Methylglyoxal-derived posttranslational arginine modifications are abundant histone marks

James J. Galligan, James A. Wepy, Matthew D. Streeter, Philip J. Kingsley, Michelle M. Mitchener, Orrette R. Wauchope, William N. Beavers, Kristie L. Rose, Tina Wang, David A. Spiegel, Lawrence J. Marnett

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)9228-9233
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number37
DOIs
StatePublished - Sep 11 2018
Externally publishedYes

Keywords

  • DJ-1
  • Glyoxalase 1
  • Histone
  • Methylglyoxal
  • QuARKMod

ASJC Scopus subject areas

  • General

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