SUZ12‐dependent pathways may regulate the intestinal epithelial inflammatory response

Polycomb Repressive complex 2, containing SUZ12 and the histone H3 lysine 27 methyltransferase EZH2, controls stem cell renewal. The H3K27 methyl mark is reduced in subsets of inflammatory genes. Whether SUZ12 and H3K27 methyl marks regulate intestinal epithelial cell (IEC) inflammatory response is not known. Thus, we verified the role of SUZ12 in IEC. IEC‐6 rat cells were depleted in SUZ12 by infection with a lentiviral vector expressing a shRNA against SUZ12. mRNA expression was assessed by microarray analysis. SUZ12, EZH2 and H3K27 methylation levels were determined by Western blot. C/EBPbeta, phospho‐p38 and phospho‐JNK protein levels, and specific inflammatory gene mRNAs, were analysed respectively by Western blot and by semi‐quantitative RT‐PCR, in response to IL‐1beta. mRNA stability was assessed after actinomycin D treatment. Results SUZ12 and EZH2 were expressed along the crypt‐villus axis. Reduced IEC‐6 SUZ12 protein levels led to 1) decrease in EZH2 expression and H3K27 tri‐methylation, 2) increases in basal expression of a subset of inflammatory genes, 3) increased C/EBPbeta protein levels, 4) decreased p38 MAPkinase activation in response to IL‐1beta, as opposed to JNK activation, 5) increased stability of some inflammatory gene mRNAs. The H3K27methyl mark may regulate the IEC inflammatory response at both transcriptional and post‐transcriptional levels. Supported by CCFC.