Loss of Setd2 associates with aberrant microRNA expression and contributes to inflammatory bowel disease progression in mice

Both SETD2-mediated H3K36me3 and miRNAs play critical epigenetic roles in inflammatory bowel disease (IBD) and involve in the dysfunctional intestinal barrier. However, little is known about cross-talk between these two types of regulators in IBD progression. We performed small RNA sequencing of Setd2 epithelium-specific knockout mice (Setd2Vil-KO) and wild-type controls, both with DSS-induced colitis, and designed a framework for integrative analysis. Firstly, we integrated the downloaded ChIP-seq data with miRNA expression profiles and identified a significant intersection of pre-miRNA expression and H3K36me3 modification. A significant inverse correlation was detected between changes of H3K36me3 modification and expression of the 171 peak-covered miRNAs. We further integrated RNA-seq data with predicted miRNA targets to screen negatively regulated miRNA-mRNA pairs and found the H3K36me3-associated differentially expressed microRNAs significantly enriched in cell-cell junction and signaling pathways. Using network analysis, we identified ten hub miRNAs, among which six are H3K36me3-associated, suggesting therapeutic targets for IBD patients with SETD2deficiency.

Automated summary

Both SETD2-mediated H3K36me3 and miRNAs are crucial in IBD and its related dysfunctional intestinal barrier. Integrative analysis of ChIP-seq, miRNA expression profiles, and RNA-seq data revealed a significant inverse correlation between H3K36me3 modification and the expression of 171 peak-covered miRNAs, with enrichment in cell-cell junction and signaling pathways. Ten hub miRNAs, including six H3K36me3-associated ones, were identified as potential therapeutic targets for IBD patients with SETD2 deficiency.