title: c-Jun/c-Fos heterodimers regulate cellular genes via a newly identified class of methylated DNA sequence motifs.
abstract: CpG methylation in mammalian DNA is known to interfere with gene expression by inhibiting the binding of transactivators to their cognate sequence motifs or recruiting proteins involved in gene repression. An Epstein-Barr virus-encoded transcription factor, Zta, was the first example of a sequence-specific transcription factor that preferentially recognizes and selectively binds DNA sequence motifs with methylated CpG residues, reverses epigenetic silencing and activates gene transcription. The DNA binding domain of Zta is homologous to c-Fos, a member of the cellular AP-1 (activator protein 1) transcription factor family, which regulates cell proliferation and survival, apoptosis, transformation and oncogenesis. We have identified a novel AP-1 binding site termed meAP-1, which contains a CpG dinucleotide. If methylated, meAP-1 sites are preferentially bound by the AP-1 heterodimer c-Jun/c-Fos in vitro and in cellular chromatin in vivo. In activated human primary B cells, c-Jun/c-Fos locates to these methylated elements in promoter regions of transcriptionally activated genes. Reminiscent of the viral Zta protein, c-Jun/c-Fos is the first identified cellular member of the AP-1 family of transactivators that can induce expression of genes with methylated, hence repressed promoters, reversing epigenetic silencing.
authors.affiliation: Research Unit Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health and German Centre for Infection Research (DZIF), Munich, D-81377, Germany, Biocenter at the Department of Biology II, Ludwig-Maximilians University Munich, Martinsried D-82152, Germany, Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg D-85764, Germany and Institute of Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health, Garching D-85748, Germany.
authors.forename: Montse
authors.initials: M
authors.lastname: Gustems
authors.forename: Anne
authors.initials: A
authors.lastname: Woellmer
authors.forename: Ulrich
authors.initials: U
authors.lastname: Rothbauer
authors.forename: Sebastian H
authors.initials: SH
authors.lastname: Eck
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
authors.forename: Dominik
authors.initials: D
authors.lastname: Lutter
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hammerschmidt
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism; D001665:Binding Sites; D002460:Cell Line; D018899:CpG Islands; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D019175:DNA Methylation; D004279:DNA, Viral / Q000737:chemistry / Q000378:metabolism; D019281:Dimerization; D015894:Genome, Human; D004854:Herpesvirus 4, Human / Q000235:genetics; D006801:Humans; D059372:Nucleotide Motifs; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D050436:Regulatory Elements, Transcriptional; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D004279:DNA, Viral; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D044503:5-Methylcytosine; D004247:DNA