Separation-of-function mutants reveal the NF-κB-independent involvement of IκBα in the regulation of intestinal stemness
Summary: We have previously shown that the nuclear factor κB (NF-κB) inhibitor IκBα binds chromatin together with polycomb repressor complex 2 (PRC2) to confer responsiveness to PRC2 targets in the presence of inflammatory cues. This alternative function has been elusive in both physiological and di...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-07-01
|
| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221112472500720X |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Summary: | Summary: We have previously shown that the nuclear factor κB (NF-κB) inhibitor IκBα binds chromatin together with polycomb repressor complex 2 (PRC2) to confer responsiveness to PRC2 targets in the presence of inflammatory cues. This alternative function has been elusive in both physiological and disease conditions because of the predominant role of IκBα as a negative regulator of NF-κB. Here, we uniquely characterize the specific residues of IκBα that allow the generation of separation-of-function (SOF) mutants that are defective for either NF-κB-related (SOFΔNF-κB) or chromatin-related (SOFΔH2A,H4) activities. Expression of IκBα SOFΔNF-κB, but not SOFΔH2A/H4, is sufficient to negatively regulate a specific stemness program in intestinal cells, thereby rescuing the differentiation block imposed by IκBα deficiency. Using a chromatin immunoprecipitation (ChIP) assay, we demonstrate that IκBα binds to several stemness genes that are transcriptionally repressed upon IκBα SOFΔNF-κB induction. Our data suggest that SOF mutants provide an exclusive tool for studying IκBα functions in physiology and disease. |
|---|---|
| ISSN: | 2211-1247 |