The murine polycomb-group genes Ezh1 and Ezh2 map close to Hox gene clusters on mouse chromosomes 11 and 6

Polycomb-group (Pc-G) genes encode chromosomal proteins that restrict expression patterns of the homeotic selector genes (HOMC cluster) and presumably many other developmentally important loci (reviewed by Paro and Harte 1996). Of the similar to 40 Pc-G loci that have been predicted from genetic analyses in Drosophila (Juergens 1985), currently 11 Pc-G genes have been isolated (reviewed by Pirrotta 1997). Among these, Enhancer of zeste [E(z)] (Jones and Gelbart 1993) seems to provide a central role(s), because it is one of only two Pc-G genes that appear to be conserved in lower eukaryotes (Korf et al. 1998). In addition to homeotic transformations, loss-of-function mutations of Drosophila E(z) also result in maternal sterility and reduced mitotic indices during early embryogenesis (Phillips and Shearn 1990). E(z) mutants can induce partial decondensation of polytene chromosomes (Rastelli et al. 1993), a phenotype that is further reflected by increased chromosome breakage and cell cycle defects (Gatti and Baker 1989). Thus, E(z) appears to be a pleiotropic Pc-G gene with functions in chromatin architecture, gene regulation, and growth control. A crucial role(s) for Pc-G activity during normal and perturbed development has been corroborated by the functional analysis of several mammalian Pc-G homologs, some of which are implicated in the onset of leukemia (reviewed by van Lohuizen 1998). Although loss-of-function mutations of mammalian E(z)-related genes are currently not described, a human E(Z) homolog has been shown to associate with the VAV proto-oncoprotein (Horbert et al. 1996b), an interaction that suggests involvement in signal-dependent T-cell proliferation. In addition, E(z)-related genes share the SET domain (Tschiersch et al. 1994)--which is characteristic for the SET family of chromatin regulators (Jenuwein et al. 1998)--with the human trithorax homolog ALL-1/HRX, another proto-oncogene that is frequently disrupted by 11q23 translocations in acute leukemias (Tkachuk et al. 1992; Djabali et al. 1992). Since the SET domain appears to be a target for phosphorylation-dependent signaling pathways (Cui et al. 1998), mammalian E(z)-related genes are likely to participate in developmental switches that may trigger differentiation or proliferation. We have recently isolated murine (Ezh1) and human (EZH2) cDNAs of mammalian E(z) homologs (Laible et al. 1997). To characterize the genomic organization and chromosomal assignment of the two murine Ezh loci, w