Cancer Research Program, CIBERONC, Institut Mar d'Investigacions Mèdiques, Hospital del Mar, Barcelona, Spain.
Faculty of Science and Technology, Bioinformatics and Medical Statistics Group, University of Vic-Central University of Catalonia, Vic, Spain.
EMBO Rep. 2020 Jun 4;21(6):e49708. doi: 10.15252/embr.201949708. Epub 2020 Apr 9.
The intestinal epithelium is a paradigm of adult tissue in constant regeneration that is supported by intestinal stem cells (ISCs). The mechanisms regulating ISC homeostasis after injury are poorly understood. We previously demonstrated that IκBα, the main regulator of NF-κB, exerts alternative nuclear functions as cytokine sensor in a subset of PRC2-regulated genes. Here, we show that nuclear IκBα is present in the ISC compartment. Mice deficient for IκBα show altered intestinal cell differentiation with persistence of a fetal-like ISC phenotype, associated with aberrant PRC2 activity at specific loci. Moreover, IκBα-deficient intestinal cells produce morphologically aberrant organoids carrying a PRC2-dependent fetal-like transcriptional signature. DSS treatment, which induces acute damage in the colonic epithelium of mice, results in a temporary loss of nuclear P-IκBα and its subsequent accumulation in early CD44-positive regenerating areas. Importantly, IκBα-deficient mice show higher resistance to damage, likely due to the persistent fetal-like ISC phenotype. These results highlight intestinal IκBα as a chromatin sensor of inflammation in the ISC compartment.
肠上皮是一种不断再生的成年组织范例，由肠干细胞（ISC）支持。然而，我们对损伤后调节 ISC 稳态的机制知之甚少。我们之前证明，NF-κB 的主要调节剂 IκBα 在 PRC2 调控基因的亚组中作为细胞因子传感器发挥替代核功能。在这里，我们表明核 IκBα存在于 ISC 隔室中。缺乏 IκBα的小鼠表现出肠道细胞分化改变，具有持续的胎儿样 ISC 表型，与特定基因座的异常 PRC2 活性相关。此外，IκBα 缺陷的肠道细胞产生形态异常的类器官，具有 PRC2 依赖性的胎儿样转录特征。DSS 处理会导致小鼠结肠上皮的急性损伤，导致核 P-IκBα的暂时丢失，并随后在早期 CD44 阳性的再生区域中积累。重要的是，IκBα 缺陷型小鼠对损伤的抵抗力更高，这可能是由于持续存在的胎儿样 ISC 表型。这些结果强调了肠道 IκBα作为 ISC 隔室炎症的染色质传感器的作用。
