The Cytosine Deaminase AICDA Regulates FGF/ERK Signaling to Achieve the Naïve Pluripotent State During Reprogramming.

Induced pluripotent stem cells (iPSCs) derived by in vitro reprogramming of somatic cells retain the capacity to self-renew and to differentiate into many cell types. Pluripotency encompasses multiple states, with naïve iPSCs considered as ground state, possessing high levels of self-renewal capacity and maximum potential without lineage restriction. We showed previously that activation-induced cytidine deaminase (AICDA), facilitates stabilization of pluripotency during reprogramming. Here we report that Acida-/- iPSCs, even when successfully reprogrammed, fail to achieve the naïve pluripotent state, and remain primed for differentiation, because of a failure to suppress FGF/ERK signaling. While the mutant cells display marked genomic hypermethylation, suppression of FGF/ERK signaling by AICDA is independent of deaminase activity. Thus, our study identifies AICDA as a novel regulator of naïve pluripotency through its activity on FGF/ERK signaling. SIGNIFICANCE STATEMENT: Growth factor signaling requirements that modulate pluripotent state are well studied. However, the epigenetic basis of how the dynamic state of pluripotent cells is regulated and stabilized is largely a black box. The current study is important because we show that AID is essential for reprogramming to ground state. A better understanding for how to stabilize ground state pluripotent cells is of fundamental importance for the use of pluripotent cell sources in disease modeling and potential cellular therapies. © AlphaMed Press 2019.