High Yap and Mll1 promote a persistent regenerative cell state induced by Notch signaling and loss of p53

Abstract

Significance Using organoids, this study shows that Notch activity and loss of p53 induce a regenerative cell state and recapitulate tumorigenesis. Mutant organoids self-renew and grow independently of essential growth factors and exhibit elevated levels of nuclear Yap, Mll1, and H3K4 trimethylation. These factors are also elevated in human colorectal cancer (CRC) and control viability of patient-derived CRC organoids. Yap interacts with Mll1, and both promote a regenerative cell state that links regenerative processes to tumorigenesis. Specified intestinal epithelial cells reprogram and contribute to the regeneration and renewal of the epithelium upon injury. Mutations that deregulate such renewal processes may contribute to tumorigenesis. Using intestinal organoids, we show that concomitant activation of Notch signaling and ablation of p53 induce a highly proliferative and regenerative cell state, which is associated with increased levels of Yap and the histone methyltransferase Mll1. The induced signaling system orchestrates high proliferation, self-renewal, and niche-factor-independent growth, and elevates the trimethylation of histone 3 at lysine 4 (H3K4me3). We demonstrate that Yap and Mll1 are also elevated in patient-derived colorectal cancer (CRC) organoids and control growth and viability. Our data suggest that Notch activation and p53 ablation induce a signaling circuitry involving Yap and the epigenetic regulator Mll1, which locks cells in a proliferative and regenerative state that renders them susceptible for tumorigenesis.