Chromatin modifications shape cell heterogeneity by activating and repressing defined sets of genes involved in cell proliferation, differentiation and development. Polycomb‐repressive complexes (PRCs) act synergistically during development and differentiation by maintaining transcriptional repression of common genes. PRC2 exerts this activity by catalysing H3K27 trimethylation. Here, we show that in the intestinal epithelium PRC2 is required to sustain progenitor cell proliferation and the correct balance between secretory and absorptive lineage differentiation programs. Using genetic models, we show that PRC2 activity is largely dispensable for intestinal stem cell maintenance but is strictly required for radiation‐induced regeneration by preventing Cdkn2a transcription. Combining these models with genomewide molecular analysis, we further demonstrate that preferential accumulation of secretory cells does not result from impaired proliferation of progenitor cells induced by Cdkn2a activation but rather from direct regulation of transcription factors responsible for secretory lineage commitment. Overall, our data uncover a dual role of PRC2 in intestinal homeostasis highlighting the importance of this repressive layer in controlling cell plasticity and lineage choices in adult tissues.
See also: P Vizán et al (November 2016)
PRC2 exerts a dual role in intestinal homeostasis by controlling progenitor cell proliferation via repression of Cdkn2a and restricting secretory commitment by targeting key regulators of cell differentiation.
PRC2 regulates progenitor cell proliferation by repressing the Cdkn2a locus without affecting general tissue homeostasis.
Cdkn2a activation limits progenitor cell plasticity to regenerate the intestinal epithelium after damage.
PRC2 regulates lineage choices restricting secretory cell commitment independently of Cdkn2a repression.
PRC2 serves as direct repressive barrier for the activation of master regulators of secretory lineage commitment.
The EMBO Journal (2016) 35: 2301–2314
- Received April 14, 2016.
- Revision received August 8, 2016.
- Accepted August 10, 2016.
- © 2016 The Authors
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