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Chromatin activity of IκBα mediates the exit from naïve pluripotency (Methylation array)

ABSTRACT: Inflammatory signals are key in development and cell differentiation but their orchestration with pluripotency and stemness signals is poorly understood. Our previous work identified a chromatin function of IκBα, the NF-κB inhibitor, that is crucial for differentiation in different types of somatic stem cells. Here we demonstrate that deficiency of IκBα imposes a profound chromatin rewiring defect that impacts on DNA methylation, histone post-translational modifications and transcriptional regulation, stabilizing mouse embryonic stem cells (ESCs) in a ground state of pluripotency while preventing them from pluripotency exit and differentiation. By engineering separation-of-function mutants of IκBα with specific binding to either NF-κB or histones, we demonstrate that regulation of pluripotency state by IκBα is independent of NF-kB but requires the chromatin-related IκBα function.

ORGANISM(S): Mus musculus

PROVIDER: GSE239562 | GEO | 2025/03/25

REPOSITORIES: GEO

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Chromatin activity of IκBα mediates the exit from naïve pluripotency (RNA-Seq)

Project description:Inflammatory signals are key in development and cell differentiation but their orchestration with pluripotency and stemness signals is poorly understood. Our previous work identified a chromatin function of IκBα, the NF-κB inhibitor, that is crucial for differentiation in different types of somatic stem cells. Here we demonstrate that deficiency of IκBα imposes a profound chromatin rewiring defect that impacts on DNA methylation, histone post-translational modifications and transcriptional regulation, stabilizing mouse embryonic stem cells (ESCs) in a ground state of pluripotency while preventing them from pluripotency exit and differentiation. By engineering separation-of-function mutants of IκBα with specific binding to either NF-κB or histones, we demonstrate that regulation of pluripotency state by IκBα is independent of NF-kB but requires the chromatin-related IκBα function.

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Chromatin activity of IκBα mediates the exit from naïve pluripotency (ChIP-seq Histone marks)

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Expression data from RH30 vector and RH30 IκBα SR cells

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Rad21-mediated NF-κB signaling limits hematopoietic stem cell self-renewal in aging and inflammation

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Dynamic association of IκBα to chromatin during intestinal differentiation is regulated by Acetylation and N-terminal cleavage of histone H4

Project description:IκBs exert a principal function as cytoplasmic inhibitors of the NF-kB transcription factors. Additional functions for specific IκB homologues have also been described including their association to chromatin to directly regulate gene transcription. Phosphorylated and SUMOylated IκBα (pS-IκBα) specifically binds histones H2A and H4 in the stem and progenitor compartment of skin and intestine, but the mechanisms that control the recruitment of nuclear pS-IκBα to the chromatin are largely unstudied. We here show thatserine 32-36 phosphorylation of IκBα favors its binding with nucleosomes and demonstrated that p-IκBαassociation to H4 is favored by acetylation at specific H4 lysine (K) residues. Acetylated N-terminal tail of H4 is lost during intestinal cell differentiation due to histone cleavage at amino acids 17-19 by the action of trypsin or chymotrypsin, which interferes p-IκBα association to chromatin. Paradoxically, pharmacologic or genetic inhibition of trypsin and chymotrypsin activity in HT29 cells increased p-IκBα chromatin binding, associated to impaired goblet cell differentiation, which was comparable to IκBα deletion. Together our results indicate that dynamic binding of IκBα to chromatin is a requirement for intestinal cell differentiation and provide a molecular base for the restricted nuclear distribution of p-IκBα at specific stem cell compartments.

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A critical requirement for IκBα in controlling dormancy in Hematopoietic stem cells via retinoic acid during embryonic development [RNA-seq]

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Chromatin activity of IκBα mediates the exit from naïve pluripotency

Project description:Chromatin activity of IκBα mediates the exit from naïve pluripotency

| PRJNA999699 | ENA

Tubular epithelial NF-κB activity regulates acute ischemic kideny injury [130402-EV-EmxdN]

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