The <i>Polycomb</i>-Group Gene<i>Ezh2</i> Is Required for Early Mouse Development

TLDR

Polycomb‑group genes repress developmental genes through chromatin modulation, and the highly conserved E(z) protein, containing a SET domain linked to histone methyltransferase activity, is part of a histone deacetylase complex in mammals. The study aimed to investigate the in vivo function of Ezh2. The authors generated Ezh2‑deficient mice to study this function. Ezh2 knockout causes early embryonic lethality, with embryos arresting after implantation or failing gastrulation, impaired blastocyst outgrowth preventing embryonic stem cell derivation, and its expression peaks at fertilization and preimplantation, underscoring an essential early developmental role linked to eed and YY1.

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.