title: A Metabolic Function for Phospholipid and Histone Methylation.
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.
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9038, USA.
authors.forename: Cunqi
authors.initials: C
authors.lastname: Ye
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9038, USA.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Sutter
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9038, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9038, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Kuang
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9038, USA. Electronic address: benjamin.tu@utsouthwestern.edu.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Tu
mesh_terms: D003545:Cysteine / Q000378:metabolism; D004734:Energy Metabolism; D020869:Gene Expression Profiling / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic; D015966:Gene Expression Regulation, Fungal; D006657:Histones / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D009154:Mutation; D018384:Oxidative Stress; D010713:Phosphatidylcholines / Q000378:metabolism; D050918:Phosphatidylethanolamine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000378:metabolism*; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic
chemical_list: D006657:Histones; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D029701:Saccharomyces cerevisiae Proteins; C483858:phosphatidylethanolamine; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; C494486:CHO2 protein, S cerevisiae; D050918:Phosphatidylethanolamine N-Methyltransferase; D054648:Protein Phosphatase 2; D008239:Lysine; D003545:Cysteine
keywords: H3K36; S-adenosylmethionine; cysteine; epigenetics; glutathione; histone methylation; methyltransferase; phospholipids; transsulfuration