In:
Gut, BMJ, Vol. 70, No. 3 ( 2021-03), p. 485-498
Abstract:
The 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. Design We 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. Results Deletion 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. Conclusion SETDB1 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.
Type of Medium:
Online Resource
ISSN:
0017-5749
,
1468-3288
DOI:
10.1136/gutjnl-2020-321339
Language:
English
Publisher:
BMJ
Publication Date:
2021
detail.hit.zdb_id:
1492637-4
