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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\u2010performance liquid chromatography or liquid chromatography\u2010electrospray ionization\u2010tandem mass spectrometry. Global DNA and protein arginine methylation status were evaluated as the contents of 5\u2010methyldeoxycytidine in DNA and of methylarginines in proteins, respectively. In addition, histone arginine methylation was assessed by Western blotting. CBS\u2010deficient mice exhibited increased (&gt;6\u2010fold) 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\u201335%) 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\u2010deficient 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.\u2014Esse, 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. 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