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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. This Article Full Text (PDF) All Versions of this Article: blood-2007-06-096701v1 110/10/3648    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Jamaluddin, M. S Articles by Wang, H. Search for Related Content PubMed PubMed Citation Articles by Jamaluddin, M. S Articles by Wang, H. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted June 20, 2007 Accepted July 26, 2007 Homocysteine inhibits endothelial cell growth via DNA hypomethylation of the cyclin A gene Md S Jamaluddin, Irene Chen, Fan Yang, Xiaohua Jiang, Michael Jan, Xiaoming Liu, Andrew I Schafer, William Durante, Xiaofeng Yang, and Hong Wang* Department of Pharmacalogy, Temple University School of Medicine, Philadelphia, PA Dept of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO Department of Medicine, Weill Cornell Medical College, New York, NY * Corresponding author; email: hongw{at}temple.edu. 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 biological role in human EC. 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). Bisulphite-sequencing followed by PCR amplification of the cyclin A promoter (-267/37) showed that Hcy eliminated methylation at two 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 six-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 EC. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Hyperhomocysteinemia: DNA hypomethylation and endothelial degeneration Ming-Hui Zou Blood 2007 110: 3495-3496. [Full Text] [PDF] This article has been cited by other articles: D. Zhang, X. Jiang, P. Fang, Y. Yan, J. Song, S. Gupta, A. I. Schafer, W. Durante, W. D. Kruger, X. Yang, et al. Hyperhomocysteinemia Promotes Inflammatory Monocyte Generation and Accelerates Atherosclerosis in Transgenic Cystathionine {beta}-Synthase-Deficient Mice Circulation, November 10, 2009; 120(19): 1893 - 1902. [Abstract] [Full Text] [PDF] S. Dayal, R. N. Rodionov, E. Arning, T. Bottiglieri, M. Kimoto, D. J. Murry, J. P. Cooke, F. M. Faraci, and S. R. Lentz Tissue-specific downregulation of dimethylarginine dimethylaminohydrolase in hyperhomocysteinemia Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H816 - H825. [Abstract] [Full Text] [PDF]

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