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

John Smestad; Luke Erber; Yue Chen; L. James Maher

doi:10.1016/j.isci.2018.03.012

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

John Smestad, Luke Erber, Yue Chen, L. James Maher

Research output: Contribution to journal › Article › peer-review

93 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	63-75
Number of pages	13
Journal	iScience
Volume	2
DOIs	https://doi.org/10.1016/j.isci.2018.03.012
State	Published - Apr 27 2018

Bibliographical note

Funding Information:
This work was facilitated by the Mayo Clinic Metabolomics Resource Core Facility (NIH grant U24DK100469), the Mayo Clinic Medical Genome Facility Sequencing Core, the Mayo Clinic Epigenetics Development Laboratory, and the Mayo Clinic Research Computing Facility. Financial support for this work was from the Mayo Clinic; NIH grants R01CA166025 (L.J.M.), T32GM065841 (Mayo Clinic Medical Scientist Training Program), and F30CA220660 (J.S.); and generous support from the Paradifference Foundation (L.J.M.). Conceptualization, L.J.M. J.S. and Y.C.; methodology, L.J.M. J.S. L.E. and Y.C.; validation, J.S. and L.E.; formal analysis, J.S. L.E. and Y.C.; investigation, J.S. and L.E.; resources, L.J.M. and J.S.; data curation, J.S.; writing: original draft, J.S. and L.E.; writing: review and editing, L.J.M. J.S. Y.C. and L.E.; visualization, J.S.; supervision, L.J.M. and Y.C.; project administration, L.J.M. and Y.C.; funding acquisition, L.J.M. The authors declare no competing interests.

Funding Information:
This work was facilitated by the Mayo Clinic Metabolomics Resource Core Facility ( NIH grant U24DK100469 ), the Mayo Clinic Medical Genome Facility Sequencing Core, the Mayo Clinic Epigenetics Development Laboratory, and the Mayo Clinic Research Computing Facility. Financial support for this work was from the Mayo Clinic ; NIH grants R01CA166025 (L.J.M.), T32GM065841 (Mayo Clinic Medical Scientist Training Program), and F30CA220660 (J.S.); and generous support from the Paradifference Foundation (L.J.M.).

Publisher Copyright:
© 2018 The Author(s)

Keywords

Cellular Physiology
Molecular Mechanism of Gene Regulation
Proteomics

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title = "Chromatin Succinylation Correlates with Active Gene Expression and Is Perturbed by Defective TCA Cycle Metabolism",

abstract = "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.",

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N2 - 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.

AB - 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.

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

Abstract

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Keywords

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