title: PRC2 preserves intestinal progenitors and restricts secretory lineage commitment.
abstract: 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.
authors: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy fulvio.chiacchiera@ieo.eu diego.pasini@ieo.eu.
authors: Fulvio
authors: F
authors: Chiacchiera
authors: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors: Alessandra
authors: A
authors: Rossi
authors: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors: SriGanesh
authors: S
authors: Jammula
authors: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors: Marika
authors: M
authors: Zanotti
authors: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy fulvio.chiacchiera@ieo.eu diego.pasini@ieo.eu.
authors: Diego
authors: 0000-0002-9879-6486
authors: D
authors: Pasini
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D053595:Embryonic Stem Cells / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D008822:Mice, Transgenic; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism*
chemical_list: D006657:Histones; D063151:Polycomb Repressive Complex 2
keywords: H3K27 methylation; PRC2; chromatin modifications; intestinal homeostasis and differentiation; polycomb