Zmiz1 is a novel regulator of lymphatic endothelial cell gene expression and function

Abstract

AbstractZinc Finger MIZ-Type Containing 1 (Zmiz1), also known as ZIMP10 or RAI17, is a transcription cofactor and member of the Protein Inhibitor of Activated STAT (PIAS) family of proteins. Zmiz1 is critical for a variety of biological processes including vascular development. However, its role in the lymphatic vasculature is unknown. In this study, we utilized human dermal lymphatic endothelial cells (HDLECs) and an inducible, lymphatic endothelial cell (LEC)-specificZmiz1knockout mouse model to investigate the role of Zmiz1 in LECs. Transcriptional profiling ofZmiz1-deficient HDLECs revealed downregulation of genes crucial for lymphatic vessel development. Additionally, our findings demonstrated that loss of Zmiz1 results in reduced expression of proliferation and migration genes in HDLECs and reduced proliferation and migrationin vitro. We also presented evidence that Zmiz1 regulates Prox1 expressionin vitroandin vivoby modulating chromatin accessibility at Prox1 regulatory regions. Furthermore, we observed that loss ofZmiz1in mesenteric lymphatic vessels significantly reduced valve density. Collectively, our results highlight a novel role of Zmiz1 in LECs and as a transcriptional regulator of Prox1, shedding light on a previously unknown regulatory factor in lymphatic vascular biology.