SETD8 involved in the progression of IBD via epigenetically regulating p62 expression.

Background and aims Epigenetic modification is an important part of the pathogenesis of inflammatory bowel disease (IBD). Some studies proved that p62 was involved in inflammatory response and up-regulated in IBD patients, and histone modification play an important role in regulating p62 expression. SETD8, a histone H4K20 methyltransferase, has been reported down-regulated in some inflammatory diseases. Here, we investigated the role of SETD8 in the development of IBD and its underlying mechanisms. Methods An inflammatory cell model was established to elucidate whether SETD8 involved in inflammatory response in macrophages. 3% dextran sodium sulfate (DSS) induced colitis murine model injection with SETD8 inhibitor was used in our study to investigate whether SETD8 inhibition can affect the progress of IBD. The expression of SETD8, p62 was measured by qRT-PCR and western blot. The mRNA level of inflammatory cytokines was analyzed by qRT-PCR. In addition, ChIP-PCR was performed to identified the mechanism by which SETD8 regulate p62. Results SETD8 expression obviously decreased in vitro, in vivo models and in IBD patients. In lipopolysaccharide (LPS)-activated RAW264.7 cells, knock-down SETD8 significantly increased the mRNA expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-ɑ, IL-6, IL-1β and MCP-1. Based on the dataset, we verified that p62 was a target gene of SETD8 and chromatin immunoprecipitation-PCR (ChIP-PCR) assay identified that silence of SETD8 distinctly decrease the H4K20me1 enrichment in the promoter of p62. Moreover, silencing of p62 partly reverse the SETD8 inhibition-mediated pro-inflammatory effect in vitro. Finally, SETD8 pharmacological inhibitor (UNC0379) aggravated the disease progression in DSS-induced murine colitis. Conclusion Our findings elucidate an epigenetic mechanism by which SETD8 regulates the p62 expression and restrain the inflammatory response in colitis. Our result suggests that targeting SETD8 may be a promising therapy for IBD.