Chromatin-linked and NF-kB independent ikBa function in embryonic stem cell pluripotency exit and differentiation

Abstract

Pluripotent stem cells (PSCs) have the ability to self-renew and give rise to almost every somatic cell type. Because of their enormous potential as a tool for regenerative medicine, understanding molecular mechanisms that drive and maintain pluripotency identity is crucial not only to obtain somatic cell products but also to better know how pluripotency dysregulation can lead to diseases such as cancer. In this regard, NF-κB constitutes a key pathway which mediates immune response and inflammation, although its implication in pluripotency has not yet been elucidated. Specifically, the main inhibitor of NF-κB, IκBα, has been reported to have nuclear and alternative functions independent to NF-κB which are linked to developmental gene regulation in adult stem cells. In this doctoral thesis, I study the functional implication of nuclear IκBα in the context of pluripotency, and how it can regulate gene regulation upon differentiation of mouse embryonic stem cells. I demonstrated that IκBα is essential for pluripotency exit after mESCs differentiation in vitro and in vivo. Mechanistically, loss of IκBα in mESCs induces a global loss of DNA methylation which persists upon differentiation. Interestingly, identification of separation-of-function IκBα mutants has allowed to demonstrate for the first time that pluripotency blockade in IκBα-/- mESCs is.