Remodelling of the endothelial cell transcriptional program via paracrine and DNA-binding activities of MPO [ATAC-seq]

Myeloperoxidase (MPO) is an enzyme, which functions in host defence by catalysing the formation of reactive oxygen intermediates. Synthesized majorly by myeloid progenitor cell types and neutrophils MPO is released into vascular lumen during inflammation, where it may adhere and internalize the endothelial cells coating vascular walls. Here we describe the moonlighting properties of MPO and its regulation of gene transcription in endothelial cells upon nuclear internalization. We show that MPO independently of its enzymatic activity possess chromatin binding properties in vitro and in cyto. Upon nuclear translocation, MPO changes chromatin condensation. Locally at sites of binding, MPO drives de-condensation of chromatin and at the regions flanking MPO binding sites drives an increased chromatin condensation. MPO-guided changes in chromatin condensation lead to activation of endothelial-to-mesenchymal transition in ECs and enhanced migratory potential. Moreover, MPO directly binds to the double-stranded RNA binding protein and transcription factor ILF3 and facilitates translocation of its isoform NF90 into the nucleus. This results in positive regulation of expression of VEGFA, as well lowered stability of CXCL1 and CXCL8 transcripts due to loss of cytoplasmic ILF3. ATAC-Seq, MPO treated and untreated HUVECs