Serra received grants from Fundacion Cientifica AECC (LABAE16020PORTT) and an ERAPERMED2019-215. J. Mateo gratefully acknowledges funding from the European Union's Horizon 2020 research and innovation program (Marie Skłodowska-Curie grant 837900), Instituto de Salud Carlos III (Grant PI18/01384), Fundación AECC, CRIS Cancer Foundation and the US Department of Defense CDMRP (Impact Award PC170510P1). S. Arce-Gallego Research.
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.
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