MRG15 Regulates Embryonic Development and Cell Proliferation

Abstract

MRG15 is a highly conserved protein, and orthologs exist in organisms from yeast to humans. MRG15 associates with at least two nucleoprotein complexes that include histone acetyltransferases and/or histone deacetylases, suggesting it is involved in chromatin remodeling. To study the role of MRG15 in vivo, we generated knockout mice and determined that the phenotype is embryonic lethal, with embryos and the few stillborn pups exhibiting developmental delay. Immunohistochemical analysis indicates that apoptosis in Mrg15^−/− embryos is not increased compared with wild-type littermates. However, the number of proliferating cells is significantly reduced in various tissues of the smaller null embryos compared with control littermates. Cell proliferation defects are also observed in Mrg15^−/− mouse embryonic fibroblasts. The hearts of the Mrg15^−/− embryos exhibit some features of hypertrophic cardiomyopathy. The increase in size of the cardiomyocytes is most likely a response to decreased growth of the cells. Mrg15^−/− embryos appeared pale, and microarray analysis revealed that α-globin gene expression was decreased in null versus wild-type embryos. We determined by chromatin immunoprecipitation that MRG15 was recruited to the α-globin promoter during dimethyl sulfoxide-induced mouse erythroleukemia cell differentiation. These findings demonstrate that MRG15 has an essential role in embryonic development via chromatin remodeling and transcriptional regulation.

ACKNOWLEDGMENTS

We acknowledge the assistance of Ryan Robetorye, Peter J. Hornsby, and Qin Huang in photographing the histology figures. We also thank Lei Chen for injection of ES cells into blastocysts, Simona Varani for help with the ES cell strategies, Julio Agno for maintaining mice, Kevin G. Becker and Diane Teichberg for microarray analysis, Johanna Echigo for maintaining mice and microarray analysis, Meihua Song for purification of antibodies and real-time PCR analysis, and Emiko Tominaga for MEF culture.

This work was supported by NIH grants P01AG2752 (J.R.S. and O.M.P.-S.) and CD60651 (to M.M.M.), the Ellison Medical Foundation (O.M.P.-S.), the American Federation for Aging Research (K.T. and J.G.J.), and DOD grant for Breast Cancer Research DAMD 17-03-1-0324 (J.G.J.).