Developmentally Regulated Post-translational Modification of Nucleoplasmin Controls Histone Sequestration and Deposition

Nucleoplasmin (Npm) is an abundant histone chaperone in vertebrate oocytes and embryos. During embryogenesis, regulation of Npm histone binding is critical for its function in storing and releasing maternal histones to establish and maintain the zygotic epigenome. Here, we demonstrate that Xenopus laevis Npm post-translational modifications (PTMs) specific to the oocyte and egg promote either histone deposition or sequestration, respectively. Mass spectrometry and Npm phosphomimetic mutations used in chromatin assembly assays identified hyperphosphorylation on the N-terminal tail as a critical regulator for sequestration. C-terminal tail phosphorylation and PRMT5-catalyzed arginine methylation enhance nucleosome assembly by promoting histone interaction with the second acidic tract of Npm. Electron microscopy reconstructions of Npm and TTLL4 activity toward the C-terminal tail demonstrate that oocyte- and egg-specific PTMs cause Npm conformational changes. Our results reveal that PTMs regulate Npm chaperoning activity by modulating Npm conformation and Npm-histone interaction, leading to histone sequestration in the egg. [Display omitted] •Npm is phosphorylated, glutamylated, and arginine methylated in oocytes and eggs•Npm phosphorylation is essential for histone sequestration•Npm conformation is altered in a PTM-dependent fashion to expose acidic tract•N- and C-terminal modifications distinctly regulate sequestration and deposition Onikubo et al. demonstrate that developmental phosphorylation, glutamylation, and arginine methylation of Xenopus laevis nucleoplasmin alters its conformation, histone binding, and histone deposition activity. Egg nucleoplasmin completely sequesters histones from DNA and from other histone chaperones, consistent with its primary function of histone storage in the egg and early embryo.