Program
| MSD6a | |
|---|---|
| Steven Kleinstein | |
| Yale University, USA | |
| Title | Transcriptional cascades during anti-viral responses in human dendritic cells |
| Abstract | Dendritic cells (DCs) play a key role in the early immune response to viral infections, especially in the production of Type I interferons. These molecules signal through the Jak-Stat pathway and activate genes containing ISRE elements in their promoters, ultimately leading to the up-regulation of many potent anti-viral factors. Pathogenic viruses express interferon antagonists (e.g., the NS1 protein of influenza) that subvert the normal interferon response. To better understand uninhibited human DC function we are studying the human DC response to infection by an avian Newcastle Disease Virus (NDV), which lacks the ability to evade the human interferon response. We have attempted to systematically define the genome-wide gene expression changes that occur in human DCs during the first 18 hours post-infection. Using a model-based analysis method, we estimated the up-regulation time of critical genes from time-series microarray experiments in different human donors. We found that this timing was highly correlated across donors. The high level of conservation we observed over so many hours was unexpected, and we thus sought to determine the mechanisms underlying this temporally-ordered cascade. Through a computational promoter analysis, we found that the specific base-composition and location of ISRE elements in the promoter region of each gene was one driving force that was especially important during the first ~12 hours of the response. However, this mechanism provided a reasonable explanation for only a subset of up-regulated genes. To investigate the extent to which the timing of gene expression could be driven by a transcriptional cascade, we performed a statistically rigorous enrichment analysis that examined combined patterns of gene expression and cis-regulatory element detection. This approach identified a single transcriptional cascade that spanned the experimental time-series and could account for observed expression changes in ~60% of all up-regulated genes. The predicted cascade includes many transcription factors that are already known to be involved in anti-viral responses including NFkB along with various IRFs and STATs. Several novel transcription factors were also identified as having important roles. |
| Location | Woodward 6 |