MAMMALIAN HOMOLOGS OF THE POLYCOMB-GROUP GENE ENHANCER OF ZESTE MEDIATE GENE SILENCING IN DROSOPHILA HETEROCHROMATIN AND AT SACCHAROMYCES-CEREVISIAE TELOMERES

Gene silencing is required to stably maintain distinct patterns of gen e expression during eukaryotic development and has been correlated wit h the induction of chromatin domains that restrict gene activity, We d escribe the isolation of human (EZH2) and mouse (Ezh1) homologues of t he Drosophila Polycomb-group (Pc-G) gene Enhancer of zeste [E(z)], a c rucial regulator of homeotic gene expression implicated in the assembl y of repressive protein complexes in chromatin, Mammalian homologues o f E(z) are encoded by two distinct loci in mouse and man, and the two murine Ezh genes display complementary expression profiles during mous e development, The E(z) gene family reveals a striking functional cons ervation in mediating gene repression in eukaryotic chromatin: extra g ene copies of human EZH2 or Drosophila E(z) in transgenic flies enhanc e position effect variegation of the heterochromatin-associated white gene, and expression of either human EZH2 or murine Ezh1 restores gene repression in Saccharomyces cerevisiae mutants that are impaired in t elomeric silencing, Together, these data provide a functional link bet ween Pc-G-dependent gene repression and inactive chromatin domains, an d indicate that silencing mechanism(s) may be broadly conserved in euk aryotes.