Iκbα Deficiency Imposes a Fetal Phenotype to Intestinal Stem Cells

Abstract

The intestinal epithelium is a paradigm of adult tissue in constant regeneration that is supported by intestinal stem cells (ISC). The mechanisms regulating ISC homeostasis after injury are poorly understood. We previously demonstrated that IκBα, not only controls NF-κB activation, but also exerts nuclear functions as cytokine sensor in a subset of PRC2-regulated genes. We have now detected nuclear phosphorylated IκBα (P-IκBα) in the ISC compartment where it binds highly histone methylated genomic regions. Mice deficient for IκBα show aberrant distribution of the H3K27me3 mark, and altered intestinal cell differentiation with persistence of a fetal-like ISC gene expression signature. In vitro, IκBα deficient intestinal cells produce morphologically aberrant organoids carrying a PRC2, Notch and IFN-dependent fetal-like transcriptional signature. Induction of the fetal-like phenotype by DSS treatment is associated with loss of nuclear P-IκBα in the damaged colonic epithelium and its subsequent accumulation in early CD44 positive regenerating areas. Importantly, IκBα deficient animals show higher resistance to damage, likely due to the persistent fetal-like phenotype. These results point out intestinal IκBα as a chromatin sensor of inflammation in the ISC compartment.