Journal
NUCLEIC ACIDS RESEARCH
Volume 42, Issue 5, Pages 3059-3072Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkt1323
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Funding
- Alexander von Humboldt Foundation [Humboldt-Forschungsstipendium fur Postdoktoranden]
- Deutsche Forschungsgemeinschaft [SPP1230, SFB 1054, SFB 1064, SFB-TR36]
- National Institutes of Health [CA70723]
- Helmholtz Zentrum Munchen
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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.
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