A Semi-automated Organoid Screening Method Demonstrates Epigenetic Control of Intestinal Epithelial Differentiation

Frontiers in Cell and Developmental Biology

Philippe Jay²  François Gerbe²  Alberto Díez-Sánchez³  Håvard T. Lindholm³  Rosalie T. Zwiggelaar³  Naveen Parmar³  Menno J. Oudhoff³  Jenny Ostrop³  Korbinian Bösl⁴  Cheryl Arrowsmith⁵  Kim B. Jensen⁶  Marianne Terndrup Pedersen⁶  Jens Peter von Kries⁸  Silke Radetzki⁸ 

[1] BRIC - Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark;Cancer Biology Department, Institute of Functional Genomics, University of Montpellier, Montpellier, France;Centre of Molecular Inflammation Research (CEMIR), Department of Clinical and Molecular Medicine (IKOM), NTNU - Norwegian University of Science and Technology, Trondheim, Norway;Department of Bioinformatics, Computational Biological Unit, University of Bergen, Bergen, Norway;Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada;Novo Nordisk Foundation Center for Stem Cell Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark;Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada;Screening Unit, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany;Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada;

关键词: organoids;    epigenetic modifiers;    intestinal stem cell biology;    bioimage analysis;    PRMT1;    EP300;   

DOI  :  10.3389/fcell.2020.618552

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown