title: Protein arginine hypomethylation in a mouse model of cystathionine β-synthase deficiency.
abstract: Accumulation of the homocysteine (Hcy) precursor S-adenosylhomocysteine (AdoHcy) may cause cellular hypomethylation in the setting of hyperhomocysteinemia because of cystathionine β-synthase (CBS) deficiency, an inborn error of metabolism. To test this hypothesis, DNA and protein arginine methylation status were assessed in liver, brain, heart, and kidney obtained from a previously described mouse model of CBS deficiency. Metabolite levels in tissues and serum were determined by high-performance liquid chromatography or liquid chromatography-electrospray ionization-tandem mass spectrometry. Global DNA and protein arginine methylation status were evaluated as the contents of 5-methyldeoxycytidine in DNA and of methylarginines in proteins, respectively. In addition, histone arginine methylation was assessed by Western blotting. CBS-deficient mice exhibited increased (>6-fold) Hcy and AdoHcy levels in all tissues examined compared with control levels. In addition, global DNA methylation status was not affected, but global protein arginine methylation status was decreased (10-35%) in liver and brain. Moreover, asymmetric dimethylation of arginine 3 on histone H4 (H4R3me2a) content was markedly decreased in liver, and no differences were observed for the other histone arginine methylation marks examined. Our results show that CBS-deficient mice present severe accumulation of tissue Hcy and AdoHcy, protein arginine hypomethylation in liver and brain, and decreased H4R3me2a content in liver. Therefore, protein arginine hypomethylation arises as a potential player in the pathophysiology of CBS deficiency.
authors.affiliation: Department of Clinical Chemistry, Metabolic Unit, VU University Medical Center, Amsterdam, The Netherlands; Institute for Medicines and Pharmaceutical Sciences (iMed.UL) and.
authors.forename: Ruben
authors.initials: R
authors.lastname: Esse
authors.affiliation: Department of Clinical Chemistry, Metabolic Unit, VU University Medical Center, Amsterdam, The Netherlands; Service de Biochimie-Hormonologie, Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France;
authors.forename: Apolline
authors.initials: A
authors.lastname: Imbard
authors.affiliation: Institute for Medicines and Pharmaceutical Sciences (iMed.UL) and.
authors.forename: Cristina
authors.initials: C
authors.lastname: Florindo
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA;
authors.forename: Sapna
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Biomedical Mass Spectrometry Laboratory, University of Florida, Gainesville, Florida, USA; and.
authors.forename: Eoin P
authors.initials: EP
authors.lastname: Quinlivan
authors.affiliation: Department of Clinical Chemistry, Metabolic Unit, VU University Medical Center, Amsterdam, The Netherlands;
authors.forename: Mariska
authors.initials: M
authors.lastname: Davids
authors.affiliation: Department of Clinical Chemistry, Metabolic Unit, VU University Medical Center, Amsterdam, The Netherlands;
authors.forename: Tom
authors.initials: T
authors.lastname: Teerlink
authors.affiliation: Institute for Medicines and Pharmaceutical Sciences (iMed.UL) and Department of Biochemistry and Human Biology, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal;
authors.forename: Isabel
authors.initials: I
authors.lastname: Tavares de Almeida
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA;
authors.forename: Warren D
authors.initials: WD
authors.lastname: Kruger
authors.affiliation: Department of Clinical Chemistry, Metabolic Unit, VU University Medical Center, Amsterdam, The Netherlands; Laboratory for Clinical Biochemistry and Metabolism, Department of General Pediatrics, Center for Pediatrics and Adolescent Medicine, University Hospital, Freiburg, Germany henk.blom@uniklinik-freiburg.de.
authors.forename: Henk J
authors.initials: HJ
authors.lastname: Blom
authors.affiliation: Institute for Medicines and Pharmaceutical Sciences (iMed.UL) and Department of Biochemistry and Human Biology, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal;
authors.forename: Rita
authors.initials: R
authors.lastname: Castro
mesh_terms: D000818:Animals; D001120:Arginine / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D003541:Cystathionine beta-Synthase / Q000235:genetics; D019175:DNA Methylation; D004195:Disease Models, Animal; D006657:Histones / Q000378:metabolism; D006710:Homocysteine / Q000378:metabolism*; D006712:Homocystinuria / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008745:Methylation; D051379:Mice; D012435:S-Adenosylhomocysteine / Q000378:metabolism*
chemical_list: D006657:Histones; D006710:Homocysteine; D001120:Arginine; D012435:S-Adenosylhomocysteine; D003541:Cystathionine beta-Synthase
keywords: H4R3me2a; S-adenosylhomocysteine; homocystinuria; methylarginines