SETDB1 is required for intestinal epithelial differentiation and the prevention of intestinal inflammation.
SETDB1 is required for intestinal epithelial differentiation and the prevention of intestinal inflammation.
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SETDB1是肠上皮分化和预防肠道炎症所必需的。
DOI：
10.1136/gutjnl-2020-321339
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发表时间：
2021-03
期刊：
影响因子：
24.5
通讯作者：
Zeissig S
中科院分区：
文献类型：
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作者：
Južnić L;Peuker K;Strigli A;Brosch M;Herrmann A;Häsler R;Koch M;Matthiesen L;Zeissig Y;Löscher BS;Nuber A;Schotta G;Neumeister V;Chavakis T;Kurth T;Lesche M;Dahl A;von Mässenhausen A;Linkermann A;Schreiber S;Aden K;Rosenstiel PC;Franke A;Hampe J;Zeissig S
肠上皮是一种快速更新的组织，在营养吸收、屏障功能和预防肠道炎症中起着重要作用。上皮细胞分化的控制对这些过程是必不可少的，并且依赖于与可接近的染色质结合的转录因子的细胞类型特异性活性。在这里，我们研究了SET结构域分叉组蛋白赖氨酸甲基转移酶1，也称为ESET（SETDB1），一种组蛋白H3K9甲基转移酶，在肠上皮稳态和IBD中的作用。我们研究了Setdb 1组成型和诱导型肠上皮缺失的小鼠，研究了IBD患者和IBD小鼠模型中SETDB 1的表达，并研究了健康个体和IBD患者中SETDB 1变体的丰度。小鼠肠上皮Setdb1的缺失与肠上皮分化缺陷、屏障破坏、炎症和死亡率相关。机制研究表明，SETDB1的缺失导致内源性逆转录病毒的去沉默、DNA损伤和肠上皮细胞死亡。在人类SETDB1中预测的功能丧失变体的观察频率远低于预期，这与SETDB1在人类生物学中的关键作用一致。虽然绝大多数IBD患者的黏膜SETDB 1表达未受损，但IBD和非IBD外显子组的比较显示IBD中SETDB 1中个别罕见错义变体的过度表达，其中一些预计与功能丧失相关，并可能导致肠道炎症的发病机制。SETDB1在肠上皮细胞的稳态中起着重要作用。未来的工作需要调查SETDB1中的罕见变异是否有助于IBD的发病机制。
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. 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. 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. 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.
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