Epigenetic modifications driving ground state pluripotency exit require an NF-κB-independent chromatin IκBα function

Summary 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-κB but requires the chromatin-related IκBα function.