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

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

Research output: Contribution to journalArticle

11 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)63-75
Number of pages13
JournalFood Science and Human Wellness
Volume2
DOIs
StatePublished - Apr 27 2018

Fingerprint

Citric Acid Cycle
tricarboxylic acid cycle
Chromatin
chromatin
Gene Expression
gene expression
metabolism
Nucleosomes
nucleosomes
DNA Repair
Lysine
DNA repair
lysine
transcription (genetics)
Acylation
Chromatin Immunoprecipitation
Post Translational Protein Processing
acylation
Anions
protein structure

Keywords

  • Cellular Physiology
  • Molecular Mechanism of Gene Regulation
  • Proteomics

ASJC Scopus subject areas

  • Food Science
  • General

Cite this

Chromatin Succinylation Correlates with Active Gene Expression and Is Perturbed by Defective TCA Cycle Metabolism. / Smestad, John; Erber, Luke; Chen, Yue; Maher III, L James.

In: Food Science and Human Wellness, Vol. 2, 27.04.2018, p. 63-75.

Research output: Contribution to journalArticle

@article{64e7398a04a54354bd4e7a6f7dad7b99,
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.",
keywords = "Cellular Physiology, Molecular Mechanism of Gene Regulation, Proteomics",
author = "John Smestad and Luke Erber and Yue Chen and {Maher III}, {L James}",
year = "2018",
month = "4",
day = "27",
doi = "10.1016/j.isci.2018.03.012",
language = "English (US)",
volume = "2",
pages = "63--75",
journal = "Food Science and Human Wellness",
issn = "2213-4530",
publisher = "Elsevier BV",

}

TY - JOUR

T1 - Chromatin Succinylation Correlates with Active Gene Expression and Is Perturbed by Defective TCA Cycle Metabolism

AU - Smestad, John

AU - Erber, Luke

AU - Chen, Yue

AU - Maher III, L James

PY - 2018/4/27

Y1 - 2018/4/27

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.

KW - Cellular Physiology

KW - Molecular Mechanism of Gene Regulation

KW - Proteomics

UR - http://www.scopus.com/inward/record.url?scp=85050316335&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85050316335&partnerID=8YFLogxK

U2 - 10.1016/j.isci.2018.03.012

DO - 10.1016/j.isci.2018.03.012

M3 - Article

AN - SCOPUS:85050316335

VL - 2

SP - 63

EP - 75

JO - Food Science and Human Wellness

JF - Food Science and Human Wellness

SN - 2213-4530

ER -