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 IBa, not only controls NF-B activation, but also exerts nuclear functions as cytokine sensor in a subset of PRC2-regulated genes. We now uncover nuclear phosphorylated IBa (P-IBa) in the ISC compartment where it binds highly histone methylated genomic regions. Mice deficient for IBa show aberrant distribution of H3K27me3 mark, and altered intestinal differentiation with persistence of a fetal-like ISC signature. In vitro, IBa deficient intestinal cells produced 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-IBa in the damaged colonic epithelium and it subsequent accumulation in early CD44 positive regenerating areas. Importantly, IBa deficient animals showed higher resistance to damage, likely due to persistent fetal-like phenotype. These results point out intestinal IBa as chromatin sensor of inflammation in the ISC compartment. SOURCE: Lluis Espinosa (lespinosa@imim.es) - Stem Cell and Cancer Hospital del Mar

Pluto Bioinformatics

GSE131186: IB deficiency imposes a fetal phenotype to intestinal stem cells [RNA-seq]