UC San Diego

The innate immune system elicits a complex pathogen- specific inflammatory gene expression program involving hundreds of genes to provide the first line of host defense against pathogens. Two major transcription factor families, nuclear factor [kappa]B (NF[kappa]B) and the interferon regulatory factors (IRFs) are known to bind the [kappa]B-site and the interferon regulatory element (IRE), respectively. To our surprise, we identified the NF[kappa]B p50 homodimer as a negative regulator of IRF and anti-viral responses by directly binding to the IRE containing promoters via a newly defined subclass of guanine-rich IRE (G-IRE). Furthermore, we found the expression of the antiviral regulator IFN[Beta] to be stimulus-restricted by p50 homodimer binding to the G-IRE- containing enhancer to suppress cytotoxic IFN signaling. The inflammatory expression program is believed to be a complicated gene regulatory network that involves more than 100 transcriptional regulators. Utilizing defined cellular stimuli and mathematical modeling of stereotypical promoter architectures, we categorized the inflammatory gene activation response into three surprisingly simple and separable gene programs that are functional targets of NF[kappa]B, bZIP and IRF/ISGF3. We did not identify a class of genes whose expression depends on synergy between different transcription factors, however, we discovered a new class of pathogen specific gene expression which depends on synergy between regulated mRNA stability and transcription. MicroRNA-mediated gene repression has emerged as a potent mechanism of biological regulation pertaining to cancer and immunity, yet identifying target genes of specific miRNAs has been difficult. We pursued a computational discovery strategy that is inclusive of post-transcriptional modifications to miRNA seed sequences. We identified a specific A-to-I edited miR-155 seed sequence to be enriched in the 3'UTR of gene repression programs in macrophages and inflammatory TH1 cells, but not in anti-inflammatory TH2 cells or non-immune cells. In fact, edited forms of many highly expressed miRNAs emerge as candidate gene repression factors, in correlation with the strength of IFN signaling and the expression of an interferon inducible adenosine deaminase, ADAR1