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

Item Type:Article
Title:High Yap and Mll1 promote a persistent regenerative cell state induced by Notch signaling and loss of p53
Creators Name:Heuberger, J. and Grinat, J. and Kosel, F. and Liu, L. and Kunz, S. and Vidal, R.O. and Keil, M. and Haybaeck, J. and Robine, S. and Louvard, D. and Regenbrecht, C. and Sporbert, A. and Sauer, S. and von Eyss, B. and Sigal, M. and Birchmeier, W.
Abstract: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.
Keywords:Cancer, Kmt2a, Notch, Yap, Regeneration
Source:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
Page Range:e2019699118
Date:1 June 2021
Additional Information:Published under the PNAS license (https://www.pnas.org/author-center/publication-charges).
Official Publication:https://doi.org/10.1073/pnas.2019699118
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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