Chromatin enhancer activity of IκBα mediates the exit from naïve pluripotency

Inflammation is crucial in development and cell differentiation, albeit their involvement in the transition from naïve to primed pluripotency remains elusive. One of the main sensors of inflammation is IκBα, which exerts its function through activation of NF-κB. Our previous work identified a chromatin role of IκBα that is crucial for the proper regulation of adult stem cells. Here, we demonstrate that IκBα depletion causes profound epigenetic rewiring in pluripotent stem cells characterized by altered histone post-translational modifications and DNA methylation, which is associated with changes in transcriptional regulation. These changes led to stabilization of cells in a ground state of naïve pluripotency when cultured in Serum/LIF conditions and differentiation impairment. Mechanistically, IκBα binds to intergenic chromatin regions in the naïve pluripotency state, which result in altered activation status of a subset of enhancers, including several associated to pluripotency-related genes. Through the engineering of separation-of-function mutants, we demonstrate that the effects of IκBα in the regulation of stem cell pluripotency are NF-κB-independent, but mainly relies on its chromatin-related function. Altogether, our results highlight a novel mechanism by which IκBα participates in regulating the pluripotent states of embryonic stem cells, shedding light on the interplay between inflammatory signals and pluripotency regulation. ### Competing Interest Statement patent on IkBa SOF mutants