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

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 ablat...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2021-06, Vol.118 (22), p.1-9
Main Authors: Heuberger, Julian, Grinat, Johanna, Kosel, Frauke, Liu, Lichao, Kunz, Séverine, Vidal, Ramon Oliveira, Keil, Marlen, Haybaeck, Johannes, Robine, Sylvie, Louvard, Daniel, Regenbrecht, Christian, Sporbert, Anje, Sauer, Sascha, von Eyss, Björn, Sigal, Michael, Birchmeier, Walter
Format: Article
Language:English
Subjects:
Ablation
Biological Sciences
Circuits
Colorectal carcinoma
Deregulation
Epigenetics
Epithelial cells
Epithelium
Histone methyltransferase
Histones
Intestine
Lysine
Methylation
Mutation
Organoids
p53 Protein
Regeneration
Signalling systems
Tumorigenesis
Yes-associated protein
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2019699118