Ostrop Jenny, Zwiggelaar Rosalie T, Terndrup Pedersen Marianne, Gerbe François, Bösl Korbinian, Lindholm Håvard T, Díez-Sánchez Alberto, Parmar Naveen, Radetzki Silke, von Kries Jens Peter, Jay Philippe, Jensen Kim B, Arrowsmith Cheryl, Oudhoff Menno J
Centre of Molecular Inflammation Research (CEMIR), Department of Clinical and Molecular Medicine (IKOM), NTNU - Norwegian University of Science and Technology, Trondheim, Norway.
BRIC - Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
Front Cell Dev Biol. 2021 Jan 21;8:618552. doi: 10.3389/fcell.2020.618552. eCollection 2020.
Intestinal organoids are an excellent model to study epithelial biology. Yet, the selection of analytical tools to accurately quantify heterogeneous organoid cultures remains limited. Here, we developed a semi-automated organoid screening method, which we applied to a library of highly specific chemical probes to identify epigenetic regulators of intestinal epithelial biology. The role of epigenetic modifiers in adult stem cell systems, such as the intestinal epithelium, is still undefined. Based on this resource dataset, we identified several targets that affected epithelial cell differentiation, including HDACs, EP300/CREBBP, LSD1, and type I PRMTs, which were verified by complementary methods. For example, we show that inhibiting type I PRMTs, which leads enhanced epithelial differentiation, blocks the growth of adenoma but not normal organoid cultures. Thus, epigenetic probes are powerful tools to study intestinal epithelial biology and may have therapeutic potential.
肠道类器官是研究上皮生物学的优秀模型。然而，用于准确量化异质性类器官培养物的分析工具选择仍然有限。在此，我们开发了一种半自动类器官筛选方法，并将其应用于一个高度特异性化学探针库，以鉴定肠道上皮生物学的表观遗传调节因子。表观遗传修饰因子在成体干细胞系统（如肠道上皮）中的作用仍不明确。基于这个资源数据集，我们鉴定出了几个影响上皮细胞分化的靶点，包括组蛋白去乙酰化酶（HDACs）、EP300/CREBBP、赖氨酸特异性去甲基化酶1（LSD1）和I型蛋白精氨酸甲基转移酶（PRMTs），这些靶点通过互补方法得到了验证。例如，我们发现抑制I型PRMTs可增强上皮分化，并阻断腺瘤生长，但不影响正常类器官培养物的生长。因此，表观遗传探针是研究肠道上皮生物学的有力工具，可能具有治疗潜力。
