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.

ORF45-Mediated Prolonged c-Fos Accumulation Accelerates Viral Transcription during the Late Stage of Lytic Replication of Kaposi's Sarcoma-Associated Herpesvirus

“…A recent study has shown that ORF45-RSK2 increases the recruitment of RNA polymerase II to the HIV-1 LTR and activates transcription, whereas active RSK2 does not (40), suggesting that sustained RSK activation by ORF45 preferentially targets c-Fos or another nuclear substrate(s) to distinct viral promoters. Second, a type of methylated AP-1 site is preferentially bound by the c-Jun/c-Fos heterodimer (56), and GpC methylation is altered during KSHV reactivation (57); thus, methylation of the AP-1 sites in the KSHV promoter may alter the affinity with c-Fos. Third, prolonged c-Fos accumulation presents at the late stage of lytic replication without any change in the c-Jun level (Fig.…”

The Epigenetic Life Cycle of Epstein–Barr Virus

“…It could be that BZLF1 has adopted its genuine binding properties to methylated DNA from its cellular counterpart c-FOS or other members of the AP-1 family. In fact, the prototypical c-JUN/c-FOS heterodimer is able to bind to methylated DNA sequence motifs in cellular chromatin and activate gene transcription from methylated templates as BZLF1 does (Gustems et al 2014). DNA binding to methylated AP-1 sequence motifs is infrequent in cellular chromatin as compared to the consensus normal AP-1 target sites that lack CpG dinucleotide pairs, but it appears that EBV has optimized an existing cellular principle of gene regulation, which it can use to establish latent infections in all cells it infects.…”

Motif clustering with implications for transcription factor interactions

“…For instance, RAD21 and SMC3 are known to interact with CTCF as part of the cohesin complex (Wendt et al, 2008); IRF3 is known to bind NFY motifs and SP1 is known to co-bind with NFY (Wang et al, 2012;Kheradpour and Kellis, 2014); and CHD2 and BRCA1 are known to indirectly bind to DNA via ZBTB33 (Wang et al, 2012). We also find connections between JUN, JUND, FOS, FOSL2, and ATF2 as part of a larger cluster, which are known to interact (Gustems et al, 2014). Another large connected component contains several TFs binding to E-boxes, namely MYC, MAX, MXI1, USF1, USF2, and BHLHE40 (Mordelet et al, 2013;Foley and Sidow, 2013).…”

“…PeerJ Engel, 1993), and the known AP1 motif, which is bound by JUN/FOS hetero-dimers (Gustems et al, 2014).…”