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. Author manuscript; available in PMC: 2015 Aug 1.
Published in final edited form as: Vascul Pharmacol. 2014 May 27;62(2):88–93. doi: 10.1016/j.vph.2014.05.007

Figure 2. Hemodynamic forces and endothelial DNA methylome.

Figure 2

Disturbed flow (DF) globally and gene-specifically influences endothelial DNA methylation via DNMT1 [31,32] and DNMT3A [33] pathways. A mechanism regulating KLF4 promoter methylation that contributes to suppression of transcription (and described in the text) is illustrated. DF-induced DNMT3A enrichment of endothelial KLF4 promoter near the TSS increased CpG methylation. The resulting hypermethylation of KLF4 promoter induced gene silencing by preventing the chromatin binding of MEF2 to the KLF4 promoter. Decreased KLF4 expression inhibited its transcription targets Thrombomodulin (THBD) and Nitric Oxide Synthase 3 (NOS3) and de-repressed expression of Monocyte Chemoattractant Factor-1 (MCP-1) leading to a pro-inflammatory, pro-atherosclerosis phenotype. Intervention by DNMT inhibitors (RG108; 5-Azacytidine) rescued this pathway. Adapted from Reference 33 with permission.