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Vol. 19, Issue 9, 3997-4005, September 2008

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Effect of 27nt Small RNA on Endothelial Nitric-Oxide Synthase Expression

Ming-Xiang Zhang^*,, Cheng Zhang^*,, Ying H. Shen, Jian Wang, Xiao-Nan Li^*,, Liang Chen^*, Yun Zhang^*, Joseph S. Coselli, and Xing Li Wang

*Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Shandong University, Qilu Hospital, Jinan, Shandong 250012, China; and Adult Section of Cardiothoracic Surgery, Texas Heart Institute at St. Luke's Episcopal Hospital, Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030

Submitted November 28, 2007; Revised May 30, 2008; Accepted June 26, 2008
Monitoring Editor: William P. Tansey

We have reported previously that the 27nt repeat polymorphism in endothelial nitric-oxide synthase (eNOS) intron 4—a source of 27nt small RNA—inhibits eNOS expression. In the current study, we have investigated how 27nt small RNA suppresses eNOS expression. Using a chromatin immunoprecipitation assay, we examined histone acetylation in the 27nt repeat element of eNOS intron 4, the promoter region up to –1486 bp, and the 5' enhancer region (–4583/–4223bp) in human aortic endothelial cells (HAECs) treated with 27nt RNA duplex. 27nt RNA duplex induced hyperacetylation in H3 (lysine8, 12, and 23) and H4 (lysine 9 and 12) at the 27nt repeat element, which then interacted with nuclear actin, histone deacetylase 3 (HDAC3), and NonO proteins. In contrast, the histone H3 and H4 became hypoacetylated at the eNOS core promoter. HAECs treated with 27nt RNA duplex had reduced eNOS expression, but treatment with either HDAC3 small interfering RNA or NonO siRNA significantly attenuated the 27nt small RNA-induced suppression. We further found that 27nt small RNA induced DNA methylation in a region approximately 750nt upstream of the intron 4 repeats, and a methyltransferase inhibitor reversed the effect on methylation and eNOS expression. Our study demonstrates that 27nt small RNA may suppress eNOS expression by altering histone acetylation and DNA methylation in regions adjacent to the 27nt repeat element and core promoter.

Address correspondence to: Xing Li Wang (xlwang{at}bcm.edu) or Ming-Xiang Zhang (zhangmingxiang123{at}hotmail.com)