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Proc Natl Acad Sci U S A. 2018 Sep 11;115(37):9228-9233. doi: 10.1073/pnas.1802901115. Epub 2018 Aug 27.

Methylglyoxal-derived posttranslational arginine modifications are abundant histone marks.

Author information

1
A.B. Hancock Memorial Laboratory for Cancer Research, Vanderbilt University, Nashville, TN 37232.
2
Department of Biochemistry, Vanderbilt University, Nashville, TN 37232.
3
Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232.
4
Department of Chemistry, Vanderbilt University, Nashville, TN 37232.
5
Department of Chemistry, Yale University, New Haven, CT 06520.
6
Mass Spectrometry Resource Center, Vanderbilt University, Nashville, TN 37232.
7
A.B. Hancock Memorial Laboratory for Cancer Research, Vanderbilt University, Nashville, TN 37232; larry.marnett@vanderbilt.edu.

Abstract

Histone posttranslational modifications (PTMs) regulate chromatin dynamics, DNA accessibility, and transcription to expand the genetic code. Many of these PTMs are produced through cellular metabolism to offer both feedback and feedforward regulation. Herein we describe the existence of Lys and Arg modifications on histones by a glycolytic by-product, methylglyoxal (MGO). Our data demonstrate that adduction of histones by MGO is an abundant modification, present at the same order of magnitude as Arg methylation. These modifications were detected on all four core histones at critical residues involved in both nucleosome stability and reader domain binding. In addition, MGO treatment of cells lacking the major detoxifying enzyme, glyoxalase 1, results in marked disruption of H2B acetylation and ubiquitylation without affecting H2A, H3, and H4 modifications. Using RNA sequencing, we show that MGO is capable of altering gene transcription, most notably in cells lacking GLO1. Finally, we show that the deglycase DJ-1 protects histones from adduction by MGO. Collectively, our findings demonstrate the existence of a previously undetected histone modification derived from glycolysis, which may have far-reaching implications for the control of gene expression and protein transcription linked to metabolism.

KEYWORDS:

DJ-1; QuARKMod; glyoxalase 1; histone; methylglyoxal

PMID:
30150385
PMCID:
PMC6140490
DOI:
10.1073/pnas.1802901115
[Indexed for MEDLINE]
Free PMC Article

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