A semi-automated intestinal organoid screening method demonstrates epigenetic control of epithelial maturation

The intestinal epithelium maintains an important barrier throughout life. It consists of several epithelial cell lineages that are derived from LGR5+ intestinal stem cells. Although epigenetic regulation of embryonic stem cell differentiation is well established, its role in adult stem cell systems such as the intestinal epithelium is still undefined. Yet, targeting of epigenetic regulatory enzymes may be relevant for new therapeutics, for example in cancer treatment. Here, we combine a newly established organoid toolbox with an epigenetic probe library to identify epigenetic regulators of intestinal epithelial biology. We discover several probes that alter intestinal epithelial biology including those targeting HDACs, EP300/CREBBP, LSD1, and type I PRMTs. We conclude that epigenetic modifiers are primarily involved in mediating maturation of the epithelium rather than dictating specific cell lineage differentiation. Furthermore, we show that inhibiting type I PRMTs, which leads to epithelial maturation, blocks the growth of adenoma but not normal organoid cultures. Thus, epigenetic probes are a powerful tool in defining biological processes and demonstrate therapeutic potential