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Esse R , Imbard A , Florindo C , Gupta S , Quinlivan EP , Davids M , Teerlink T , Tavares de Almeida I , Kruger WD , Blom HJ , Castro R
Protein arginine hypomethylation in a mouse model of cystathionine beta-synthase deficiency
FASEB J. 2014 Jun;28(6) :2686-95
PMID: 24532665    PMCID: PMC4021445    URL: https://www.ncbi.nlm.nih.gov/pubmed/24532665
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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 beta-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.
Notes
Esse, Ruben Imbard, Apolline Florindo, Cristina Gupta, Sapna Quinlivan, Eoin P Davids, Mariska Teerlink, Tom Tavares de Almeida, Isabel Kruger, Warren D Blom, Henk J Castro, Rita eng CA06927/CA/NCI NIH HHS/ R01 GM098772/GM/NIGMS NIH HHS/ R01 DK101404/DK/NIDDK NIH HHS/ R01GM098772/GM/NIGMS NIH HHS/ P30 CA006927/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. FASEB J. 2014 Jun;28(6):2686-95. doi: 10.1096/fj.13-246579. Epub 2014 Feb 14.