Gong Wuming, Das Satyabrata, Sierra-Pagan Javier E, Skie Erik, Dsouza Nikita, Larson Thijs A, Garry Mary G, Luzete-Monteiro Edgar, Zaret Kenneth S, Garry Daniel J
Cardiovascular Division, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA.
Nat Cell Biol. 2022 May;24(5):672-684. doi: 10.1038/s41556-022-00901-3. Epub 2022 May 12.
The vasculature is an essential organ for the delivery of blood and oxygen to all tissues of the body and is thus relevant to the treatment of ischaemic diseases, injury-induced regeneration and solid tumour growth. Previously, we demonstrated that ETV2 is an essential transcription factor for the development of cardiac, endothelial and haematopoietic lineages. Here we report that ETV2 functions as a pioneer factor that relaxes closed chromatin and regulates endothelial development. By comparing engineered embryonic stem cell differentiation and reprogramming models with multi-omics techniques, we demonstrated that ETV2 was able to bind nucleosomal DNA and recruit BRG1. BRG1 recruitment remodelled chromatin around endothelial genes and helped to maintain an open configuration, resulting in increased H3K27ac deposition. Collectively, these results will serve as a platform for the development of therapeutic initiatives directed towards cardiovascular diseases and solid tumours.
脉管系统是一个向身体所有组织输送血液和氧气的重要器官，因此与缺血性疾病、损伤诱导的再生以及实体肿瘤生长的治疗相关。此前，我们证明ETV2是心脏、内皮和造血谱系发育所必需的转录因子。在此我们报告，ETV2作为一个先驱因子，可使紧密染色质松弛并调节内皮发育。通过使用多组学技术比较工程化胚胎干细胞分化和重编程模型，我们证明ETV2能够结合核小体DNA并招募BRG1。BRG1的招募重塑了内皮基因周围的染色质，并有助于维持开放构型，导致H3K27ac沉积增加。总的来说，这些结果将为针对心血管疾病和实体肿瘤的治疗方案开发提供一个平台。
