The histone methyltransferase SETD1A regulates thrombomodulin transcription in vascular endothelial cells

Thrombomodulin (TM, encoded by the THBD gene) expressed in vascular endothelial cells plays pivotal roles maintaining the equilibrium of coagulation and anti-coagulation. TM levels can be regulated at the transcriptional level although the epigenetic mechanism is underexplored. Here we report that transcriptional activation of TM in both immortalized vascular endothelial cells (EAhy926) and primary human aortic endothelial cells (HAEC) by all-trans retinoic acid (RA) paralleled accumulation of trimethylated histone H3K4, a prominent marker for active chromatin, surrounding the THBD promoter. RA treatment up-regulated the expression of SETD1A (SET1), a dedicated H3K4 methyltransferase, and augmented SETD1A occupancies on the THBD promoter. Further analysis revealed that the sequence-specific transcription factor Kruppel-like factor 4 (KLF4) interacted with and recruited SETD1A to the THBD promoter. Interestingly, SETD1A was recruited to the KLF4 promoter by retinoic acid receptor (RAR) and mediated the up-regulation of KLF4 expression by RA stimulation. In summary, our data illustrate a previously unrecognized pathway in which SETD1A contributes to RA-induced TM expression in vascular endothelial cells by modulating the activity and expression of KLF4.