title: The histone H3K27 methylation mark regulates intestinal epithelial cell density-dependent proliferation and the inflammatory response.
abstract: Polycomb-group proteins form multimeric protein complexes involved in transcriptional silencing. The Polycomb Repressive complex 2 (PRC2) contains the Suppressor of Zeste-12 protein (Suz12) and the histone methyltransferase Enhancer of Zeste protein-2 (Ezh2). This complex, catalyzing the di- and tri-methylation of histone H3 lysine 27, is essential for embryonic development and stem cell renewal. However, the role of Polycomb-group protein complexes in the control of the intestinal epithelial cell (IEC) phenotype is not known. We show that Suz12 and Ezh2 were differentially expressed along the intestinal crypt-villus axis. ShRNA-mediated Suz12 depletion in the IEC-6 rat crypt-derived cell line decreased Ezh2 expression and H3K27 di-trimethylation. Suz12-depleted cells achieved higher cell densities after confluence, with increased cyclin D2 and cyclin D3 protein levels, and increased STAT3 activation in post-confluent cells. Suz12 depletion specifically increased mostly developmental, cell adhesion and immune response gene expression, including neuronal and inflammatory genes. Suz12 depletion directly and indirectly de-regulated the IL-1β-dependent inflammatory response, as demonstrated by decreased MAPK p38 activation as opposed to JNK activation, and altered basal and stimulated expression of inflammatory genes, including transcription factors such as C/EBPβ. Of note, this positive effect on cell proliferation and inflammatory gene expression was revealed in the absence of the cyclin-dependent kinase inhibitor p16, a main target negatively regulated by PRC2. These results demonstrate that the PRC2 complex, in addition to keeping in check non-IEC differentiation pathways, insures the proper IEC response to cell density as well as to external growth and inflammatory signals, by controlling specific signaling pathways.
authors.affiliation: Faculté de médecine et des sciences de la santé, Département d'anatomie et biologie cellulaire, Pavillon de recherche appliquée sur le cancer, Université de Sherbrooke, Sherbrooke, Québec, Canada J1E 4K8.
authors.forename: Naomie
authors.initials: N
authors.lastname: Turgeon
authors.forename: Mylène
authors.initials: M
authors.lastname: Blais
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Delabre
authors.forename: Claude
authors.initials: C
authors.lastname: Asselin
mesh_terms: D000818:Animals; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D000071221:Enhancer of Zeste Homolog 2 Protein; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006657:Histones / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics / Q000473:pathology*; D053583:Interleukin-1beta / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007422:Intestines / Q000473:pathology*; D008239:Lysine / Q000378:metabolism*; D008745:Methylation / Q000187:drug effects; D051379:Mice; D008871:Microvilli / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism; D051381:Rats; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism
chemical_list: D006657:Histones; D053583:Interleukin-1beta; D050796:STAT3 Transcription Factor; D051176:beta Catenin; C578253:EZH2 protein, rat; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2; D008239:Lysine