The role of SETDB1 in intestinal homeostasis and inflammation
Final Report Abstract
In this work, we have demonstrated that loss of epithelial SETDB1, an H3K9 methyltransferase critical for heterochromatin formation, is associated with de-silencing of endogenous retroviruses and DNA damage as well as p53 accumulation, which triggers cell death within the intestinal epithelium. The loss of differentiated epithelial cells, including the intestinal stem cell compartment, facilitates the breakdown of the intestinal epithelial barrier. This is accompanied by an innate immune response characterized by a type I interferon signature, which promotes intestinal inflammation. Necroptosis of IECs, progressive inflammation, and loss of functional intestinal epithelium contribute to absorption defects and associated osmotic fluid shift. This ultimately causes death due to severe metabolic dysfunction. Accordingly, attempts to constitutively delete Setdb1 in the intestinal epithelium were futile due to embryonic lethality. As such, these data highlight a critical role of SETDB1 and SETDB1-dependent heterochromatin formation in intestinal epithelial homeostasis, differentiation and survival. While SETDB1 expression was tightly regulated in IBD, without disease-associated alterations in expression, we identified IBD-associated rare, hypomorphic missense variants in SETDB1. In vitro studies in an intestinal epithelial cell line model, as well as analysis of intestinal biopsies suggested that IBD-associated SETDB1 variants p.A266T, p.S262G and p.T1164I are associated with DNA damage and increased cell death. High levels of DNA damage and cell death were also detected in intestinal biopsies of the patient carrying the SETDB1 p.A266T variant, compared to both healthy individuals and IBD patients with or without active inflammation. In line with observations in mice with IEC-specific deletion of SETDB1, this suggests that rare, hypomorphic SETDB1 variants can contribute to the pathogenesis of IBD. In conclusion, our work demonstrates a critical role of SETDB1 in intestinal epithelial homeostasis and the prevention of intestinal inflammation and suggests that rare variants in SETDB1 may contribute to IBD pathogenesis. Together, these data unveil a critical role of SETDB1 in maintenance of genome stability in IECs, and consequently intestinal epithelial homeostasis and prevention of intestinal inflammation. Rare variants of SETDB1 are over-represented in IBD patients, and likely contribute to IBD pathogenesis.
Publications
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SETDB1 is required for intestinal epithelial differentiation and the prevention of intestinal inflammation. Gut, 70(3), 485-498.
Južnić, Lea; Peuker, Kenneth; Strigli, Anne; Brosch, Mario; Herrmann, Alexander; Häsler, Robert; Koch, Michael; Matthiesen, Liz; Zeissig, Yvonne; Löscher, Britt-Sabina; Nuber, Alexander; Schotta, Gunnar; Neumeister, Volker; Chavakis, Triantafyllos; Kurth, Thomas; Lesche, Mathias; Dahl, Andreas; von Mässenhausen, Anne; Linkermann, Andreas ... & Zeissig, Sebastian
