Protein arginine hypomethylation in a mouse model of cystathionine β-synthase deficiency

Ruben Esse, Apolline Imbard, Cristina Florindo, Sapna Gupta, Eoin P. Quinlivan, Mariska Davids, Tom Teerlink, Isabel Tavares De Almeida, Warren D. Kruger, Henk J. Blom, Rita Castro

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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.

Original languageEnglish (US)
Pages (from-to)2686-2695
Number of pages10
JournalFASEB Journal
Volume28
Issue number6
DOIs
StatePublished - Jun 2014

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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    Esse, R., Imbard, A., Florindo, C., Gupta, S., Quinlivan, E. P., Davids, M., Teerlink, T., Tavares De Almeida, I., Kruger, W. D., Blom, H. J., & Castro, R. (2014). Protein arginine hypomethylation in a mouse model of cystathionine β-synthase deficiency. FASEB Journal, 28(6), 2686-2695. https://doi.org/10.1096/fj.13-246579