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 (Setd2 Vil-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 SETD2-deficiency. • Multi-omics analysis to unravel the relationship between H3K36me3 and miRNAs • H3K36me3 modification correlates with miRNA expression in Setd2 Vil-KO mice. • H3K36me3-associated mRNAs and miRNAs affect distinct pathways in IBD progression. • H3K36me3-associated miRNAs may aggravate IBD by interfering with cell-cell junction. [ABSTRACT FROM AUTHOR]