The Development and Application of a Systems Biology Approach to Mapping Monocyte

approved: ______________________________________________________ Stephen A. Ramsey While monocytes are vital for host defense against pathogens, in cases of non-resolving inflammation, monocytes and their differentiated progeny can secrete tissue-damaging factors, present auto-antigens, and promote the inflammatory response. In this study, a systems biology approach was used to map human monocyte gene regulatory regions by integrating expression quantitative trait loci (eQTL) and transcription factor (TF) binding site data from previous studies. We hypothesized that monocyte-specific TFs will have binding sites that are concentrated in the vicinity of the monocyte eQTLs. A block permutation test was used to determine the significance of the overlap between monocyte eQTLs and TF binding sites. P values were obtained for each TF experiment, and TFs were ranked according to monocyte specificity. This approach offers an efficient method to identify monocyte-specific TFs and gain insight into the TF regulatory network controlling population variation in human monocyte gene expression. We have developed a putative network of interactions among top-ranked TFs identified in this study. Additionally, candidate monocyte TFs that were uncovered in this analysis include BCLAF1, SIN3A, TAF1, and TBP. This integrative approach could potentially yield novel targets for therapies for chronic inflammatory disorders. Moreover, it can be utilized to predict mammalian gene regulatory networks for various cell types.