Lim Ching-Aeng, Yao Fei, Wong Joyce Jing-Yi, George Joshy, Xu Han, Chiu Kuo Ping, Sung Wing-Kin, Lipovich Leonard, Vega Vinsensius B, Chen Joanne, Shahab Atif, Zhao Xiao Dong, Hibberd Martin, Wei Chia-Lin, Lim Bing, Ng Huck-Hui, Ruan Yijun, Chin Keh-Chuang
Laboratory of Immunology and Virology, Genome Institute of Singapore, 138672 Singapore.
Mol Cell. 2007 Aug 17;27(4):622-35. doi: 10.1016/j.molcel.2007.06.038.
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.
核因子-κB（NF-κB）是炎症的关键介质。在此，我们绘制了脂多糖（LPS）刺激的人单核细胞中由NF-κB的RELA亚基结合的全基因组位点图谱，并结合全基因组基因表达谱分析，发现与NF-κB靶基因相关的RELA结合位点中E2F1结合基序过度富集。敲低内源性E2F1会损害促炎细胞因子CCL3（MIP-1α）、IL23A（p19）、肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL1-β）的LPS诱导性。在LPS刺激下，E2F1通过一种依赖于NF-κB激活的机制与p50/RELA异二聚体一起迅速被招募到这些基因的启动子处。结合在LPS刺激的细胞中E2F1与p50/RELA发生物理相互作用这一观察结果，我们的研究结果表明NF-κB招募E2F1以完全激活NF-κB靶基因的转录。随后的全基因组基因表达谱分析揭示了一系列受E2F1正向调控的NF-κB靶基因，进一步证明了E2F1在Toll样受体4途径中的关键作用。
