Chromatin activity of IκBα mediates the exit from naïve pluripotency

Abstract

Maintenance of pluripotency is a multifactorial process in which NF-{kappa}B is a negative regulator. Our previous work identified a chromatin role for I{kappa}B, the master regulator of NF-{kappa}B signaling, that is critical for the proper regulation of various tissue stem cells. Here, we found that I{kappa}B accumulates specifically in the chromatin fraction of pluripotent embryonic stem cells. I{kappa}B 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 I{kappa}B depletion affect a subset of pluripotency genes and are associated with altered gene transcription. At the cellular level, I{kappa}B-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 I{kappa}B in regulating stem cell pluripotency are NF-{kappa}B-independent, but mainly rely on its chromatin-related function. Taken together, our results reveal a novel mechanism by which I{kappa}B 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.