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