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 Blood, 15 November 2007, Vol. 110, No. 10, pp. 3648-3655.
Prepublished online as a Blood First Edition Paper on August 13, 2007; DOI 10.1182/blood-2007-06-096701.

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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY

Homocysteine inhibits endothelial cell growth via DNA hypomethylation of the cyclin Agene

Md S. Jamaluddin1, Irene Chen1, Fan Yang1, Xiaohua Jiang1, Michael Jan1, Xiaoming Liu2, Andrew I. Schafer3, William Durante2, Xiaofeng Yang1, and Hong Wang1

1 Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA; 2 Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia; 3 Department of Medicine, Weill Cornell Medical College, New York, NY

We reported previously that homocysteine (Hcy) inhibits endothelial cell (EC) growth by transcriptional inhibition of the cyclin A gene via a hypomethylation-related mechanism. In this study, we examined the effect of Hcy on epigenetic modification of the cyclin A gene and its biologic role in human ECs. Cyclin A mRNA levels were significantly suppressed by Hcy and a DNA methyltransferase inhibitor. The cyclin A promoter contains a CpG island spanning a 477-bp region (–277/200). Bisulfite sequencing followed by polymerase chain reaction (PCR) amplification of the cyclin A promoter (–267/37) showed that Hcy eliminated methylation at 2 CpG sites in the cyclin A promoter, one of which is located on the cycle-dependent element (CDE). Mutation of CG sequence on the CDE leads to a 6-fold increase in promoter activity. Hcy inhibited DNA methyltransferase 1 (DNMT1) activity by 30%, and reduced the binding of methyl CpG binding protein 2 (MeCP2) and increased the bindings of acetylated histone H3 and H4 in the cyclin A promoter. Finally, adenovirus-transduced DNMT1 gene expression reversed the inhibitory effect of Hcy on cyclin A expression and EC growth inhibition. In conclusion, Hcy inhibits cyclin A transcription and cell growth by inhibiting DNA methylation through suppression of DNMT1 in ECs.


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Related Article in Blood Online:

Hyperhomocysteinemia: DNA hypomethylation and endothelial degeneration
Ming-Hui Zou
Blood 2007 110: 3495-3496. [Full Text] [PDF]





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