience Vol. 2; pp. 63 - 75
• Main Authors: Smestad, John, Erber, Luke, Chen, Yue, Maher, L. James
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.04.2018; Elsevier
• Subjects: Cellular Physiology; Molecular Mechanism of Gene Regulation; Proteomics; Molecular Mechanism of Gene Regulation; Cellular Physiology; Proteomics
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2018.03.012

Succinylation is a post-translational protein acylation modification that converts the cationic lysine side chain to an anion with large potential impacts on protein structure and function. Here we characterize the epigenome-wide distribution of succinyllysine marks in chromatin using chromatin immunoprecipitation sequencing (ChIP-seq). We estimate that more than one-third of all nucleosomes contain lysine succinylation marks and demonstrate a potential role of chromatin succinylation in modulating gene expression. We further demonstrate that defective tricarboxylic acid (TCA) cycle metabolism perturbs the succinyllysine distribution in chromatin, correlating with transcriptional responses. This is consistent with previous observations linking nucleosome succinylation with enhanced in vitro transcription. We additionally demonstrate that defective TCA cycle metabolism results in a DNA repair defect and sensitivity to genotoxic agents, consistent with previously reported chromatin hypersuccinylation effects observed in the context of SIRT7 depletion. Chromatin succinylation may thus represent a mechanism by which metabolism modulates both genome-wide transcription and DNA repair activities. [Display omitted] •SDH loss TCA cycle defect results in succinyl-CoA increase and hypersuccinylation•Succinyllysine modification of chromatin correlates with active gene expression•Chromatin succinyllysine change in SDH loss correlates with transcriptional change Cellular Physiology; Molecular Mechanism of Gene Regulation; Proteomics