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

被引：32

作者：

Esse, Ruben ^{[1
,2
]}

Imbard, Apolline ^{[1
,4
]}

Florindo, Cristina ^{[2
]}

Gupta, Sapna ^{[5
]}

Quinlivan, Eoin P. ^{[6
]}

Davids, Mariska ^{[1
]}

Teerlink, Tom ^{[1
]}

de Almeida, Isabel Tavares ^{[2
,3
]}

Kruger, Warren D. ^{[5
]}

Blom, Henk J. ^{[1
,7
]}

Castro, Rita ^{[2
]}

机构：

[1] Vrije Univ Amsterdam, Med Ctr, Metab Unit, Dept Clin Chem, Amsterdam, Netherlands

[2] Univ Lisbon, Inst Med & Pharmaceut Sci iMed UL, P-1699 Lisbon, Portugal

[3] Univ Lisbon, Fac Pharm, Dept Biochem & Human Biol, P-1699 Lisbon, Portugal

[4] Hop Robert Debre, AP HP, Serv Biochim Hormonol, F-75019 Paris, France

[5] Fox Chase Canc Ctr, Canc Biol Program, Philadelphia, PA 19111 USA

[6] Univ Florida, Biomed Mass Spectrometry Lab, Gainesville, FL USA

[7] Univ Hosp, Lab Clin Biochem & Metab, Dept Gen Pediat, Ctr Pediat & Adolescent Med, D-79106 Freiburg, Germany

来源：

FASEB JOURNAL | 2014年 / 28卷 / 06期

基金：

美国国家卫生研究院;

关键词：

homocystinuria; S-adenosylhomocysteine; H4R3me2a; methylarginines; MYELIN BASIC-PROTEIN; S-ADENOSYLHOMOCYSTEINE; DNA METHYLATION; LIQUID-CHROMATOGRAPHY; ASYMMETRIC DIMETHYLARGININE; MICE DEFICIENT; HISTONE H4; PLASMA; ADENOSYLMETHIONINE; ATHEROSCLEROSIS;

D O I：

10.1096/fj.13-246579

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Accumulation of the homocysteine (Hcy) precursor S-adenosylhomocysteine (AdoHcy) may cause cellular hypomethylation in the setting of hyperhomo-cysteinemia 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 (>6fold) 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.

引用

页码：2686 / 2695

页数：10

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