1. Genome-wide Mapping of RELA(p65) Binding Identifies E2F1 as a Transcriptional Activator Recruited by NF-κB upon TLR4 Activation
- Author
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Huck-Hui Ng, Leonard Lipovich, Joyce Jing Yi Wong, Han Xu, Bing Lim, Chia-Lin Wei, Ching Aeng Lim, Martin L. Hibberd, Yijun Ruan, Keh Chuang Chin, Xiao Dong Zhao, Fei Yao, Joanne Chen, Wing-Kin Sung, Atif Shahab, Vinsensius B. Vega, Kuo Ping Chiu, and Joshy George
- Subjects
Lipopolysaccharides ,endocrine system ,Amino Acid Motifs ,Molecular Sequence Data ,Biology ,Retinoblastoma Protein ,Cell Line ,Proinflammatory cytokine ,Consensus Sequence ,Humans ,E2F1 ,Gene ,Molecular Biology ,Cell Nucleus ,Gene knockdown ,Binding Sites ,RELA ,Base Sequence ,Genome, Human ,Transcription Factor RelA ,Promoter ,Cell Biology ,Molecular biology ,Toll-Like Receptor 4 ,Gene expression profiling ,Protein Transport ,Gene Expression Regulation ,Trans-Activators ,TLR4 ,Cytokines ,Inflammation Mediators ,biological phenomena, cell phenomena, and immunity ,E2F1 Transcription Factor ,Protein Binding - Abstract
NF-kappaB is a key mediator of inflammation. Here, we mapped the genome-wide loci bound by the RELA subunit of NF-kappaB 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-kappaB target genes. Knockdown of endogenous E2F1 impaired the LPS inducibility of the proinflammatory cytokines CCL3(MIP-1alpha), IL23A(p19), TNF-alpha, and IL1-beta. 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-kappaB activation. Together with the observation that E2F1 physically interacts with p50/RELA in LPS-stimulated cells, our findings suggest that NF-kappaB recruits E2F1 to fully activate the transcription of NF-kappaB target genes. Global gene expression profiling subsequently revealed a spectrum of NF-kappaB target genes that are positively regulated by E2F1, further demonstrating the critical role of E2F1 in the Toll-like receptor 4 pathway.
- Published
- 2007
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