Genome-wide Mapping of RELA(p65) Binding Identifies E2F1 as a Transcriptional Activator Recruited by NF-@kB upon TLR4 Activation

Mol Cell 27(4):14 (2007) PMID 17707233

NF-@kB is a key mediator of inflammation. Here, we mapped the genome-wide loci bound by the RELA subunit of NF-@kB in lipopolysaccharide (LPS)-stimulated human monocytic cells, and together with global gene expression profiling, found an overrepresentation of the E2F1-binding motif among RELA-bound loci associated with NF-@kB target genes. Knockdown of endogenous E2F1 impaired the LPS inducibility of the proinflammatory cytokines CCL3(MIP-1@a), IL23A(p19), TNF-@a, and IL1-@b. Upon LPS stimulation, E2F1 is rapidly recruited to the promoters of these genes along with p50/RELA heterodimer via a mechanism that is dependent on NF-@kB activation. Together with the observation that E2F1 physically interacts with p50/RELA in LPS-stimulated cells, our findings suggest that NF-@kB recruits E2F1 to fully activate the transcription of NF-@kB target genes. Global gene expression profiling subsequently revealed a spectrum of NF-@kB target genes that are positively regulated by E2F1, further demonstrating the critical role of E2F1 in the Toll-like receptor 4 pathway.