The role of SETDB1 in intestinal homeostasis and inflammation

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Inflammatory bowel diseases (IBD) are a group of chronic inflammatory diseases of the intestine, the susceptibility to which is regulated by host genetics. We and others have described Mendelian forms of IBD in which deleterious variants in individual genes can give rise to IBD in a monogenic manner. These Mendelian forms of IBD have provided tremendous insight into the pathogenesis of chronic intestinal inflammation and have highlighted novel pathways to personalized treatment of IBD. In the work leading to this proposal, we have identified a female patient with severe, very early-onset, stricturing and fistulizing Crohn’s disease. Exome sequencing in this patient revealed a missense variant predicted to be deleterious in SETDB1, which encodes SET Domain Bifurcated Histone Lysine Methyltransferase 1. SETDB1 is a methyltransferase with high specificity for the lysine 9 residue of histone H3 and is critical for heterochromatin formation. We found that SETDB1 expression in the intestine was largely confined to the intestinal epithelium and attempts to delete SETDB1 or engineer the IBD-associated genetic variant in cultured human intestinal epithelial cells were associated with cell death and inhibition of epithelial growth. We therefore developed mice with tamoxifen-inducible intestinal epithelial deletion of SETDB1. Epithelial deletion of SETDB1 was associated with structural alterations in the intestinal epithelium, loss of differentiated secretory and absorptive enterocytes, hypoglycemia and death within 10 days of Setdb1 deletion. Together, these data reveal an unanticipated, critical role of SETDB1 in intestinal homeostasis and epithelial differentiation. Based on these findings, we propose to (i) characterize the role of SETDB1 in intestinal epithelial lineage specification and to study the metabolic and immunological consequences of loss of epithelial SETDB1. In addition, we propose (ii) to delineate the molecular pathways of SETDB1-dependent regulation of epithelial differentiation and (iii) to study the role of SETDB1 in human intestinal homeostasis and IBD. The proposed studies will characterize a novel and critical regulator of intestinal homeostasis and will delineate a potential contribution of SETDB1 variants to IBD.