Histones to the cytosol: Exportin 7 is essential for normal terminal erythroid nuclear maturation

Abstract

Global nuclear condensation, culminating in enucleation during terminal erythropoiesis, is poorly understood. Proteomic examination of extruded erythroid nuclei from fetal liver revealed a striking depletion of most nuclear proteins, suggesting that nuclear protein exporthadoccurred. Expression of the nuclear exportprotein, Exportin 7(Xpo7), ishighly erythroid-specific, induced during erythropoiesis, and abundant in very late erythro-blasts. Knockdown of Xpo7 in primary mouse fetal liver erythroblasts resulted in severe inhibition of chromatin condensation and enucleation but otherwise had little effect on erythroid differentiation, including hemoglobin accumulation. Nuclei in Xpo7-knockdown cells were larger and less dense than normal and accumulated most nuclear proteins as measuredby mass spectrometry. Strikingly, many DNA binding proteins such as histones H2A and H3 were found to have migrated into the cytoplasm of normal late erythroblasts prior to and during enucleation, but not in Xpo7-knockdown cells. Thus, terminal erythroid maturation involves migration ofhistones into the cytoplasm via a process likely facilitated by Xpo7.