SETDB1 is required for intestinal epithelial differentiation and the prevention of intestinal inflammation

Abstract

ObjectiveThe intestinal epithelium is a rapidly renewing tissue which plays central roles in nutrient uptake, barrier function and the prevention of intestinal inflammation. Control of epithelial differentiation is essential to these processes and is dependent on cell type-specific activity of transcription factors which bind to accessible chromatin. Here, we studied the role of SET Domain Bifurcated Histone Lysine Methyltransferase 1, also known as ESET (SETDB1), a histone H3K9 methyltransferase, in intestinal epithelial homeostasis and IBD.DesignWe investigated mice with constitutive and inducible intestinal epithelial deletion of Setdb1, studied the expression of SETDB1 in patients with IBD and mouse models of IBD, and investigated the abundance of SETDB1 variants in healthy individuals and patients with IBD.ResultsDeletion of intestinal epithelial Setdb1 in mice was associated with defects in intestinal epithelial differentiation, barrier disruption, inflammation and mortality. Mechanistic studies showed that loss of SETDB1 leads to de-silencing of endogenous retroviruses, DNA damage and intestinal epithelial cell death. Predicted loss-of-function variants in human SETDB1 were considerably less frequently observed than expected, consistent with a critical role of SETDB1 in human biology. While the vast majority of patients with IBD showed unimpaired mucosal SETDB1 expression, comparison of IBD and non-IBD exomes revealed over-representation of individual rare missense variants in SETDB1 in IBD, some of which are predicted to be associated with loss of function and may contribute to the pathogenesis of intestinal inflammation.ConclusionSETDB1 plays an essential role in intestinal epithelial homeostasis. Future work is required to investigate whether rare variants in SETDB1 contribute to the pathogenesis of IBD.

COVID-19 in Children: Expressions of Type I/II/III Interferons, TRIM28, SETDB1, and Endogenous Retroviruses in Mild and Severe Cases

“…Intestinal symptoms are among the most frequent disturbances in MIS-C and were present in almost all of our MIS-C patients. SETDB1 is essential for intestinal epithelial homeostasis and the prevention of local inflammation [ 89 ], while its decreased expression, as in MIS-C, may promote bowel inflammation [ 90 ]. Briefly, our findings suggest that aberrant expressions of TRIM28 and SETDB1 in COVID-19 children may condition the evolution of the infection via their crucial regulatory functions on the immune system, from the innate response to the adaptive response.…”

Structure, Activity and Function of the SETDB1 Protein Methyltransferase

“…Not only deletions but also slight or transient SETDB1 dysregulation due to environmental factors may promote intestinal inflammation. All this justifies the potential implication of the rare SETDB1 variants observed in IBD patients with disease pathogenesis [ 158 ].…”

A unique death pathway keeps RIPK1 D325A mutant mice in check at embryonic day 10.5

“…If, however, caspase-8 activity is inhibited and cellular RIPK3 amount is sufficient, RIPK1 recruits RIPK3 via its RIP homotypic interaction motif (RHIM), thus promoting activation of RIPK3, which, in turn, recruits and phosphorylates mixed lineage kinase domain-like (MLKL). Phosphorylated MLKL then oligomerizes and translocates to the plasma membrane, causing plasma membrane rupture and necroptotic cell death [ 16 , 17 ], which might lead to necroinflammation in vivo [ 18 – 20 ]. Caspase-8 is an aspartate-specific cysteine protease, which can either exert function via its catalytic activity or as a scaffold for complex assembly and signaling transduction.…”