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IκBα deficiency imposes a fetal phenotype to intestinal stem cells
Author(s) -
Marruecos Laura,
Bertran Joan,
Guillén Yolanda,
González Jéssica,
Batlle Raquel,
LópezArribillaga Erika,
Garrido Marta,
RuizHerguido Cristina,
Lisiero Dominique,
GonzálezFarré Mónica,
ArceGallego Sara,
Iglesias Mar,
Nebreda Angel R,
Miyamoto Shigeki,
Bigas Anna,
Espinosa Lluís
Publication year - 2020
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201949708
Subject(s) - phenotype , stem cell , biology , fetus , microbiology and biotechnology , genetics , pregnancy , gene
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.