title: A role for E2F6 in the restriction of male-germ-cell-specific gene expression.
abstract: E2F transcription factors play a pivotal role in the regulation of cellular proliferation and can be subdivided into activating and repressing family members [1]. Like other E2Fs, E2F6 binds to E2F consensus sites, but in contrast to E2F1-5, it lacks an Rb binding domain and functions as an Rb-independent transcriptional repressor [2, 3, 4 and 5]. Instead, E2F6 has been shown to complex with Polycomb (PcG) group proteins [6 and 7], which have a well-established role in gene silencing. Here, we show that E2F6 plays an unexpected and essential role in the tissue specificity of gene expression. E2F6-deficient mice ubiquitously express the alpha-tubulin 3 and 7 genes, which are expressed strictly testis-specifically in control mice. Like an additional E2F6 target gene, Tex12, that we identified, tubulin 3 and 7 are normally expressed in male germ cells only. The promoters of the alpha-tubulin and Tex12 genes share a perfectly conserved E2F site, which E2F6 binds to. Mechanistically, E2F6-mediated repression involves CpG hypermethylation locking target promoters in an inactive state. Thus, E2F6 is essential for the long-term somatic silencing of certain male-germ-cell-specific genes, but it is dispensable for cell-cycle regulation.
authors.affiliation: Children's Hospital, Laboratory for Molecular Biology, Charité-CCM, Humboldt University, Ziegelstrasse 5-9, D-10098 Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Pohlers
authors.forename: Matthias
authors.initials: M
authors.lastname: Truss
authors.forename: Ute
authors.initials: U
authors.lastname: Frede
authors.forename: Axel
authors.initials: A
authors.lastname: Scholz
authors.forename: Michael
authors.initials: M
authors.lastname: Strehle
authors.forename: Ralf-Jürgen
authors.initials: RJ
authors.lastname: Kuban
authors.forename: Bettina
authors.initials: B
authors.lastname: Hoffmann
authors.forename: Markus
authors.initials: M
authors.lastname: Morkel
authors.forename: Carmen
authors.initials: C
authors.lastname: Birchmeier
authors.forename: Christian
authors.initials: C
authors.lastname: Hagemeier
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D047369:Chromatin Immunoprecipitation; D002846:Chromatography, Affinity; D018983:DNA Footprinting; D019175:DNA Methylation; D017931:DNA Primers; D050701:E2F6 Transcription Factor; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D013737:Testis / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D050701:E2F6 Transcription Factor; C111236:E2f6 protein, mouse; D014157:Transcription Factors; D014404:Tubulin