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J Exp Med. 2019 Jan 7;216(1):152-175. doi: 10.1084/jem.20181505. Epub 2018 Dec 7.

Cohesin-mediated NF-κB signaling limits hematopoietic stem cell self-renewal in aging and inflammation.

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Leibniz Institute on Aging, Fritz Lipmann Institute (FLI), Jena, Germany.
RNA Bioinformatics and High-Throughput Analysis, Friedrich Schiller University Jena, Jena, Germany.
European Virus Bioinformatics Center (EVBC), Jena, Germany.
Matthias Schleiden Institute for Genetics, Bioinformatics and Molecular Botany, Faculty of Biological Sciences, Friedrich Schiller University Jena, Jena, Germany.
Institute of Medical Systems Biology, Ulm University, Ulm, Germany.
Leibniz Institute on Aging, Fritz Lipmann Institute (FLI), Jena, Germany
Leibniz Institute on Aging, Fritz Lipmann Institute (FLI), Jena, Germany
Faculty of Medicine, Friedrich-Schiller-University, Jena, Germany.


Organism aging is characterized by increased inflammation and decreased stem cell function, yet the relationship between these factors remains incompletely understood. This study shows that aged hematopoietic stem and progenitor cells (HSPCs) exhibit increased ground-stage NF-κB activity, which enhances their responsiveness to undergo differentiation and loss of self-renewal in response to inflammation. The study identifies Rad21/cohesin as a critical mediator of NF-κB signaling, which increases chromatin accessibility in the vicinity of NF-κB target genes in response to inflammation. Rad21 is required for normal differentiation, but limits self-renewal of hematopoietic stem cells (HSCs) during aging and inflammation in an NF-κB-dependent manner. HSCs from aged mice fail to down-regulate Rad21/cohesin and inflammation/differentiation signals in the resolution phase of inflammation. Inhibition of cohesin/NF-κB reverts hypersensitivity of aged HSPCs to inflammation-induced differentiation and myeloid-biased HSCs with disrupted/reduced expression of Rad21/cohesin are increasingly selected during aging. Together, Rad21/cohesin-mediated NF-κB signaling limits HSPC function during aging and selects for cohesin-deficient HSCs with myeloid-skewed differentiation.

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