The histone H3K27 methylation mark regulates intestinal epithelial cell density-dependent proliferation and the inflammatory response.

Authors: Turgeon, N  Blais, M  Delabre, JF  Asselin, C 
Citation: Turgeon N, etal., J Cell Biochem. 2013 May;114(5):1203-15. doi: 10.1002/jcb.24463.
Pubmed: (View Article at PubMed) PMID:23192652
DOI: Full-text: DOI:10.1002/jcb.24463

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-1beta-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/EBPbeta. 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.

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CRRD Object Information
CRRD ID: 9586745
Created: 2014-10-06
Species: All species
Last Modified: 2014-10-06
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.