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E2F transcription factors play an important role in regulating mammalian cell proliferation. E2F6, the most recently identified E2F family member, is a transcriptional repressor. In an effort to ascertain the in vivo biological function of E2F6, we have generated an E2f6 mutant mouse strain. Mice lacking E2F6 are viable and healthy. Surprisingly, E2f6-/- embryonic fibroblasts proliferate normally. However, E2f6-/- animals display overt homeotic transformations of the axial skeleton that are strikingly similar to the skeletal transformations observed in polycomb mutant mice. This observation is compatible with the recent finding that endogenous E2F6 and one or more mammalian polycomb proteins are components of the same multiprotein complex. The accumulated evidence suggests that, during development, E2F6 participates in the recruitment of polycomb proteins to specific target promoters. Epigenetic gene repression is essential mechanism for the establishment and maintenance of tissue identity. Over the past years it has become clear that E2F6 represses genes by either preventing binding of activator E2Fs to promoters of target genes or actively by recruiting a Polycomb multiprotein complex that contains histone methyltransferases. Using cDNA microarray experiments comparing wild-type and E2f6-/- MEFs, we found the first E2F6 target genes that are actively repressed. Interestingly, these E2F6 target genes are a subset of meiotic genes that require the presence of E2F6 to be silenced in somatic cells. E2F6 binds to and represses the promoters of these genes through a conserved binding site. Repression by E2F6 involves the methylation of histone H3 on lysine 9 and 27. These findings suggest a molecular mechanism for the stable transcriptional silencing of meiotic genes in somatic cells by E2F6.