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Iκbα Deficiency Imposes a Fetal Phenotype to Intestinal Stem Cells

50 Pages Posted: 18 May 2019 Sneak Peek Status: Review Complete

See all articles by Laura Marruecos

Laura Marruecos

Autonomous University of Barcelona, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Cancer Research Program, CIBERONC

Joan Bertran

Autonomous University of Barcelona, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Cancer Research Program, CIBERONC; University of Vic-Central University of Catalonia - Faculty of Science and Technology, Bioinformatics and Medical Statistics Group

Yolanda Guillén

Autonomous University of Barcelona, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Cancer Research Program, CIBERONC

Jéssica González

Autonomous University of Barcelona, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Cancer Research Program, CIBERONC

Raquel Batlle

The Barcelona Institute of Science and Technology (BIST) - Institute for Research in Biomedicine (IRB Barcelona)

Erika López-Arribillaga

Autonomous University of Barcelona, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Cancer Research Program, CIBERONC

Marta Garrido

Autonomous University of Barcelona, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Cancer Research Program, CIBERONC

Cristina Ruiz-Herguido

Autonomous University of Barcelona, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Cancer Research Program, CIBERONC

Dominique Lisiero

University of Wisconsin - Madison - McArdle Laboratory of Cancer Research; University of Wisconsin - Madison - Department of Oncology

Mónica González-Farré

Autonomous University of Barcelona, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Department of Pathology

Sara Arce

Autonomous University of Barcelona, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Cancer Research Program, CIBERONC

Mar Iglesias

Autonomous University of Barcelona, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Department of Pathology

Angel R. Nebreda

The Barcelona Institute of Science and Technology (BIST) - Institute for Research in Biomedicine (IRB Barcelona); Catalan Institution of Research and Advanced Studies (ICREA)

Shigeki Miyamoto

University of Wisconsin - Madison - McArdle Laboratory of Cancer Research; University of Wisconsin - Madison - Department of Oncology

Anna Bigas

Autonomous University of Barcelona, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Cancer Research Program, CIBERONC

Lluis Espinosa

Autonomous University of Barcelona, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Cancer Research Program, CIBERONC

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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.

Keywords: intestinal stem cells, regeneration, fetal-like conversion, nuclear IkappaB, polycomb

Suggested Citation

Marruecos, Laura and Bertran, Joan and Guillén, Yolanda and González, Jéssica and Batlle, Raquel and López-Arribillaga, Erika and Garrido, Marta and Ruiz-Herguido, Cristina and Lisiero, Dominique and González-Farré, Mónica and Arce, Sara and Iglesias, Mar and Nebreda, Angel R. and Miyamoto, Shigeki and Bigas, Anna and Espinosa, Lluis, Iκbα Deficiency Imposes a Fetal Phenotype to Intestinal Stem Cells (May 16, 2019). CELL-STEM-CELL-D-19-00327. Available at SSRN: https://ssrn.com/abstract=3389376 or http://dx.doi.org/10.2139/ssrn.3389376
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Laura Marruecos

Autonomous University of Barcelona, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Cancer Research Program, CIBERONC ( email )

Barcelona
Spain

Joan Bertran

Autonomous University of Barcelona, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Cancer Research Program, CIBERONC ( email )

Barcelona
Spain

University of Vic-Central University of Catalonia - Faculty of Science and Technology, Bioinformatics and Medical Statistics Group ( email )

Vic
Spain

Yolanda Guillén

Autonomous University of Barcelona, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Cancer Research Program, CIBERONC ( email )

Barcelona
Spain

Jéssica González

Autonomous University of Barcelona, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Cancer Research Program, CIBERONC ( email )

Barcelona
Spain

Raquel Batlle

The Barcelona Institute of Science and Technology (BIST) - Institute for Research in Biomedicine (IRB Barcelona) ( email )

Parc Científic de Barcelona
C/ Baldiri Reixac 10
Barcelona, 08028
Spain

Erika López-Arribillaga

Autonomous University of Barcelona, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Cancer Research Program, CIBERONC ( email )

Barcelona
Spain

Marta Garrido

Autonomous University of Barcelona, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Cancer Research Program, CIBERONC ( email )

Barcelona
Spain

Cristina Ruiz-Herguido

Autonomous University of Barcelona, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Cancer Research Program, CIBERONC ( email )

Barcelona
Spain

Dominique Lisiero

University of Wisconsin - Madison - McArdle Laboratory of Cancer Research ( email )

Madison, WI
United States

University of Wisconsin - Madison - Department of Oncology ( email )

Madison, WI
United States

Mónica González-Farré

Autonomous University of Barcelona, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Department of Pathology ( email )

Barcelona
Spain

Sara Arce

Autonomous University of Barcelona, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Cancer Research Program, CIBERONC ( email )

Barcelona
Spain

Mar Iglesias

Autonomous University of Barcelona, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Department of Pathology

Barcelona
Spain

Angel R. Nebreda

The Barcelona Institute of Science and Technology (BIST) - Institute for Research in Biomedicine (IRB Barcelona) ( email )

Parc Científic de Barcelona
C/ Baldiri Reixac 10
Barcelona, 08028
Spain

Catalan Institution of Research and Advanced Studies (ICREA) ( email )

Barcelona, 08010
Spain

Shigeki Miyamoto

University of Wisconsin - Madison - McArdle Laboratory of Cancer Research ( email )

Madison, WI
United States

University of Wisconsin - Madison - Department of Oncology ( email )

Madison, WI
United States

Anna Bigas (Contact Author)

Autonomous University of Barcelona, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Cancer Research Program, CIBERONC ( email )

Barcelona
Spain

Lluis Espinosa

Autonomous University of Barcelona, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Cancer Research Program, CIBERONC ( email )

Barcelona
Spain

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