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

Proc Natl Acad Sci U S A. 2021 Jun 1;118(22):e2019699118. doi: 10.1073/pnas.2019699118.


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: Kmt2a; Notch; Yap; cancer; regeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins / metabolism
  • Cell Cycle Proteins / physiology*
  • Cell Line, Tumor
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Histone-Lysine N-Methyltransferase / physiology*
  • Humans
  • Mutation
  • Myeloid-Lymphoid Leukemia Protein / physiology*
  • Organoids / metabolism
  • Receptors, Notch / metabolism*
  • Signal Transduction*
  • Transcription Factors / metabolism
  • Transcription Factors / physiology*
  • Tumor Suppressor Protein p53 / genetics*


  • Cell Cycle Proteins
  • KMT2A protein, human
  • Receptors, Notch
  • TP53 protein, human
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • YY1AP1 protein, human
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase