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Abstract
Somatic cell nuclear cloning has repeatedly demonstrated striking reversibility of epigenetic regulation of cell differentiation. Upon injection into eggs, the donor nuclei exhibit global chromatin decondensation, which might contribute to reprogramming the nuclei by derepressing dormant genes. Decondensation of sperm chromatin in eggs is explained by the replacement of sperm-specific histone variants with egg-type histones by the egg protein nucleoplasmin (Npm). However, little is known about the mechanisms of chromatin decondensation in somatic nuclei that do not contain condensation-specific histone variants. Here we found that Npm could widely decondense chromatin in undifferentiated mouse cells without overt histone exchanges but with specific epigenetic modifications that are relevant to open chromatin structure. These modifications included nucleus-wide multiple histone H3 phosphorylation, acetylation of Lys 14 in histone H3, and release of heterochromatin proteins HP1β and TIF1β from the nuclei. The protein kinase inhibitor staurosporine inhibited chromatin decondensation and these epigenetic modifications with the exception of H3 acetylation, potentially linking these chromatin events. At the functional level, Npm pretreatment of mouse nuclei facilitated activation of four oocyte-specific genes from the nuclei injected into Xenopus laevis oocytes. Future molecular elucidation of chromatin decondensation by Npm will significantly contribute to our understanding of the plasticity of cell differentiation.
We thank K. Gonda for the preliminary work of this project, G. Ahlstrand for the electron microscopy, L. Higgins and T. Krick for the mass spectrometry, E. Coucouvanis for S2 cells, and M. Tatsuka for the histone H3 plasmid. We also thank J. B. Gurdon for teaching us the oocyte injection technique and M. A. Surani for comments on the work.
This work was supported by the Undergraduate Research Opportunity Program to D.N., a Grant-in-Aid for Scientific Research in Priority Areas (15080211) and Project for the Realization of Regenerative Medicine (the research field for the technical development of stem cell manipulation) to T.W., and the Minnesota Medical Foundation (J.W. and N.K.).