Myocardin-related transcription factor A cooperates with brahmarelated gene 1 to activate P-selectin transcription

Expression of P-selectin in injured or activated endothelia cells serves as a permissive step towards leukocyte recruitment and perpetuation of inflammation in the pathogenesis of atherosclerosis. P-selectin can be induced by pro-inflammatory stimuli via the transcription factor NF-kB, but the epigenetic mechanisms remain incompletely understood. Previously we reported that myocardin-related transcription factor A (MRTF-A) mediates the transactivation of a slew of adhesion molecules by oxidized low-density lipoprotein (oxLDL), likely through a crosstalk with brahma-related gene 1 (BRG1), a chromatin remodeling protein. Here, we show that MRTF-A was both sufficient and necessary for the transactivation of P-selectin gene in endothelial cells treated with TNF-a. Depletion of MRTF-A using small interfering RNA (siRNA) abrogated the binding of BRG1 on the P-selectin promoter. Overexpression of BRG1 up-regulated the activity of P-selectin promoter activity while BRG1 knockdown attenuated P-selectin expression. Finally, BRG1 silencing suppressed the accumulation of acetylated histone H3 and methylated histone H3K4, and altered the binding of NF-kB on the P-selectin promoter. Therefore, our data demonstrate an essential role for MRTF-A and BRG1 in P-selectin transactivation in endothelial cells.