Chromatin activity of IκBα mediates the exit from naïve pluripotency
Summary Maintenance of pluripotency is a multifactorial process in which NF-κB is a negative regulator. Our previous work identified a chromatin role for IκBα, the master regulator of NF-κB signaling, that is critical for the proper regulation of various tissue stem cells. Here, we found that IκBα accumulates specifically in the chromatin fraction of pluripotent embryonic stem cells. IκBα depletion does not affect NF-kB-dependent transcription, but causes a profound epigenetic rewiring in pluripotent stem cells, including alterations in H3K27me3, a histone mark catalyzed by Polycomb repression complex 2. Chromatin changes induced by IκBα depletion affect a subset of pluripotency genes and are associated with altered gene transcription. At the cellular level, IκBα-deficient embryonic stem cells are arrested in a naive pluripotency state when cultured in serum/LIF conditions and fail to exit pluripotency under differentiation conditions. By constructing separation-of-function mutants, we show that the effects of IκBα in regulating stem cell pluripotency are NF-κB-independent, but mainly rely on its chromatin-related function. Taken together, our results reveal a novel mechanism by which IκBα participates in the regulation of the pluripotent state of embryonic stem cells and shed light on the interplay between inflammatory signals and the regulation of pluripotency.
Authors
- August Vidal (ORCID: https://orcid.org/0000-0001-5727-2099)
- Alberto Villanueva (ORCID: https://orcid.org/0000-0001-5164-0006)
- Pablo Menéndez (ORCID: https://orcid.org/0000-0001-9372-1007)
- Manel Esteller (ORCID: https://orcid.org/0000-0003-4490-6093)
- Arnau Iglesias (ORCID: https://orcid.org/0000-0002-7195-7868)
- Grégoire Stik (ORCID: https://orcid.org/0000-0002-1404-1992)
- Cecilia Ballaré (ORCID: https://orcid.org/0000-0002-9442-807X)
- María Maqueda (ORCID: https://orcid.org/0000-0001-9304-1714)
- Luciano Di Croce (ORCID: https://orcid.org/0000-0003-3488-6228)
- Virginia Rodríguez-Cortez
- Luis G Palma (ORCID: https://orcid.org/0000-0001-5170-0507)
- Clara Bueno (ORCID: https://orcid.org/0000-0003-1442-6216)
- Mercedes Barrero (ORCID: https://orcid.org/0000-0001-7178-1885)
- Anna Bigas (ORCID: https://orcid.org/0000-0003-4801-6899)
- Daniel Álvarez‐Villanueva (ORCID: https://orcid.org/0000-0003-2585-622X)
- Joan Bertran (ORCID: https://orcid.org/0000-0002-4276-336X)
- Bernhard Payer (ORCID: https://orcid.org/0000-0002-4694-2082)
- Carlos A. García‐Prieto (ORCID: https://orcid.org/0000-0001-5021-6916)
- Lluı́s Espinosa (ORCID: https://orcid.org/0000-0002-2897-4099)
- Damiana Álvarez‐Errico
Institutions
- Universitat de Vic - Universitat Central de Catalunya (ES)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Universitat Pompeu Fabra (ES)
- Instituto de Salud Carlos III (ES)
- Institut d'Investigació Biomédica de Bellvitge (ES)
- Josep Carreras Leukaemia Research Institute (ES)
- Institut Català d'Oncologia (ES)
- Centre for Genomic Regulation (ES)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- Universitat de Barcelona (ES)
Publication Details
- Published
- 2025-08-27
- DOI
- https://doi.org/10.7554/elife.102784.2
- Primary Topic
- Genomics and Chromatin Dynamics
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Generalitat de Catalunya
- Ministerio de Ciencia e Innovación