Neural differentiation is a complex process regulated by multiple signaling at different regulatory levels. Though great progresses have been made in understanding the mechanisms of neural differentiation, post-translational regulation of neural differentiation remains largely unknown. In this study, we found Prmt4, one of the methyltransferases catalyzing protein arginine methylation, is highly expressed in neural stem cells (NSCs) and associated with neural differentiation. Knockout of Prmt4 in mESCs blocked neural differentiation by inhibiting NF-kappa B activation. Mechanistically, Prmt4 interacts with NF-kappa B component p65 to promote its methylation, resulting in increased activation of NF-kappa B signaling during neural differentiation. Our study not only identified Prmt4 as novel regulator of neural differentiation, but also highlighted the importance of protein arginine methylation in cell fate transition. (C) 2020 Elsevier Inc. All rights reserved.