Epigenetic control of colonic epithelial antigen processing, barrier function, and the microbiome via methyl-CpG binding domain protein 2

Abstract Background Methyl-CpG binding domain protein 2 (MBD2) is a transcriptional co-repressor that binds to methylated DNA. It can recruit a nucleosome–remodelling complex with histone deacetylase and chromatin remodelling functions that in turn affect gene expression. Colon epithelial cells display broad immunomodulatory capabilities via antigen processing, bacterial sensing, and cytokine and chemokine secretion. However, the epigenetic modulation of colon epithelial cell function and its effect on the microbiome are poorly described. We aimed to assess the role of epigenetic processes in controlling colon epithelial cell responses in the steady state and in colonic inflammation. Methods Colon epithelial cells from naive Mbd2 –/– mice, day 6 Mbd2 –/– mice treated with 2% dextran sodium sulphate (DSS), day 35 Mbd2 –/– mice infected with Trichuris muris (200 eggs), and wild-type (WT) littermates were assessed for surface expression of the following markers by flow cytometry (EpCAM, CD45, Ly6A/E, and MHC class II). Colon epithelial cells from naive and DSS-treated Mbd2 –/– mice and littermate controls were purified by fluorescence activated cell sorting and assessed by microarray (MouseRef-6, Illumina, SanDiego, CA, USA). The 16S component of faeces from naive Mbd2 –/– mice and WT littermate controls was sequenced with the MiSeq platform (Illumina) and analysed with mothur software (version 1.36.1). Findings Colon epithelial cells from naive, DSS-treated and T muris -treated Mbd2 –/– mice displayed significantly greater expression of MHC class II and the activation marker Ly6A/E than did WT controls. Colon epithelial cells from both naive and DSS-treated mice displayed significantly increased expression (LogFCu003e2, adj p H2-Q8, H2-K1, H2-T23, Psmb8, Psmb9 ) and MHC class II, ( Cd74, H2-Aa, H2-Dmb1, H2-Eb1 ), and decreased expression of tight junction proteins ( Cldn1, Cldn4 ) with significant (p Mbd2 –/– and WT mice were significantly different independent of cohousing in Yue and Clayton taxonomic analysis with significant increases in three species of Clostridiales and decreases in Parabacteroides observed. Interpretation These findings suggest for the first time (to our knowledge) that epigenetic processes can modulate the antigen processing capabilities of colon epithelial cells both in the steady state and in mouse models of colitis. They also suggest that the intestinal microbiota can be shaped by epigenetic processes despite equivalent environmental exposures. Taken together, MBD2 targets in colon epithelial cells represent exciting new avenues for therapeutic modulation of gastrointestinal inflammation. Funding Wellcome Trust.