The Polycomb-Group GeneEzh2 Is Required for Early Mouse Development

Abstract

Polycomb-group (Pc-G) genes are required for the stable repression of the homeotic selector genes and other developmentally regulated genes, presumably through the modulation of chromatin domains. Among the Drosophila Pc-G genes, Enhancer of zeste [E(z)] merits special consideration since it represents one of the Pc-G genes most conserved through evolution. In addition, the E(Z) protein family contains the SET domain, which has recently been linked with histone methyltransferase (HMTase) activity. Although E(Z)-related proteins have not (yet) been directly associated with HMTase activity, mammalian Ezh2 is a member of a histone deacetylase complex. To investigate its in vivo function, we generated mice deficient for Ezh2. The Ezh2 null mutation results in lethality at early stages of mouse development. Ezh2 mutant mice either cease developing after implantation or initiate but fail to complete gastrulation. Moreover, Ezh2-deficient blastocysts display an impaired potential for outgrowth, preventing the establishment of Ezh2-null embryonic stem cells. Interestingly, Ezh2 is up-regulated upon fertilization and remains highly expressed at the preimplantation stages of mouse development. Together, these data suggest an essential role forEzh2 during early mouse development and genetically linkEzh2 with eed and YY1, the only other early-acting Pc-G genes.

ACKNOWLEDGMENTS

We thank Gotthold Schaffner for sequence analysis and oligonucleotide synthesis, Hans-Christian Theussl for blastocyst injection of ES cell clones, Terry Magnuson and Elizabeth M. Morin-Kensicki (Case Western Reserve University, Cleveland, Ohio) for kind teaching of early embryological techniques, Annette Neubüser for advice on Ezh2 mutant morphology, and Stephen Rea for critical reading of the manuscript.

Research in T.J.'s laboratory is supported by the IMP through Boehringer Ingelheim, the Austrian Research Promotion Fund, and the Vienna Economy Promotion Fund. Research in M.A.S.'s laboratory is supported by a Wellcome Trust Grant (036481), and S.E. holds a Ph.D. scholarship from Boehringer Ingelheim.