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Regulation of Histone Methylation via Methionine Metabolism
Author(s) -
Haws Spencer A.,
Denu John M.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.755.9
Subject(s) - methionine , methyltransferase , methylation , histone , biochemistry , chemistry , metabolism , histone methyltransferase , histone methylation , epigenetics , histone h3 , ezh2 , dna methylation , amino acid , gene expression , gene
S‐adenosylmethionine (SAM) is the sole methyl‐donor for methyltransferase reactions in the cell. However, given SAM's inherent instability and high energetic cost of synthesis, the mechanism by which methyltransferases acquire this metabolite poses an interesting problem as uptake via diffusion appears inefficient. Recent data suggest that SAM may be directly channeled from its synthetase to histone methyltransferases (HMTs) in response to glucose‐derived serine metabolism as well as oxidative stress. We have investigated the influence of one‐carbon metabolism on nuclear SAM utilization, using methionine restriction to mimic methyl‐donor metabolite depletion in HCT116 cells. When HCT116 cells are subjected to methionine restriction, we identify significant alterations in one‐carbon metabolism, including a complete loss of free intracellular methionine after 5 minutes and a 5‐fold reduction in SAM concentrations after 1 hour. To determine how these fluctuations in one‐carbon metabolism influence histone post‐translational modifications (PTMs), we used mass spectrometry to identify the global histone PTM profiles of HCT116 cells subjected to a methionine restriction time course. While we observed an overall decrease in histone methylation throughout the time course, we also detected a preservation of mono‐methyl PTMs on H3K9 and H3K27. Knowing that the mammalian SAM synthetase MAT2A is responsive to methionine availability, we next analyzed the histone PTM profiles of MAT2A knockdown cells via mass spectrometry. In agreement with the methionine restriction results, we observed maintenance of mono‐methyl PTMs on H3K9 and H3K27 while global histone methylation levels decreased. These results suggest that MAT2A may be preferentially providing SAM to H3K9 and H3K27 mono‐methyl HMTs during one‐carbon metabolite depletion in an attempt to preserve crucial epigenetic memory until environmental conditions improve. Support or Funding Information This project was supported by NIH GM059789‐15/P250V A.