Polycomb Complex PRC1 Preserves Intestinal Stem Cell Identity by Sustaining Wnt/β-Catenin Transcriptional Activity

• Published in: Cell stem cell 2016-01, Vol.18 (1), p.91-103
• Main Authors: Chiacchiera, Fulvio, Rossi, Alessandra, Jammula, SriGanesh, Piunti, Andrea, Scelfo, Andrea, Ordóñez-Morán, Paloma, Huelsken, Joerg, Koseki, Haruhiko, Pasini, Diego
• Format: Article
• Language: English
• Subjects: Adult Stem Cells - cytology; Alleles; Animals; beta Catenin - metabolism; Cell Proliferation; Cells, Cultured; Chromatin Immunoprecipitation; Flow Cytometry; Green Fluorescent Proteins - metabolism; Homeostasis; Intestines - cytology; Mice; Mice, Knockout; Phenotype; Polycomb-Group Proteins - metabolism; Tissue Distribution; Transcription, Genetic; Wnt Proteins - metabolism; Wnt Signaling Pathway
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2015.09.019

Polycomb repressive complexes (PRCs) are among the most important gatekeepers of establishing and maintaining cell identity in metazoans. PRC1, which plays a dominant role in this context, executes its functions via multiple subcomplexes, which all contribute to H2AK119 mono-ubiquitination (H2Aubq). Despite our comprehensive knowledge of PRC1-dependent H2Aubq in embryonic stem cells and during early development, its role in adult stem cells still remains poorly characterized. Here we show that PRC1 activity is required for the integrity of the intestinal epithelium, regulating stem cell self-renewal via a cell-autonomous mechanism that is independent from Cdkn2a expression. By dissecting the PRC1-dependent transcription program in intestinal stem cells, we demonstrate that PRC1 represses a large number of non-lineage-specific transcription factors that directly affect β-catenin/Tcf transcriptional activity. Our data reveal that PRC1 preserves Wnt/β-catenin activity in adult stem cells to maintain intestinal homeostasis and supports tumor formation induced by the constitutive activation of this pathway. [Display omitted] •PRC1 activity controls the self-renewal of intestinal stem cells•Intestinal identity is maintained by suppressing non-tissue-specific transcription•Activated TFs directly interfere with nuclear β-catenin transcriptional activity•Wnt/β-catenin signaling is sustained under normal and pathological conditions Chiacchiera et al. show that PRC1 activity is essential to maintain integrity of the intestinal epithelium during homeostasis and in cancer. Mechanistically, PRC1 represses non-lineage-specific transcription factors that in turn directly affect β-catenin/Tcf transcriptional activity and Wnt-dependent intestinal stem cell self-renewal.