Department of Cell and Molecular Biology, Tulane University, New Orleans, LA, United States of America.
Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, United States of America.
PLoS One. 2024 May 8;19(5):e0302926. doi: 10.1371/journal.pone.0302926. eCollection 2024.
Zinc 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)-specific Zmiz1 knockout mouse model to investigate the role of Zmiz1 in LECs. Transcriptional profiling of ZMIZ1-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 migration in vitro. We also presented evidence that Zmiz1 regulates Prox1 expression in vitro and in vivo by modulating chromatin accessibility at Prox1 regulatory regions. Furthermore, we observed that loss of Zmiz1 in 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.
锌指 MIZ 型结构域包含蛋白 1（Zmiz1），也被称为 ZIMP10 或 RAI17，是一种转录共因子，属于蛋白抑制剂激活 STAT（PIAS）家族的蛋白质。Zmiz1 对于多种生物学过程至关重要，包括血管发育。然而，其在淋巴管中的作用尚不清楚。在这项研究中，我们利用人真皮淋巴管内皮细胞（HDLECs）和一种可诱导的、淋巴管内皮细胞（LEC）特异性 Zmiz1 敲除小鼠模型，研究了 Zmiz1 在 LEC 中的作用。对 ZMIZ1 缺陷的 HDLECs 的转录谱分析显示，淋巴管发育关键基因的下调。此外，我们的研究结果表明，Zmiz1 的缺失导致 HDLECs 中增殖和迁移基因的表达减少，体外增殖和迁移减少。我们还提供了证据表明，Zmiz1 通过调节 Prox1 调节区域的染色质可及性，在体外和体内调节 Prox1 的表达。此外，我们观察到肠系膜淋巴管中 Zmiz1 的缺失显著降低了瓣膜密度。综上所述，我们的研究结果突出了 Zmiz1 在 LEC 中的新作用以及作为 Prox1 的转录调节剂的作用，揭示了淋巴管血管生物学中一个以前未知的调节因子。
