SETD8 involved in the progression of inflammatory bowel disease via epigenetically regulating p62 expression

Abstract

Background and Aim: 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 upregulated in IBD patients, and histone modification plays an important role in regulating p62 expression. SETD8, a histone H4K20 methyltransferase, has been reported downregulated 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. Three percent dextran sodium sulfate-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 and p62 was measured by qRT-PCR and western blot. The mRNA level of inflammatory cytokines was analyzed by qRT-PCR. In addition, chromatin immunoprecipitation-PCR was performed to identify the mechanism by which SETD8 regulates p62. Results: SETD8 expression obviously decreased in vitro, in vivo models and in IBD patients. In lipopolysaccharide-activated RAW264.7 cells, knockdown of SETD8 significantly increased the mRNA expression of inducible nitric oxide synthase, cyclooxygenase-2, TNF-α, 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 assay identified that silence of SETD8 distinctly decreases the H4K20me1 enrichment in the promoter of p62. Moreover, silencing of p62 partly reverses the SETD8 inhibition-mediated pro-inflammatory effect in vitro. Finally, SETD8 pharmacological inhibitor (UNC0379) aggravated the disease progression in dextran sodium sulfate-induced murine colitis. Conclusion: Our findings elucidate an epigenetic mechanism by which SETD8 regulates the p62 expression and restrains the inflammatory response in colitis. Our result suggests that targeting SETD8 may be a promising therapy for IBD.P Chen et al.SETD8 inhibition promote colitis via p62

Role of Histone Post-Translational Modifications in Inflammatory Diseases

“…A large proportion of genes enriched in newly diagnosed pediatric IBD patients maintained a significant level of H3K4me3, which was related to the severity of intestinal inflammation during the progression of IBD ( 34 ). SETD8 is a typical histone H4K20 methyltransferase in which silence of SETD8 could significantly decrease the enrichment of H4K20me1 in the p62 promoter to regulate the expression of p62 and inhibit the inflammatory response in colitis ( 35 ). The level of H3K9 acetylation was decreased upon dextran sulfate sodium (DSS) treatment, which was reported to induce colitis by lessening the macrophage amount and the secreted inflammatory cytokines ( 188 ).…”

YAP represses intestinal inflammation through epigenetic silencing of JMJD3

“…The treatment started on day 0 and continued until the mice were sacrificed. The DAI score was used to quantify the severity of colitis, as previously described [ 66 ] and shown in Table 1 ).…”

The Role of Genetic and Epigenetic Regulation in Intestinal Fibrosis in Inflammatory Bowel Disease: A Descending Process or a Programmed Consequence?

“…The results showed that silencing SETD8 regulates the expression of the p62 protein, thus blocking the inflammatory response of the colon. The authors suggest that SETD8 may be used in the future as a potential therapy for patients with IBD [ 92 ]. Another study using Lactobacillus casei probiotic in mice with colitis investigated the effect of L. casei on the immune response and histone modifications.…”