A Metabolic Function for Phospholipid and Histone Methylation

Cunqi Ye, Benjamin M. Sutter, Yun Wang, Zheng Kuang, Benjamin P. Tu

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

S-adenosylmethionine (SAM) is the methyl donor for biological methylation modifications that regulate protein and nucleic acid functions. Here, we show that methylation of a phospholipid, phosphatidylethanolamine (PE), is a major consumer of SAM. The induction of phospholipid biosynthetic genes is accompanied by induction of the enzyme that hydrolyzes S-adenosylhomocysteine (SAH), a product and inhibitor of methyltransferases. Beyond its function for the synthesis of phosphatidylcholine (PC), the methylation of PE facilitates the turnover of SAM for the synthesis of cysteine and glutathione through transsulfuration. Strikingly, cells that lack PE methylation accumulate SAM, which leads to hypermethylation of histones and the major phosphatase PP2A, dependency on cysteine, and sensitivity to oxidative stress. Without PE methylation, particular sites on histones then become methyl sinks to enable the conversion of SAM to SAH. These findings reveal an unforeseen metabolic function for phospholipid and histone methylation intrinsic to the life of a cell. Ye et al. show that methylation of phosphatidylethanolamine for the synthesis of phosphatidylcholine is the major consumer of SAM and is required for the efficient synthesis of cysteine and glutathione. Cells lacking phospholipid methylation accumulate SAM and exhibit hypermethylation of histones, revealing a role for phospholipids and histones as methyl group sinks, which is required for optimal cellular metabolism, signaling, and transcriptional regulation.

Original languageEnglish (US)
JournalMolecular Cell
DOIs
StateAccepted/In press - Jul 1 2016

Keywords

  • Cysteine
  • Epigenetics
  • Glutathione
  • H3K36
  • Histone methylation
  • Methyltransferase
  • Phospholipids
  • S-adenosylmethionine
  • Transsulfuration

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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